EXCLI Journal

Risks of obesity and diabetes development in the population of the Ivano-Frankivsk region in Ukraine

2023-09-18T07:09:05+02:00

The epidemic of obesity that parallels diabetes mellitus and its complications are diseases of major concern to modern societies. Community-based screening is an effective strategy to identify people at high risk of developing overweight, obesity, prediabetes, diabetes, and related health problems. Here, we present the results of screening the population of four locations in the Ivano-Frankivsk region (Western Ukraine). The study group consisted of 400 adults and 252 children. The measured parameters were: (1) main vital signs – body temperature, resting heart rate, blood pressure; (2) anthropometric indicators – body mass and height, body mass index, waist circumference; and (3) metabolic parameters – fasting capillary blood glucose, total body fat, visceral fat, physical activity level and 10-year risk of developing type 2 diabetes. The study found that 23 % of the adults were overweight and 14.8 % obese. Among children, 9.9 % were overweight and 8.7 % obese. Adult body mass index correlated with visceral fat percentage, systolic/diastolic blood pressure and levels of fasting capillary blood glucose. Adults over 18 years of age had fasting capillary blood glucose ≥5.6 mmol/L (14.3 %), including those with undiagnosed pre-diabetes (13.3 %) and suspected diabetes mellitus (1.0 %). The percentage of visceral body fat in adults was positively associated with the 10-year risk of developing type 2 diabetes.

Acute effects of moderate-intensity continuous physical exercise performed with different amounts of muscle mass on executive function in healthy young adults

2023-09-12T06:53:07+02:00

We examined the effect of amount of muscle mass involved in moderate-intensity continuous physical exercise on executive function. To this end, fifty-five participants completed two acute physical exercise sessions on an airbike ergometer using the upper and lower limbs simultaneously and only the upper limbs, and a resting control session in a randomized order. The physical exercise session lasted 30 min and was performed at moderate intensity (between 64 %–76 % of maximal heart rate evaluated in graded maximal exercise testing). Participants took the Stroop test (congruent and incongruent trials) before and after the sessions to assess executive performance. For the congruent trial, both physical exercise interventions improved executive function performance (pre vs. post, p-value = 0.002 and 0.003 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). Furthermore, executive function performance was higher after the physical exercise interventions than after the control session (p-value = 0.002 and 0.004 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). For the incongruent trial, both physical exercise interventions also improved executive function performance (pre vs. post, p-value < 0.001 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). owever, there were no significant differences after both physical exercise interventions and resting control session (p-value = 0.175). Executive function (congruent trial) was positively impacted by acute aerobic physical exercise regardless of the amount of muscle mass involved (upper limbs or upper plus lower limbs). Therefore, we recommend aerobic physical exercise with less or more muscle mass involved to improve cognitive function.

Machine learning approaches to study the structure-activity relationships of LpxC inhibitors

2023-08-22T08:22:52+02:00

Antimicrobial resistance (AMR) has emerged as one of the global threats to human health in the 21st century. Drug discovery of inhibitors against novel targets rather than conventional bacterial targets has been considered an inevitable strategy for the growing threat of AMR infections. In this study, we applied quantitative structure-activity relationship (QSAR) modeling to the LpxC inhibitors to predict the inhibitory activity. In addition, we performed various cheminformatics analysis consisting of the exploration of the chemical space, identification of chemotypes, performing structure-activity landscape and activity cliffs as well as construction of the Structure-Activity Similarity (SAS) map. We built a total of 24 QSAR classification models using PubChem and MACCS fingerprint with 12 various machine learning algorithms. The best model with PubChem fingerprint is the Extremely Gradient Boost model (accuracy on the training set: 0.937; accuracy on the 10-fold cross-validation set: 0.795; accuracy on the test set: 0.799). Furthermore, it was found that the best model using the MACCS fingerprint was the Random Forest model (accuracy on the training set: 0.955; accuracy on the 10-fold cross-validation set: 0.803; accuracy on the test set: 0.785). In addition, we have identified eight consensus activity cliff generators that are highly informative for further SAR investigations. It is hoped that findings presented herein can provide guidance for further lead optimization of LpxC inhibitors.

Bladder cancer course, four genetic high-risk variants, and histopathological findings

2023-08-04T09:27:21+02:00

Urinary bladder cancer, a smoking and occupation related disease, was subject of several genome-wide association studies (GWAS). However, studies on the course of the disease based on GWAS findings differentiating between muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) are rare. Thus we investigated 4 single nucleotide polymorphisms (SNPs) detected in GWAS, related to the genes coding for TACC3 (transforming, acidic coiled-coil containing protein 3), for FGFR3 (fibroblast growth factor receptor 3), for PSCA (prostate stem cell antigen) and the genes coding for CBX6 (chromobox homolog 6) and APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A). This study is based on 712 bladder cancer patients and 875 controls from 3 different case control studies in Germany. The 4 SNPs of interest (PSCA rs2294008 and rs2978974, FGFR3-TACC3 rs798766, and CBX6-APOBEC3A rs1014971) were determined by real-time polymerase chain reaction. The distribution of the 4 SNPs does not vary significantly between cases and controls in the entire study group and in the 3 local subgroups, including two former highly industrialized areas and a region without such history. Also, no significant differences in the bladder cancer subgroups of MIBC and NMIBC were observed. The 4 investigated SNPs do not noticeably contribute differently to the bladder cancer risk for the bladder cancer subgroups of MIBC and NMIBC.

GLUL gene knockdown and restricted glucose level show synergistic inhibitory effect on the luminal subtype breast cancer MCF7 cells’ proliferation and metastasis

2023-08-04T08:51:54+02:00

The glutamine synthetase path is one of the most important metabolic pathways in luminal breast cancer cells, which plays a critical role in supplying glutamine as an intermediate in the biosynthesis of amino acids and nucleotides. On the other hand, glycolysis and its dominant substrate, glucose, are the most critical players in cancer metabolism. Accordingly, targeting these two critical paths might be more efficient in luminal-type breast cancer treatment. MCF7 cells were cultivated in media containing 4.5, 2, and 1 g/L glucose to study its effects on GLUL (Glutamate Ammonia Ligase) expression. Followingly, high and low glucose cell cultures were transfected with 220 pM of siGLUL and incubated for 48 h at 37 ºC. The cell cycle progression and apoptosis were monitored and assessed by flow cytometry. Expression of GLUL, known as glutamine synthetase, was evaluated in mRNA and protein levels by qRT-PCR and western blotting, respectively. To examine the migration and invasion capacity of studied cells exploited from wound healing assay and subsequent expression studies of glutathione-S-transferase Mu3 (GSTM3) and alfa-enolase (ENO1). Expression of GLUL significantly decreased in cells cultured at lower glucose levels compared to those at higher glucose levels. siRNA-mediated knockdown of GLUL expression in low glucose cultures significantly reduced growth, proliferation, migration, and invasion of the MCF7 cells and enhanced their apoptosis compared to the controls. Based on the results, GLUL suppression down-regulated GSTM3, a main detoxifying enzyme, and up-regulated Bax. According to the role of glycolysis as a ROS suppressor, decreased amounts of glucose could be associated with increased ROS; it can be considered an efficient involved mechanism in this study. Also, increased expression of Bax could be attributable to mTOR/AKT inhibition following GLUL repression. In conclusion, utilizing GLUL and glycolysis inhibitors might be a more effective strategy in luminal-type breast cancer therapy.

Antiviral activity of myricetin glycosylated compounds isolated from Marcetia taxifolia against chikungunya virus

2023-07-20T08:21:28+02:00

The chikungunya virus (CHIKV) has produced epidemic outbreaks of significant public health impact. The clinical symptoms of this disease are fever, polyarthralgia, and skin rash, generally self-limiting, although patients may develop a chronic disabling condition or suffer lethal complications. Unfortunately, there is no specific treatment or vaccine available. Thus, the search for effective therapies to control CHIKV infection is an urgent need. This study evaluated the antiviral activity of flavonoids isolated from Marcetia taxifolia by in vitro and in silico analysis. Cytotoxicity of compounds was determined by MTT assay and viral load was assessed in cell substrates supernatants by plaque-forming and RT-qPCR assays. Selected molecules were analyzed by molecular docking assays. Myricetin 3-rhamnoside (MR) and myricetin 3-(6-rhamnosylgalactoside) (MRG) were tested for antiviral assays and analyzed by the TCID50 method and RT-qPCR. MR exhibited dose-dependent antiviral activity, reducing viral titer at concentrations of 150-18.8 μg/mL by at least 1-log. Similarly, MRG showed a significant decrease in viral titer at concentrations of 37.5, 9.4, and 2.3 μg/mL. RT-qPCR analysis also displayed a substantial reduction of CHIKV RNA for both flavonoids. Furthermore, molecular docking of the selected flavonoids proposed the nsP3 macrodomain as a possible target of action. Our study reveals that MR and MRG could be considered promising anti-CHIKV therapeutic agents. Molecular modeling studies showed MR and MRG ligands with a high affinity for the N-terminal region of the nsP3 macrodomain, postulating them as a potential target of action for the CHIKV control.

Normative data in resting and maximum heart rates and a prediction equation for young Tunisian soccer players

2023-06-29T07:53:19+02:00

Heart rate (HR) is an important indicator of work intensity during physical activity. Maximum heart rate (MHR) is a physiological measure that is frequently used as a benchmark for maximal exercise intensity. The aim of this study was to establish reference curves for maximum heart rate (MHR) and resting heart rate (RHR) and to develop an estimated equation for Tunisian adolescent footballers. The study involved 801 adolescent players, aged 11 to 18, who belonged to five Tunisian first-division soccer teams. The LMS method was used for smoothing the curves and the multivariate linear regression to develop a prediction equation of MHR. Our results showed that MHR and RHR reference curves decrease with age. The values of the median curves of MHR and RHR ranged from 208.64 bpm (11 years) to 196.93 (18 years) and 73.86 (11 years) to 63.64 (18 years), respectively. The prediction equation obtained from the model was MHR= 225.08 – 1.55 X Age (years) (R²= 0.317; P < 0.001; standard error of the estimate (SEE) = 5.22). The comparisons between the estimated values and the measured values have found that our model (- 0.004 ±5.22 bpm) was to be more accurate than two other widely known models. BOX's equation underestimates the measured MHR values by -3.17 ± 5.37 bpm and TANAKA's equation overestimates by + 4.33 ±5.5 bpm. The reference curves can be used by coaches and physical trainers to classify the resting heart rate (RHR) and maximum heart rate (MHR) of each adolescent player, track their evolution over time, and design tailored training programs with specific intensities for Tunisian soccer players.

Intraperitoneal hepato-renal toxicity of zinc oxide and nickel oxide nanoparticles in male rats

2023-06-29T07:57:42+02:00

In recent years, zinc oxide (ZnO) and nickel oxide (NiO) nanoparticles (NPs) have become more prevalent in commercial and industrial products. However, questions have been raised regarding their potential harm to human health. Limited studies have been conducted on their intraperitoneal toxicity in rats, and their co-exposure effects remain uncertain. Therefore, this study aimed to investigate some biological responses induced by a single intraperitoneal injection of ZnO-NPs (200 mg/kg) and/or NiO-NPs (50 mg/kg) in rats over time intervals. Blood and organ samples were collected from 36 male rats for hematological, biochemical, oxidative stress, and histological analysis. Results showed that the administration of NPs reduced the body and organ weights as well as red blood cell (RBC) indices and altered white blood cell (WBC) and platelet (PLT) counts. The experimental groups exhibited elevated levels of aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine (CREA), urea, lipid profile, glucose (GLU), total protein (TP), albumin (ALB) and malondialdehyde (MDA), and decreased uric acid (UA), superoxide dismutase (SOD), and glutathione (GSH). Histological observations also revealed architectural damages in liver and kidneys. These alterations were time-dependent and varied in their degree of toxicity. Co-exposure of NPs initially lessened the damage but increased it afterwards compared to individual exposure. In conclusion, intraperitoneal injection of ZnO-NPs and/or NiO-NPs alters biological processes and induces oxidative stress in rats’ liver and kidneys in a time-dependent manner, with NiO-NPs being more potent than ZnO-NPs. Furthermore, co-exposed NPs initially appeared to be antagonistic to one another while further aiming toward synergism.

Where are the fastest master butterfly swimmers competing in the FINA World Masters Championships from?

2023-06-29T07:34:21+02:00

While the butterfly stroke has received considerable attention in sports science, the origin of the fastest master butterfly swimmers remains unknown. The present study investigated which geographical locations produce the top-performing master butterfly swimmers within their age groups and gender. A total of 26,512 master butterfly swimmers (11,288 women and 15,224 men) competed in 50 m, 100 m and 200 m races in World Masters Championships held between 1986 and 2019. From each swimmer, the year of competition, first name, last name, age group and distance were recorded. Descriptive data were presented using mean, standard deviation, maximum and minimum values, and/or confidence intervals. The top 10 race times for master butterfly swimming and gender were identified for descriptive purposes. Nationalities were then grouped into six categories: the top five nationalities with the most appearances in the top 10 fastest times in butterfly swimming by distance each year and one group consisting of all other nationalities. In the event of a tie, the nationality with the most participants overall was selected. Generalized linear models (GLMs) with a gamma probability distribution and log link function were used to assess the effect of age groups and gender on swimming time. In summary, Germany had the fastest women butterfly master swimmers across all distances, while the USA had the fastest men butterfly master swimmers for all distances. Men covered all distances faster than women and younger swimmers were quicker than older swimmers. The results of this study can be utilized to determine the countries that produce the most successful master butterfly swimmers, providing a foundation for further research to explore the factors that lead to their success.

Development of a new testing protocol to evaluate cooling systems

2023-05-30T09:28:56+02:00

Thermal comfort is defined as the user's sensation of thermal well-being. This sensation can be modified by extreme environmental conditions changing the body temperature of the user. Different mechanisms, the thermoregulatory system itself or an external textile system, are required to allow the body to return to their state of well-being. A cooling vest is an example of a smart garment that helps to reduce the user’s body temperature in situations of heat stress. There are two different standards to evaluate the performance of this type of clothing: the ASTM F2371-16 standard that uses a thermal manikin and the ASTM F2300-10 standard that uses human subjects for the evaluation. There is a need for simple, objective and affordable tests to evaluate the thermal comfort associated with personal protective equipment use. The aim of this work is to develop a new testing method that combines a thermal manikin with a simulation software and allows to study physiological parameters of a human subject in the body of the thermal manikin.

Predictors of half-marathon performance in male recreational athletes

2023-06-19T09:21:55+02:00

Few research has been conducted on predictors of recreational runners’ performance, especially in half-marathon running. The purpose of our study was (a) to investigate the relationship of half-marathon race time with training, anthropometry and physiological characteristics, and (b) to develop a formula to predict half-marathon race time in male recreational runners. Recreational runners (n=134, age 44.2±8.7 years; half-marathon race time 104.6±16.2 min) underwent a physical fitness battery consisting of anthropometric and physiological tests. The participants were classified into five performance groups (fast, 73-92 min; above average, 93-99 min; average 100-107 min; below average, 108-117 min; slow group, 118-160 min). A prediction equation was developed in an experimental group (EXP, n=67), validated in a control group (CON, n=67) and prediction bias was estimated with 95 % confidence intervals (CI). Performance groups differed in half-marathon race time, training days, training distance, age, weight, (body mass index) BMI, body fat (BF) and maximum oxygen uptake (VO₂max) (p≤0.001, η²≥0.132), where faster groups had better scores than the slower groups. Half-marathon race time correlated with physiological, anthropometric and training characteristics, with the faster the runner, the better the score in these characteristics (e.g., VO₂max, r=0.59; BMI, r=-0.55; weekly running distance, r=-0.53, p<0.001). Race time in EXP might be calculated (R²=0.63, standard error of the estimate=9.9) using the equation ‘Race time (min)=80.056+2.498×BMI-0.594×VO₂max-0.191×weekly training distance in km’. Validating this formula in CON, no bias was shown (difference between observed and predicted value 2.3±12.8 min, 95 % CI -0.9, 5.4, p=0.153). Half-marathon race time was related to and could be predicted by BMI, VO₂max and weekly running distance. Based on these relationships, a prediction formula for race time was developed providing a practical tool for recreational runners and professionals working with them.

Astaxanthin improves fatty acid dysregulation in diabetes by controlling the AMPK-SIRT1 pathway

2023-05-23T12:30:17+02:00

Due to the rising prevalence of metabolic disorders, including type 2 diabetes (T2DM), new prevention and treatment strategies are needed. The aim was to examine the effect of astaxanthin (AST) on the major regulatory metabolism pathway SIRT-MAPK and fatty acid (FA) profile of plasma in patients with T2DM. This clinical trial included 68 T2DM patients randomly assigned to receive 10 mg/day of oral AST (n = 34) or placebo (n = 33) for 12 weeks. The expression level of SIRT1, AMPK activity, and the level of fatty acids in the serum were examined. The results showed that AST could modify the serum levels of saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA), particularly that of Arachidonic acid, from 11.31±0.35 to 8.52±0.72 %. Also, AST increased the expression and activity levels of SIRT1 and AMPK, respectively. Pearson analysis also revealed a significant association between AMPK activity and Linoleic acid serum (LA) levels (~ -0.604, p~0.013). AST can modify the FA profile of plasma by inducing metabolizing cells to uptake them. Also, it can activate the SIRT-AMPK pathway related to metabolism regulation.

Momordicine I suppresses glioma growth by promoting apoptosis and impairing mitochondrial oxidative phosphorylation

2023-05-08T11:18:12+02:00

Glioblastoma (GBM) is the most common type of primary brain tumor. Patients with GBM have poor survival outcomes. Isolated components of Momordica charantia have anticancer effects. However, the bioactivity of M. charantia extracts against GBM remains unknown. We tested four major extracts of M. charantia and found that momordicine I reduced glioma cell viability without serious cytotoxic effects on astrocytes. Momordicine I suppressed glioma cell colony formation, proliferation, migration, and invasion. Momordicine I also induced apoptosis, intracellular reactive oxygen species (ROS) production, and senescence in glioma cells. Moreover, momordicine I decreased the oxidative phosphorylation capacity of glioma cells and inhibited tumor sphere formation in temozolomide (TMZ)-resistant GBM cells. We further explored whether the antiglioma effect of momordicine I may be related to cell cycle modulation and DLGPA5 expression. Our results indicate that the cytotoxic effect of momordicine I on glioma cells suggests its potential therapeutic application to GBM treatment.

Hexahydrocurcumin mitigates angiotensin II-induced proliferation, migration, and inflammation in vascular smooth muscle cells

2023-05-08T08:52:37+02:00

The proliferation and migration of vascular smooth muscle cells (VSMCs) play vital roles in the pathogenesis of atherosclerosis and hypertension. It has been proposed and verified that hexahydrocurcumin (HHC), a metabolite form of curcumin, has cardiovascular protective effects. This study examined the effect of HHC on angiotensin II (Ang II)-induced proliferation, migration, and inflammation in rat aortic VSMCs and explored the molecular mechanisms related to the processes. The results showed that HHC significantly suppressed Ang II-induced proliferation, migration, and inflammation in VSMCs. HHC inhibited Ang II-induction of the increase in cyclin D1 and decrease in p21 expression in VSMCs. Moreover, HHC attenuated the generation of reactive oxygen species (ROS), and the expression of nuclear factor kappa B (NF-kB), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and matrix metalloproteinases-9 (MMP9) in Ang II-induced VSMCs. The proliferation, migration, inflammation, and ROS production were also inhibited by GKT137831 (NADPH oxidase, NOX1/4 inhibitor) and the combination of HHC and GKT137831. In addition, HHC restored the Ang-II inhibited expression of peroxisome proliferator-activated receptor-g (PPAR-g) and peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α). These findings indicate that HHC may play a protective role in Ang II-promoted proliferation, migration, and inflammation by suppressing NADPH oxidase mediated ROS generation and elevating PPAR-γ and PGC-1α expression.

IMMUNEPOTENT CRP increases intracellular calcium through ER-calcium channels, leading to ROS production and cell death in breast cancer and leukemic cell lines

2023-02-02T09:13:01+01:00

IMMUNEPOTENT CRP (ICRP) is an immunotherapy that induces cell death in cancer cell lines. However, the molecular mechanisms of death are not completely elucidated. Here, we evaluated the implication of intracellular Ca²⁺ augmentation in the cell death induced by ICRP on T-ALL and breast cancer cell lines. Cell death induction and the molecular characteristics of cell death were evaluated in T-ALL and breast cancer cell lines by assessing autophagosome formation, ROS production, loss of mitochondrial membrane potential, ER stress and intracellular Ca²⁺levels. We assessed the involvement of extracellular Ca²⁺, and the implication of the ER-receptors, IP₃R and RyR, in the cell death induced by ICRP, by using an extracellular calcium chelator and pharmacological inhibitors. Our results show that ICRP increases intracellular Ca²⁺ levels as the first step of the cell death mechanism that provokes ROS production and loss of mitochondrial membrane potential. In addition, blocking the IP₃ and ryanodine receptors inhibited ER-Ca²⁺release, ROS production and ICRP-induced cell death. Taken together our results demonstrate that ICRP triggers intracellular Ca²⁺-increase leading to different regulated cell death modalities in T-ALL and breast cancer cell lines.

Association between 15 insertion/deletion genetic polymorphisms and risk of schizophrenia using pooled samples

2023-02-20T07:03:26+01:00

Schizophrenia is a psychiatric syndrome that affects approximately 1 % of the world population and is among the top 10 reasons for disability. In this case-control study, we investigated the association between 15 insertion/deletion (Indel) polymorphisms and schizophrenia risk using pooled samples. In the present case-control study, 361 individuals with schizophrenia and 360 healthy individuals were included in the study. We examined the insertion/deletion polymorphisms in APOB, ADRA2B, PDCD6IP, LRPAP1, TLR2, DHFR, VEGF, HLA-G, TPA, DBH, UCP2, FADS2, MDM2, TP53 and SLC6A4 genes. Our results revealed that the Del allele of the HLA-G 14bp Indel polymorphism increased the risk of schizophrenia (OR=1.23, 95 % CI=1.01-1.52, p=0.045) and the Alu^- allele of the TPA Alu⁺/Alu^- polymorphism negatively associated with the schizophrenia risk (OR=0.67, 95 % CI=0.54-0.82, p<0.001).

Remifentanil does not affect human microglial immune activation in response to pro-inflammatory cytokines

2023-02-20T06:33:24+01:00

Remifentanil is a potent ultra-short acting μ-opioid analgesic drug, frequently used in anaesthesia due to its favorable pharmacodynamic and pharmacokinetic profile. It may be associated with the occurrence of hyperalgesia. Preclinical studies suggest a potential role of microglia, although the molecular mechanisms have not been fully elucidated. Considering the role of microglia in brain inflammation and the relevant differences among species, the effects of remifentanil were studied on the human microglial C20 cells. The drug was tested at clinically relevant concentrations under basal and inflammatory conditions. In the C20 cells, the expression and secretion of interleukin 6, interleukin 8 and the monocyte chemotactic protein 1 were rapidly induced by a mixture of pro-inflammatory cytokines. This stimulatory effect was sustained up to 24 h. Remifentanil did not exert any toxic effect nor modify the production of these inflammatory mediators, thus suggesting the lack of direct immune modulatory actions on human microglia.

Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex

2023-02-02T08:55:00+01:00

Agonists of Benzodiazepine (BZD) receptor are exhaustively used in the control of muscle spasms, seizure, anxiety, and insomnia. BZDs have some unwanted effects; therefore, the development of new BZD receptor agonists with better efficacy and fewer unwanted effects is one of the subjects of interest. In this study, based on the pharmacophore/receptor model of the BZD binding site of GABA_A receptors, a series of new 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives (6a-f) were designed. Energy minima conformers of the designed compounds and diazepam were well matched in conformational analysis and showed proper interaction with the BZD-binding site of the GABA_A receptor model (α1β2ϒ2) in docking studies. The designed compounds were synthesized in acceptable yield and evaluated for their in vitro affinity to the benzodiazepine receptor of rat brains by radioligand receptor binding assay. The results demonstrated that the affinities of most of the novel compounds were even higher than diazepam. The novel compound 6a with the best affinity in radioligand receptor binding assay (K_i=0.44 nM and IC₅₀= 0.73±0.17 nM) had considerable hypnotic activity and weak anticonvulsant and anxiolytic effects with no negative effect on memory in animal models. Flumazenil as a selective benzodiazepine receptor antagonist was able to prevent hypnotic and anticonvulsant effects of 6a indicating the role of BZD receptors in these effects.

Mixture effects of co-formulants and two plant protection products in a liver cell line

2023-02-02T08:59:02+01:00

Plant protection products (PPPs) consist of one or more active substances and several co-formulants. Active substances provide the functionality of the PPP and are consequently evaluated according to standard test methods set by legal data requirements before approval, whereas co-formulants’ toxicity is not as comprehensively assessed. However, in some cases mixture effects of active substances and co-formulants might result in increased or different forms of toxicity. In a proof-of-concept study we hence built on previously published results of Zahn et al. (2018) on the mixture toxicity of Priori Xtra^® and Adexar^® to specifically investigate the influence of co-formulants on the toxicity of these commonly used fungicides. Products, their respective active substances in combination as well as some co-formulants were applied to human hepatoma cell line (HepaRG) in several dilutions. Cell viability analysis, mRNA expression, abundance of xenobiotic metabolizing enzymes and intracellular concentrations of active substances determined by LC-MS/MS analyses demonstrated that the toxicity of the PPPs is influenced by the presence of co-formulants in vitro. PPPs were more cytotoxic than the mix of their active substances. Gene expression profiles of cells treated with the PPPs were similar to those treated with their respective mixture combinations with marked differences. Co-formulants can cause gene expression changes on their own. LC-MS/MS analyses revealed higher intracellular concentrations of active substances in cells treated with PPPs compared to those treated with the respective active substances’ mix. Proteomic data showed co-formulants can induce ABC transporters and CYP enzymes. Co-formulants can contribute to the observed increased toxicity of PPPs compared to their active substances in combination due to kinetic interactions, necessitating a more comprehensive evaluation approach.

Amount and composition of total fatty acids in red and yellow bone marrow are altered with changes in bone mineral density

2023-02-06T12:33:45+01:00

There is general consent that with decreasing bone mineral density the amount of marrow adipose tissue increases. While image-based techniques, claim an increase in saturated fatty acids responsible for this effect, this study shows an increase in both saturated and unsaturated fatty acids in the bone marrow. Using fatty acid methyl ester gas chromatography-mass spectrometry, characteristic fatty acid patterns for patients with normal BMD (N = 9), osteopenia (N = 12), and osteoporosis (N = 9) have been identified, which differ between plasma, red bone marrow and yellow bone marrow. Selected fatty acids, e.g. FA10:0, FA14:1, or FA16:1 n-7 in the bone marrow or FA18:0, FA18:1 n-9, FA18:1 n-7, FA20:0, FA20:1 n-9, or FA20:3 n-6 in the plasma, correlated with osteoclast activity, suggesting a possible mechanism how these fatty acids may interfere with BMD. Although several fatty acids correlated well with the osteoclast activity and BMD, there was not a single fatty acid contained in our fatty acid profile that can be claimed for controlling BMD, a fact that may be attributed to the genetic heterogeneity of the patients.

The bovine dialyzable leukocyte extract, immunepotent CRP, synergically enhances cyclophosphamide-induced breast cancer cell death, through a caspase-independent mechanism

2022-12-13T08:56:52+01:00

Breast cancer (BC) is one of the leading causes of cancer death worldwide. Cyclophosphamide (CTX) remains a mainstay in cancer therapy despite harmful adverse effects and cell death-resistances. To face this, combinational therapy of chemotherapies and immunotherapies has been proposed. IMMUNEPOTENT CRP (ICRP) is an immunotherapy that has cytotoxic effects in several cancer cells without affecting peripheral blood mononuclear cells (PBMC) and CD3+ cells. The aim of this study was to evaluate cytotoxicity, the type of cytotoxic effect, and several features involved in cell death induced by the combination of CTX with ICRP (ICRP+CTX) in breast cancer cells as well as their effect on healthy cells. For this purpose, human and murine breast cancer cells, MCF-7, MDA-MB-231 and 4T1, or PBMC were treated for 24 hours with ICRP, CTX or ICRP+CTX in different combination ratios for the assessment of cell death. Flow cytometry and microscopy were used to determine biochemical and morphological characteristics of cell death. Assays showed that ICRP in combination with CTX induce potentiated cell death manifested with morphological changes, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production, and caspase activation. In addition, it was determined that ICRP+CTX-cell death is caspase-independent in all the breast cancer cells assessed. On the other hand, ICRP did not affect CTX-cytotoxicity in PBMC. For all the above, we can propose that the combination of ICRP with CTX an effective combination therapy, promoting their use even in tumoral cells with defects on proteins implicated in the apoptotic pathway.

Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells

2023-01-11T13:13:52+01:00

In metastatic breast cancer (MBC), PIK3CA mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type PIK3CA) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by PIK3CA gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of PIK3CA-mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, PIK3CA wild-type BC cells. The p110α expression was downregulated or not affected in PIK3CA-mutated cell lines, and not significantly upregulated in PIK3CA wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, PIK3CA-mutated BC cells, providing a rationale for further efforts to evaluate this combination in vivo.

PARP1pred: a web server for screening the bioactivity of inhibitors against DNA repair enzyme PARP-1

2022-11-14T10:58:24+01:00

Cancer is the leading cause of death worldwide, resulting in the mortality of more than 10 million people in 2020, according to Global Cancer Statistics 2020. A potential cancer therapy involves targeting the DNA repair process by inhibiting PARP-1. In this study, classification models were constructed using a non-redundant set of 2018 PARP-1 inhibitors. Briefly, compounds were described by 12 fingerprint types and built using the random forest algorithm concomitant with various sampling approaches. Results indicated that PubChem with an oversampling approach yielded the best performance, with a Matthews correlation coefficient > 0.7 while also affording interpretable molecular features. Moreover, feature importance, as determined from the Gini index, revealed that the aromatic/cyclic/heterocyclic moiety, nitrogen-containing fingerprints, and the ether/aldehyde/alcohol moiety were important for PARP-1 inhibition. Finally, our predictive model was deployed as a web application called PARP1pred and is publicly available at https://parp1pred.streamlitapp.com, allowing users to predict the biological activity of query compounds using their SMILES notation as the input. It is anticipated that the model described herein will aid in the discovery of effective PARP-1 inhibitors.

Antineoplastic multi-drug chemotherapy to sensitize tumors triggers multi-drug resistance and inhibits efficiency of maintenance treatment in glioblastoma cells

2022-12-06T11:48:40+01:00

Combinations of the well-known antineoplastic agents 5-fluorouracil (5-Fu), cisplatin, and paclitaxel are employed to increase radiotherapy/immunotherapy efficacy against persistent and resistant tumors. However, data remains needed on the hormetic, chronic, and long-term side effects of these aggressive combination chemotherapies. Here we investigated cellular and molecular responses associated with these combined agents, and their potential to induce multi-drug resistance against the temozolomide (TMZ) and etoposide (EP) used in glioblastoma maintenance treatment. We analyzed resistance and survival signals in U87 MG cells using molecular probes, fluorescent staining, qRT-PCR, and immunoblot. Repeated treatment with combined 5-Fu, cisplatin, and paclitaxel induced cross-resistance against TMZ and EP. Resistant cells exhibited elevated gene/protein expression of MRP1/ABCC1, ABCC2, BRCP/ABCG2, and GST. Moreover, they managed oxidative stress, cell cycle, apoptosis, and autophagy signaling to ensure survival. In these groups TMZ and etoposide efficiency dramatically reduced. Our result suggests that combined high-dose treatments of classical antineoplastic agents to sensitize tumors may trigger multi-drug resistance and inhibit maintenance treatment. When deciding on antineoplastic combination therapy for persistent/resistant glioblastoma, we recommend analyzing the long-term hormetic and chronic effects on cross-resistance and multi-drug resistance in primary cell cultures from patients.

Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices

2022-11-17T12:47:09+01:00

Loss of differentiation of primary human hepatocytes (PHHs) ex vivo is a known problem of in vitro liver models. Culture optimizations using collagen type I and Matrigel reduce the dedifferentiation process but are not able to prevent it. While neither of these extracellular matrices (ECMs) on their own correspond to the authentic hepatic ECM, a combination of them could more closely resemble the in vivo situation. Our study aimed to systematically analyze the influence of mixed matrices composed of collagen type I and Matrigel on the maintenance and reestablishment of hepatic functions. Therefore, PHHs were cultured on mixed collagen-Matrigel matrices in monolayer and sandwich cultures and viability, metabolic capacity, differentiation markers, cellular arrangement and the cells’ ability to repolarize and form functional bile canaliculi were assessed by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), functional assays and immunofluorescence microscopy. Our results show that mixed matrices were superior to pure matrices in maintaining metabolic capacity and hepatic differentiation. In contrast, Matrigel supplementation can impair the development of a proper hepatocytic polarization. Our systematic study helps to compose an optimized ECM to maintain and reestablish hepatic differentiation on cellular and multicellular levels in human liver models.

Effects of acute and chronic disease on cell junctions in mouse liver

2022-11-14T11:40:46+01:00

Cell junctions, including anchoring, occluding and communicating junctions, play an indispensable role in tissue architecture and homeostasis. Consequently, malfunctioning of cell junctions is linked with a wide range of disorders, including in liver. The present study was set up to investigate the effects of acute and chronic disease induced by chemical compounds on hepatic cell junctions in mice. Mice were either overdosed with paracetamol or repeatedly administered carbon tetrachloride followed by sampling at 24 hours or 8 weeks, respectively. mRNA and protein expression levels of adherens, gap and tight junction components were measured in liver using reverse transcription quantitative real-time polymerase chain reaction analysis and immunoblot techniques, respectively. It was found that protein levels of the adherens junction building blocks β-catenin and γ-catenin, the gap junction components Cx26 and Cx32, and the tight junction constituent zonula occludens 2 were decreased, while mRNA levels of the adherens junction building block E-cadherin, and the tight junction constituent zonula occludens 2 and claudin 1 were upregulated following paracetamol overdosing. Repeated administration of carbon tetrachloride increased protein levels of E-cadherin, β-catenin, Cx26, Cx32, Cx43 and claudin 1. The latter was reflected at the mRNA level. In conclusion, acute and chronic liver disease have different effects on cell junctions in liver.

Optimization of enzyme-linked immunosorbent assay kit protocol to detect trimethylamine N-oxide levels in humans

2023-02-14T07:05:21+01:00

The serum level of trimethylamine N-oxide (TMAO), a gut microbiota metabolite associated with diabetes, cancer, inflammatory and neurological diseases, can be determined by the micro-enzyme-linked immunosorbent assay (ELISA) method. However, we had problems obtaining accurate standard curves with the original kit protocol from Bioassay Technology Laboratory. We aimed to acquire proper standard curves by modifying the kit protocol in this study. First, we evaluated the human TMAO ELISA kit protocols and other human ELISA kits. We maintained the incubation times longer and increased the wash cycle. Moreover, we incubated the standards containing biotinylated antibody in the wells alone. Then we washed the wells and added streptavidin-HRP for the second incubation step. The data of original and modified ELISA kit protocol were analyzed with Student's t-test. We measured higher absorbance with lower standard solution concentration in experiments that followed the original kit protocol. After investigating other human TMAO ELISA kits, we noticed that the SunRed Biotechnology Company and MyBioSource companies suggested similar protocols to the Bioassay Technology Laboratory company. The ELK Biotechnology ELISA protocol was different from others. However, since there is no biotinylated antibody in the standard solution in the ELK biotechnology kit, we changed some steps by examining other human ELISA protocols from different companies. After performing the modified protocol, we found that the absorbances of the standard solutions were consistent with their concentrations, and we obtained an accurate standard curve. Higher R²values and lower absolute difference of standard concentrations were found in the modified kit protocol. The human TMAO ELISA protocol, which we modified in this study, will enable researchers to obtain more reliable results and prevent them from failing time and resources.

ChatGPT guidance for reproductive specialists: Dr. Jekyll or Mr. Hyde?

2023-08-14T08:41:21+02:00

The prey’s perspective on the rise of predatory publishing

2023-08-17T11:07:41+02:00

The underappreciated wrong of AIgiarism - bypass plagiarism that risks propagation of erroneous and bias content

2023-08-10T09:39:19+02:00

Can GPT-4 be a viable alternative for discussing complex cases in digital oral radiology?

2023-07-20T10:26:49+02:00

Towards responsible research

2023-07-20T10:22:46+02:00

Agarwood oil nanoemulsion attenuates production of lipopolysaccharide (LPS)-induced proinflammatory cytokines, IL-6 and IL-8 in human bronchial epithelial cells

2023-07-04T06:36:12+02:00

Differences in ballistic findings between autopsy and post-mortem computed tomography in the head and neck region of gunshot victims

2023-06-29T08:08:30+02:00

Recent developments in the role of protocatechuic acid in neurodegenerative disorders

2023-06-29T07:16:10+02:00

Recent insights of fucoidan probiotic and its effect on gut microbiota

2023-06-14T07:33:04+02:00

Cytotoxic mechanisms of berberine-phytantriol liquid crystalline nanoparticles against non-small-cell lung cancer

2023-06-14T11:31:09+02:00

With great power comes great responsibility – deductions of using ChatGPT for medical research

2023-05-17T10:43:52+02:00

The devastating impact of illegal mining on indigenous health

2023-04-05T08:57:11+02:00

Comparison of cycle-threshold-values between two commercial SARS-CoV-2 PCR assays

2023-04-03T06:38:31+02:00

The Pandora's box of predatory journals

2023-03-22T06:44:16+01:00

Genomes of extinct hominins and human reproductive evolution

2023-03-20T08:11:14+01:00

Adenocarcinoma - success so far and the way ahead

2023-02-22T13:17:27+01:00

Recent studies on berberine and its biological and pharmacological activities

2023-02-20T10:40:42+01:00

The versatility of 18β-glycyrrhetinic acid in attenuating pulmonary inflammatory disorders

2023-01-30T08:07:21+01:00

The vaccination status of COVID-19 hospitalized patients during the Omicron BQ.1.1 wave in Northeast Brazil suggests the need for a fifth booster dose in the elderly, with a time since the last dose of more than 6 months

2023-01-31T07:53:27+01:00

Comment on the manuscript entitled "Clinical presentation vs endoscopy for an early diagnosis of eosinophilic esophagitis: a case report" by Di Stefano et al.

2022-12-15T10:04:12+01:00

Elucidating the antiviral potential of polysaccharides

2022-12-08T10:38:09+01:00

A temporal cluster of acute promyelocytic leukemia

2022-12-08T12:41:43+01:00

Bell’s palsy or an aggressive infiltrating basaloid carcinoma post-mRNA vaccination for COVID-19?

2023-09-12T06:10:10+02:00

We report on an aggressive, infiltrating, metastatic, and ultimately lethal basaloid type of carcinoma arising shortly after an mRNA vaccination for COVID-19. The wife of the patient, since deceased, gave the consent for publishing the case. The malignancy was of cutaneous origin and the case showed symptoms consistent with Bell’s palsy and trigeminal neuralgia beginning four days post-vaccination (right side head temporal pain). The temporal pain was suggestive for inflammation and impairment of T cell immune activation. Magnetic Resonance Imaging (MRI) showed a vascular loop on the left lateral aspect of the 5^th cranial root exit of cerebellopontine angle constituting presumably a normal variant and was considered as an unrelated factor to the right-sided palsy and pain symptoms that corresponded to cranial nerves V (trigeminal nerve) and VII (facial nerve). In this study we describe all aspects of this case and discuss possible causal links between the rapid emergence of this metastatic cancer and mRNA vaccination. We place this within the context of multiple immune impairments potentially related to the mRNA injections that would be expected to potentiate more aggressive presentation and progression of cancer. The type of malignancy we describe suggests a population risk for occurrence of a large variety of relatively common basaloid phenotype cancer cells, which may have the potential for metastatic disease. This can be avoidable with early diagnosis and adequate treatment. Since facial paralysis/pain is one of the more common adverse neurological events following mRNA injection, careful inspection of cutaneous/soft tissue should be conducted to rule out malignancy. An extensive literature review is carried out, in order to elucidate the toxicity of mRNA vaccination that may have led to the death of this patient. Preventive and precise routine clinical investigations can potentially avoid future mortalities.

Upper gastrointestinal bleeding due to Dieulafoy’s lesion of the stomach

2023-08-07T09:41:19+02:00

Dieulafoy’s lesion is a life-threatening and rare vascular malformation of the submucosal vessel that protrudes to the mucosa of the gastrointestinal tract. The vessel is abnormally dilated, and if it ruptures, it can cause severe acute gastrointestinal bleeding. We report an upper GI bleeding case due to Dieulafoy’s lesion in the gastric fundus of the stomach in a 76-year-old female. The patient presented with hematemesis and melena associated with anemia. An esophagogastroduodenoscopy (OGD) was performed which showed profuse pulsatile bleeding at the gastric fundus. Following that, gastrotomy confirmed the diagnosis of Dieulafoy’s lesion. Endoscopy is the main diagnostic and therapeutic tool for Dieulafoy’s lesion. Endoscopic treatment includes injective, ablative and mechanical therapies. The majority of cases are treated endoscopically, while in some cases, surgical intervention is deemed to be necessary as it is currently the only definitive treatment of Dieulafoy’s lesion.

A systematic review of risky-choice framing effects

2023-09-11T07:26:35+02:00

Classic decision theory requires that rational agents show description invariance: which description is chosen should not matter for judgments, preferences, or choices given the descriptions are co-extensive. Framing research has amply demonstrated a failure of description invariance by showing that the choice of the description has a systematic effect on judgments, preferences, and choices. Specifically, framing research has shown that linguistically different descriptions of seemingly equivalent options frequently lead to preference reversals. I summarize the research on framing in situations entailing risk. This includes the characterization of different research designs used, the size and robustness of the framing effects reported for those designs, and the theoretical accounts put forward to explain framing effects. The theoretical accounts are evaluated with respect to their merits, empirically and theoretically. I end by providing the implications of framing research. My central point is that the existence of framing effects points to the adaptiveness of the processes underlying human judgment and choice rather than simply showing human irrationality.

Emerging role of nanotechnology in treatment of non-alcoholic fatty liver disease (NAFLD)

2023-08-10T08:51:02+02:00

Non-alcoholic fatty liver disease (NAFLD) is a prevailing health challenge that requires urgent innovative interventions. This review explores the role of nanotechnology as a promising potential in the treatment of NAFLD. It delineates the limitations of the current management strategies for NAFLD and highlights the new nanotechnology-based treatments including nanoemulsions, liposomes, micelles, polymeric nanoparticles, nanogels, inorganic nanoparticles, and zinc oxide nanoparticles. Despite the optimism surrounding the nanotechnological approach, the review underscores the need to address the limitations such as technical challenges, potential toxicity, and ethical considerations that impede the practical application of nanotechnology in NAFLD management. It advocates for collaborative efforts from researchers, clinicians, ethicists, and policymakers to achieve safe, effective, and equitable nanotechnology-based treatments for NAFLD.

Metabolic and immune dysfunctions in post-traumatic stress disorder

2023-08-21T07:56:18+02:00

Highly stressful experiences such as terrorist attacks, domestic and sexual violence may lead to persistent pathological symptoms such as those seen in posttraumatic stress disorder (PTSD). There is growing evidence of multiple metabolic and immune disorders underlying the etiology and maintenance of PTSD. However, changes in the functioning of various systems and organs associated with PTSD are not well understood. Studies of reliable animal models is one of the effective scientific tools that can be used to gain insight into the role of metabolism and immunity in the comorbidity associated with PTSD. Since much progress has been made using animal models to understand mechanisms of PTSD, we summarized metabolic and immune dysfunction in mice and humans to compare certain outcomes associated with PTSD. The systemic effects of PTSD include chronic activation of the sympathetic nervous system (psycho-emotional stress), that leads to impairment of the function of the immune system, increased release of stress hormones, and metabolic changes. We discuss PTSD as a multisystem disease with its neurological, immunological, and metabolic components.

Empirical comparison and analysis of machine learning-based approaches for druggable protein identification

2023-08-14T07:43:27+02:00

Efficiently and precisely identifying drug targets is crucial for developing and discovering potential medications. While conventional experimental approaches can accurately pinpoint these targets, they suffer from time constraints and are not easily adaptable to high-throughput processes. On the other hand, computational approaches, particularly those utilizing machine learning (ML), offer an efficient means to accelerate the prediction of druggable proteins based solely on their primary sequences. Recently, several state-of-the-art computational methods have been developed for predicting and analyzing druggable proteins. These computational methods showed high diversity in terms of benchmark datasets, feature extraction schemes, ML algorithms, evaluation strategies and webserver/software usability. Thus, our objective is to reexamine these computational approaches and conduct a comprehensive assessment of their strengths and weaknesses across multiple aspects. In this study, we deliver the first comprehensive survey regarding the state-of-the-art computational approaches for in silico prediction of druggable proteins. First, we provided information regarding the existing benchmark datasets and the types of ML methods employed. Second, we investigated the effectiveness of these computational methods in druggable protein identification for each benchmark dataset. Third, we summarized the important features used in this field and the existing webserver/software. Finally, we addressed the present constraints of the existing methods and offer valuable guidance to the scientific community in designing and developing novel prediction models. We anticipate that this comprehensive review will provide crucial information for the development of more accurate and efficient druggable protein predictors.

Phosphatidylcholine (PCL) fortified nano-phytopharmaceuticals for improvement of therapeutic efficacy

2023-08-14T11:44:00+02:00

Phytopharmaceuticals, derived from plants, are increasingly recognized for their potential therapeutic benefits. However, their effectiveness is often hindered by challenges such as poor bioavailability, stability, and targeted delivery. In this study, we aimed to address these limitations by developing PCL (phosphatidylcholine) fortified nano-phytopharmaceuticals to enhance therapeutic efficacy. PCL, a biocompatible and biodegradable polymer, was employed to encapsulate the phytopharmaceuticals, thereby improving their stability and bioavailability. The encapsulation process utilized nanoprecipitation, resulting in the formation of nanoparticles with controlled size and morphology. Various analytical techniques were employed to characterize the physicochemical properties of PCL fortified nano-phytopharmaceuticals, including dynamic light scattering, scanning electron microscopy, and Fourier-transform infrared spectroscopy. Furthermore, the release kinetics of encapsulated phytopharmaceuticals from PCL nanoparticles were evaluated, demonstrating sustained and controlled release profiles, essential for prolonged therapeutic effects. Cytotoxicity studies conducted on in vitro cell culture models confirmed the biocompatibility and non-toxic nature of the developed nano-phytopharmaceuticals. Additionally, in vivo studies were conducted to assess the therapeutic efficacy of PCL fortified nano-phytopharmaceuticals in animal models. The results showIased improved bioavailability, targeted tissue distribution, and enhanced therapeutic effects compared to free phytopharmaceuticals. Moreover, the developed nano-phytopharmaceuticals exhibited prolonged circulation time in the bloodstream, enabling improved drug delivery and reduced dosing frequency. This review highlights the promising potential of PCL fortified nano-phytopharmaceuticals as an effective approach for enhancing the therapeutic efficacy of phytopharmaceuticals. The improved stability, bioavailability, sustained release, and targeted delivery achieved through this formulation strategy offer promising opportunities for advancing plant-based therapies.

Exploring cognitive individuality and the underlying creativity in statistical learning and phase entrainment

2023-08-02T07:39:39+02:00

Statistical learning starts at an early age and is intimately linked to brain development and the emergence of individuality. Through such a long period of statistical learning, the brain updates and constructs statistical models, with the model's individuality changing based on the type and degree of stimulation received. However, the detailed mechanisms underlying this process are unknown. This paper argues three main points of statistical learning, including 1) cognitive individuality based on "reliability" of prediction, 2) the construction of information “hierarchy” through chunking, and 3) the acquisition of “1-3Hz rhythm” that is essential for early language and music learning. We developed a Hierarchical Bayesian Statistical Learning (HBSL) model that takes into account both reliability and hierarchy, mimicking the statistical learning processes of the brain. Using this model, we conducted a simulation experiment to visualize the temporal dynamics of perception and production processes through statistical learning. By modulating the sensitivity to sound stimuli, we simulated three cognitive models with different reliability on bottom-up sensory stimuli relative to top-down prior prediction: hypo-sensitive, normal-sensitive, and hyper-sensitive models. We suggested that statistical learning plays a crucial role in the acquisition of 1-3 Hz rhythm. Moreover, a hyper-sensitive model quickly learned the sensory statistics but became fixated on their internal model, making it difficult to generate new information, whereas a hypo-sensitive model has lower learning efficiency but may be more likely to generate new information. Various individual characteristics may not necessarily confer an overall advantage over others, as there may be a trade-off between learning efficiency and the ease of generating new information. This study has the potential to shed light on the heterogeneous nature of statistical learning, as well as the paradoxical phenomenon in which individuals with certain cognitive traits that impede specific types of perceptual abilities exhibit superior performance in creative contexts.

Multifunctional role of zinc in human health

2023-07-25T07:49:26+02:00

Zinc is a multipurpose trace element for the human body, as it plays a crucial part in various physiological processes, such as cell growth and development, metabolism, cognitive, reproductive, and immune system function. Its significance in human health is widely acknowledged, and this has led the scientific community towards more research that aims to uncover all of its beneficial properties, especially when compared to other essential metal ions. One notable area where zinc has shown beneficial effects is in the prevention and treatment of various diseases, including cancer. This review aims to explain the involvement of zinc in specific health conditions such as cancer, coronavirus disease 2019 (COVID-19) and neurological disorders like Alzheimer's disease, as well as its impact on the gut microbiome.

Cardiac amyloidosis

2023-07-24T09:28:39+02:00

Amyloidosis is a protein deposition disorder in which insoluble fibril structures accumulate in the bodily tissues damaging the organ function. Cardiac amyloidosis is a severe but under-reported medical condition characterized by the accumulation of amyloid in the extracellular area of the myocardium, which results in thickening and stiffening of ventricular walls. Cardiac amyloidosis has recently gained much attention with its slowly surging incidence. With this study, we seek to comprehensively compile the pathophysiology and clinical picture of cardiac amyloidosis subtypes, extending a clinically oriented, up-to-date clinical approach to diagnosis and therapy. Cardiac amyloidosis can be caused by rare genetic mutations which may be inherited or acquired. The growing incidence can be attributed to advancements in imaging methods and other diagnostic modalities. Most occurrences of cardiac amyloidosis result from two forms of precursor protein: transthyretin [TTR] amyloid and immunoglobulin-derived light-chain amyloid. Prompt identification of cardiac amyloidosis can facilitate the implementation of evolving therapeutic interventions to enhance the outcomes. The modalities for the management of CA have evolved significantly in the last ten years. Apart from therapies for modifying disease and heart failure, a myriad of novel therapeutic approaches that target specific aspects of the disease, including gene therapies, are being researched. These aim at impeding its progression and improving clinical outcomes.

ctDNA as a novel and promising approach for cancer diagnosis

2023-07-25T08:04:05+02:00

Hepatocellular carcinoma (HCC) is one of the most prevalent forms of cancer worldwide. Therefore, it is essential to diagnose and treat HCC patients promptly. As a novel discovery, circulating tumor DNA (ctDNA) can be used to analyze the tumor type and the cancer location. Additionally, ctDNA assists the cancer stage determination, which enables medical professionals to provide patients with the most appropriate treatment. This review will discuss the HCC-related mutated genes diagnosed by ctDNA. In addition, we will introduce the different and the most appropriate ctDNA diagnosis approaches based on the facilities.

Relating aging and autophagy

2023-07-24T09:21:39+02:00

The most common factor that contributes to aging is the loss of proteostasis, resulting in an excess amount of non-functional/damaged proteins. These proteins lead to various age-associated phenotypes such as cellular senescence and dysfunction in the nutrient-sensing pathways. Despite the various factors that can contribute to aging, it is still a process that can be changed. According to recent advances in the field of biology, the ability to alter the pathways that are involved in aging can improve the lifespan of a person. Autophagy is a process that helps in preserving survival during stressful situations, such as starvation. It is a common component of various anti-aging interventions, including those that target the insulin/IGF-1 and rapamycin signaling pathways. It has been shown that altered autophagy is a common feature of old age and its impaired regulation could have significant effects on the aging process. This review aims to look into the role of autophagy in aging and how it can be used to improve one's health.

Innovative therapeutic strategies for cardiovascular disease

2023-07-24T09:09:54+02:00

As a significant non-communicable disease, cardiovascular disease is the leading cause of death for both men and women, comprises almost twenty percent of deaths in most racial and ethnic groups, can affect greater than twenty-five million individuals worldwide over the age of twenty, and impacts global economies with far-reaching financial challenges. Multiple factors can affect the onset of cardiovascular disease that include high serum cholesterol levels, elevated blood pressure, tobacco consumption and secondhand smoke exposure, poor nutrition, physical inactivity, obesity, and concurrent diabetes mellitus. Yet, addressing any of these factors cannot completely eliminate the onset or progression of cardiovascular disorders. Novel strategies are necessary to target underlying cardiovascular disease mechanisms. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), a histone deacetylase, can limit cardiovascular injury, assist with stem cell development, oversee metabolic homeostasis through nicotinamide adenine dinucleotide (NAD⁺) pathways, foster trophic factor protection, and control cell senescence through the modulation of telomere function. Intimately tied to SIRT1 pathways are mammalian forkhead transcription factors (FoxOs) which can modulate cardiac disease to reduce oxidative stress, repair microcirculation disturbances, and reduce atherogenesis through pathways of autophagy, apoptosis, and ferroptosis. AMP activated protein kinase (AMPK) also is critical among these pathways for the oversight of cardiac cellular metabolism, insulin sensitivity, mitochondrial function, inflammation, and the susceptibility to viral infections such as severe acute respiratory syndrome coronavirus that can impact cardiovascular disease. Yet, the relationship among these pathways is both intricate and complex and requires detailed insight to successfully translate these pathways into clinical care for cardiovascular disorders.

Circular RNAs

2023-06-19T06:22:45+02:00

Circular RNAs (CircRNAs) are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. CircRNA dysregulation has been shown to disrupt the interaction of the Wnt/β-catenin pathway, which regulates several biological processes involved in tumorigenesis, thereby contributing to the development and progression of cancer. Interactions of tumor-derived circRNAs with the Wnt/β-catenin signaling pathway provide both clinical diagnostic biomarkers and promising therapeutic targets. In this review, we outlined current evidence on the roles of circRNAs associated with the Wnt/β-catenin pathway in regulating lung cancer formation and development. We believe that our findings will assist in the advancement or establishment of circRNA-based lung cancer therapeutic approaches.

CRISPR/Cas9 genome editing for neurodegenerative diseases

2023-06-29T07:24:20+02:00

Gene therapy has emerged as a promising therapeutic strategy for various conditions, including blood disorders, ocular disease, cancer, and nervous system disorders. The advent of gene editing techniques has facilitated the ability of researchers to specifically target and modify the eukaryotic cell genome, making it a valuable tool for gene therapy. This can be performed through either in vivo or ex vivo approaches. Gene editing tools, such as zinc finger nucleases, transcription activator-like effector nucleases, and CRISPR-Cas-associated nucleases, can be employed for gene therapy purposes. Among these tools, CRISPR-Cas-based gene editing stands out because of its ability to introduce heritable genome changes by designing short guide RNAs. This review aims to provide an overview of CRISPR-Cas technology and summarizes the latest research on the application of CRISPR/Cas9 genome editing technology for the treatment of the most prevalent neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, and Spinocerebellar ataxia.

The bridge between cell survival and cell death

2023-06-14T11:03:28+02:00

As a requirement of aerobic metabolism, regulation of redox homeostasis is indispensable for the continuity of living homeostasis and life. Since the stability of the redox state is necessary for the maintenance of the biological functions of the cells, the balance between the pro-oxidants, especially ROS and the antioxidant capacity is kept in balance in the cells through antioxidant defense systems. The pleiotropic transcription factor, Nrf2, is the master regulator of the antioxidant defense system. Disruption of redox homeostasis leads to oxidative and reductive stress, bringing about multiple pathophysiological conditions. Oxidative stress characterized by high ROS levels causes oxidative damage to biomolecules and cell death, while reductive stress characterized by low ROS levels disrupt physiological cell functions. The fact that ROS, which were initially attributed as harmful products of aerobic metabolism, at the same time function as signal molecules at non-toxic levels and play a role in the adaptive response called mithormesis points out that ROS have a dose-dependent effect on cell fate determination.

Genomic evolution of the SARS-CoV-2 Variants of Concern

2023-05-11T09:17:54+02:00

SARS-CoV-2 has mutated rapidly since its first case report in Wuhan, China, leading to the emergence of an indefinite number of variants. India has witnessed three waves of the COVID-19 pandemic. The country saw its first wave of SARS-CoV-2 illness from late January 2020 to February 2021. With a peak surge of cases in mid-September 2020, India recorded more than 11 million cases and a death toll of more than 0.165 million at this time. India faced a brutal second wave driven by the emergence of highly infectious SARS-CoV-2 variants B.1.617.2 (Delta variant) and the third wave with the leading cause of BA.2 (Omicron variant), which has led to an unprecedented rise in COVID-19 cases in the country. On September 14, 2022, India recorded a cumulative 44.51 million cases of COVID-19 with more than 0.528 million deaths. The discovery of common circulating mutants is facilitated by genome sequencing. The changes in the Spike surface glycoprotein recombinant binding domains served as the critical alterations, resulting in enhanced infectivity and transmissibility, with severe clinical effects. Further, the predominant mutation in the SARS-CoV-2 spike protein; the D614G strains served as a model for vaccine development. The mutation of the Wuhan strain to the Variant of Concern led to a significant increase in SARS-CoV-2 infections. In addition, there was a shift in the age group affected by SARS-CoV-2 variant infection. The current review summarized the COVID-19 pandemic's Variant of Concern and the advent of SARS-CoV-2 in India.

The role of microRNAs in nicotine signaling

2023-05-11T09:30:00+02:00

Cigarette smoking is a harmful habit that is widespread around the world. It is among the well-known lifestyle-related risk factors for many diseases. Nicotine, as its principal constituent, has various detrimental, and beneficial functions. Nicotinic acetylcholine receptors (nAChRs), which are present in nearly all body cells, are how nicotine works. Numerous investigations have demonstrated that nicotine causes abnormal microRNA expression (miRNAs). These short sequences of RNAs are known to regulate gene expression post-transcriptionally. A wide range of miRNAs are modulated by nicotine, and nicotine-induced miRNA changes could subsequently mediate nicotine’s effect on gene expression regulation. We will focus on the reciprocal interaction between nAChRs and miRNAs and describe the essential targets of these dysregulated miRNAs after nicotine exposure and activation of nAChRs. It appears that crucial subcellular mechanisms implicated in nicotine's effects are miRNA-related pathways. It is crucial to investigate the molecular mechanism underlying the effects of nicotine as well as the dysregulation of miRNA following nAChR activation. The finding about epigenetic mechanisms of nicotine-induced effects may shed light on the establishment of new treatment strategies to prevent the harmful effects of nicotine and perhaps may augment the beneficial effects in diverse smoking-related diseases.

Molecular alterations of driver genes in non-small cell lung cancer

2023-05-08T07:06:05+02:00

Lung cancer is the leading cause of cancer death all over the world. The majority (80-85 %) of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Within NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most often recognized. The histological and immunohistochemical examination of NSCLC is a basic diagnostic tool, but insufficient for comprehensive therapeutic decisions. In some NSCLC patients, mainly adenocarcinoma, molecular alterations in driver genes, like EGFR, KRAS, HER2, ALK, MET, BRAF, RET, ROS1, and NTRK are recognized. The frequency of some of those changes is different depending on race, and between smokers and non-smokers. The molecular diagnostics of NSCLC using modern methods, like next-generation sequencing, is essential in estimating targeted, personalized therapy. In recent years, a breakthrough in understanding the importance of molecular studies for the precise treatment of NSCLC has been observed. Many new drugs were approved, including tyrosine kinase and immune checkpoint inhibitors. Clinical trials testing novel molecules like miRNAs and trials with CAR-T cells (chimeric antigen receptor – T cells) dedicated to NSCLC patients are ongoing.

Hepatic benefits of sodium-glucose cotransporter 2 inhibitors in liver disorders

2023-04-18T10:15:09+02:00

Diabetic patients are at higher risk of liver dysfunction compared with the normal population. Thus, using hypoglycemic agents to improve liver efficiency is important in these patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are newly developed antidiabetic drugs with potent glucose-lowering effects. However, recent limited evidence suggests that they have extra-glycemic benefits and may be able to exert protective effects on the liver. Hence, these drugs could serve as promising pharmacological agents with multiple benefits against different hepatic disorders. In this review, the current knowledge about the possible effects of SGLT2 inhibitors on different forms of liver complications and possible underlying mechanisms are discussed.

Bioengineering liver microtissues for modeling non-alcoholic fatty liver disease

2023-03-16T07:44:19+01:00

Non-alcoholic fatty liver disease (NAFLD) has become the world’s most common chronic liver disease. However, due to the lack of reliable in vitro NAFLD models, drug development studies have faced many limitations, and there is no food and drug administration-approved medicine for NAFLD treatment. A functional biomimetic in vitro human liver model requires an optimized natural microenvironment using appropriate cellular composition, to provide constructive cell-cell interactions, and niche-specific bio-molecules to supply crucial cues as cell-matrix interplay. Such a suitable liver model could employ appropriate and desired biochemical, mechanical, and physical properties similar to native tissue. Moreover, bioengineered three-dimensional tissues, specially microtissues and organoids, and more recently using infusion-based cultivation systems such as microfluidics can mimic natural tissue conditions and facilitate the exchange of nutrients and soluble factors to improve physiological function in the in vitro generated constructs. This review highlights the key players involved in NAFLD initiation and progression and discussed the available cells and matrices for in vitro NAFLD modeling. The strategies for optimizing the liver microenvironment to generate a powerful and biomimetic in vitro NAFLD model were described as well. Finally, the current challenges and future perospective for promotion in this subject were discussed.

Unraveling CD69 signaling pathways, ligands and laterally associated molecules

2023-03-09T07:31:02+01:00

CD69 is an early leukocyte activation marker involved in the regulation of the immune response. Initial in vitro studies evaluated its function using monoclonal antibodies until knock-out mice were developed. Subsequently, four ligands for CD69 have been identified, namely galectin-1, S100A8/S100A9 complex, myosin light chains 9 and 12, and oxidized low-density lipoproteins. In addition, several molecules are laterally associated with and regulated by CD69, including calreticulin and two transmembrane receptors, sphingosine-1-phosphate receptor (S1P1) and the heterodimeric amino acid transporter complex SLC7A5-SLC3A2 (LAT1-CD98). Recently, CD69 engagement has been shown to induce the expression of the immunoregulatory receptor programmed cell death-1 (PD-1) in T cells. The molecular signaling induced by CD69 has been explored in different scenarios and cell types. This review provides a perspective on the molecular pathways, ligands and cellular functions known to be regulated by CD69.

Streptozotocin as a tool for induction of rat models of diabetes

2023-02-09T08:30:49+01:00

Streptozotocin (STZ) is the most used diabetogenic chemical for creating rat models of type 1 and type 2 diabetes. Despite ~60 years of using STZ in animal diabetes research, some prevailing views about STZ preparation and use are not supported by evidence. Here, we provide practical guides for using STZ to induce diabetes in rats. Susceptibility to the diabetogenic effect of STZ is inversely related to age, and males are more susceptible to STZ than females. Wistar and Sprague-Dawley rats, the most commonly-used rat strains, are sensitive to STZ, but some strains (e.g., Wistar-Kyoto rats) are less sensitive. STZ is mostly injected intravenously or intraperitoneally, but its intravenous injection produces more stable hyperglycemia. Despite the prevailing view, no fasting is necessary before STZ injection, and injection of its anomer-equilibrated solutions (i.e., more than 2 hours of dissolving) is recommended. Mortality following the injection of diabetogenic doses of STZ is due to severe hypoglycemia (during the first 24 h) or severe hyperglycemia (24 h after the injection and onwards). Some measures to prevent hypoglycemia-related mortality in rats include providing access to food soon after the injection, administration of glucose/sucrose solutions during the first 24-48 h after the injection, administration of STZ to fed animals, and using anomer-equilibrated solutions of STZ. Hyperglycemia-related mortality following injection of high doses of STZ can be overcome with insulin administration. In conclusion, STZ is a valuable chemical for inducing diabetes in rats, but some practical guides should be considered to perform well-conducted and ethical studies.

Brain insulin signaling and cognition

2023-02-09T09:00:46+01:00

Poor cognitive ability is a consequence of a wide variety of neurobehavioral disorders and is a growing health problem, especially among the elderly and patients with diabetes. The precise underlying cause of this complication is not well-defined. However, recent studies have highlighted the possible role of insulin hormone signaling in brain tissue. Insulin is a metabolic peptide integral to whole body energy homeostasis; it does, however, have extrametabolic impacts, such as upon neuronal circuits. Therefore, it has been suggested that insulin signaling may modify cognitive ability by yet unknown pathways. In the current review, we discuss the cognitive role of brain insulin signaling and consider the possible links between brain insulin signaling and cognitive ability.

The neuroscience of body memory

2023-01-30T08:26:42+01:00

The body is a very special object, as it corresponds to the physical component of the self and it is the medium through which we interact with the world. Our body awareness includes the mental representation of the body that happens to be our own, and traditionally has been defined in terms of body schema and body image. Starting from the distinction between these two types of representations, the present paper tries to reconcile the literature around body representations under the common framework of body memory. The body memory develops ontogenetically from birth and across all the life span and is directly linked to the development of the self. Therefore, our sense of self and identity is fundamentally based on multisensory knowledge accumulated in body memory, so that the sensations collected by our body, stored as implicit memory, can unfold in the future, under suitable circumstances. Indeed, these sets of bodily information had been proposed as possible key factors underpinning several mental health illnesses. Following this perspective, the Embodied Medicine approach put forward the use of advanced technologies to alter the dysfunctional body memory to enhance people’s well-being. In the last sections, recent experimental pieces of evidence will be illustrated that targeted specifically bodily information for increasing health and wellbeing, by means of two strategies: interoceptive feedback and bodily illusions.

Can melatonin reduce the severity of post-COVID-19 syndrome?

2023-01-30T08:16:20+01:00

This short review aimed at (i) providing an update on the health benefits associated with melatonin supplementation, while (ii) considering future potential research directions concerning melatonin supplementation use relative to Coronavirus disease of 2019 (COVID-19). A narrative review of the literature was undertaken to ascertain the effect of exogenous melatonin administration on humans. Night-time melatonin administration has a positive impact on human physiology and mental health. Indeed, melatonin (i) modulates the circadian components of the sleep-wake cycle; (ii) improves sleep efficiency and mood status; (iii) improves insulin sensitivity; and (iv) reduces inflammatory markers and oxidative stress. Melatonin has also remarkable neuroprotective and cardioprotective effects and may therefore prevent deterioration caused by COVID-19. We suggest that melatonin could be used as a potential therapy in the post-COVID-19 syndrome, and therefore call for action the research community to investigate on the potential use of exogenous melatonin to enhance the quality of life in patients with post-COVID-19 syndrome.

Bortezomib advanced mechanisms of action in multiple myeloma, solid and liquid tumors along with its novel therapeutic applications

2022-12-20T09:54:32+01:00

Bortezomib (BTZ) is a first-in-class reversible and selective proteasome inhibitor. It inhibits the ubiquitin proteasome pathway that leads to the degradation of many intracellular proteins. Initially, BTZ was FDA approved for the treatment of refractory or relapsed multiple myeloma (MM) in 2003. Later, its usage was approved for patients with previously untreated MM. In 2006, BTZ was approved for the treatment of relapsed or refractory Mantle Cell Lymphoma (MCL) and, in 2014, for previously untreated MCL. BTZ has been extensively studied either alone or in combination with other drugs for the treatment of different liquid tumors especially in MM. However, limited data evaluated the efficacy and safety of using BTZ in patients with solid tumors. In this review, we will discuss the advanced and novel mechanisms of action of BTZ documented in MM, solid tumors and liquid tumors. Moreover, we will shed the light on the newly discovered pharmacological effects of BTZ in other prevalent diseases.

Casposons – silent heroes of the CRISPR-Cas systems evolutionary history

2022-11-07T10:40:39+01:00

Many archaeal and bacterial organisms possess an adaptive immunity system known as CRISPR-Cas. Its role is to recognize and degrade foreign DNA showing high similarity to repeats within the CRISPR array. In recent years computational techniques have been used to identify cas1 genes that are not associated with CRISPR systems, named cas1-solo. Often, cas1-solo genes are present in a conserved neighborhood of PolB-like polymerase genes, which is a characteristic feature of self-synthesizing, eukaryotic transposons of the Polinton class. Nearly all cas1-polB genomic islands are flanked by terminal inverted repeats and direct repeats which correspond to target site duplications. Considering the patchy taxonomic distribution of the identified islands in archaeal and bacterial genomes, they were characterized as a new superfamily of mobile genetic elements and called casposons. Here, we review recent experiments on casposons' mobility and discuss their discovery, classification, and evolutionary relationship with the CRISPR-Cas systems.

Sodium-glucose cotransporter 2 inhibitors and mitochondrial functions

2022-10-27T13:00:38+02:00

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a class of newly introduced antidiabetic drugs with potent hypoglycemic effects. Recent evidence suggests that these drugs have extraglycemic impacts and are therefore able to provide additional benefits beyond glucose lowering. Mitochondrial dysfunction is a central facet of many disorders that negatively impacts many tissues and organs, especially in the setting of diabetes. Therefore, it would be hugely beneficial if an antidiabetic drug could also provide mitochondrial benefits to improve cellular function and reduce the risk of diabetic complications. In this review, we have surveyed the literature for possible mitochondrial benefits of SGLT2is and we discuss the possible mechanisms involved.