Targeting of neuroinflammation by glibenclamide in Covid-19: old weapon from arsenal.

In coronavirus disease 2019 (Covid-19) era, neuroinflammation may develop due to neuronal tropism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and/or associated immune activation, cytokine storm, and psychological stress. SARS-CoV-2 infection and linked cytokine storm may cause blood-brain barrier (BBB) injury through which activated immune cells and SARS-CoV-2 can pass into the brain causing activation of glial cells with subsequent neuroinflammation. Different therapeutic regimens were suggested to alleviate Covid-19-induced neuroinflammation. Since glibenclamide has anti-inflammatory and neuroprotective effects, it could be effective in mitigation of SARS-CoV-2 infection-induced neuroinflammation. Glibenclamide is a second-generation drug from the sulfonylurea family, which acts by inhibiting the adenosine triphosphate (ATP)-sensitive K channel in the regulatory subunit of type 1 sulfonylurea receptor (SUR-1) in pancreatic ß cells. Glibenclamide reduces neuroinflammation and associated BBB injury by inhibiting the nod-like receptor pyrin 3 (NLRP3) inflammasome, oxidative stress, and microglial activation. Therefore, glibenclamide through inhibition of NLRP3 inflammasome, microglial activation, and oxidative stress may attenuate SARS-CoV-2-mediated neuroinflammation.

Hypoxia-Inducible Factor 1 and Preeclampsia: A New Perspective.

PURPOSE OF REVIEW: Preeclampsia (PE) is a serious and distinct type of pregnancy-induced hypertension, with an incidence of 2-8% worldwide. PE is defined as pregnancy-related hypertension with proteinuria and peripheral edema after 20 weeks of gestation. Hypoxic placenta triggers the release of inflammatory and humoral substances into maternal circulation, leading to induction of oxidative stress, lipid peroxidation, endothelial dysfunction, and peripheral vasoconstriction. The objective of the present narrative review was to find the association between PE and hypoxia-inducible factor 1 (HIF-1) in pregnant women from a new perspective. RECENT FINDINGS: HIF-1 is the key transcription factor that regulates cellular responses to hypoxia and low oxygen tension. HIF-1α is involved in the differentiation and growth of the placenta mainly in the first and second trimesters. During normal gestation, HIF-1α responds to the alterations in oxygen tension, cytokine, and angiogenic factors release. HIF-1α is considered a key biomarker of placental function and vascularization during pregnancy. HIF-1α plays a crucial role in the pathogenesis of PE through activation of anti-angiogenic and inhibition of proangiogenic factors. As well, HIF-1α increases the expression of the p38MAPK and NLRP3 inflammasomes, which promote placental inflammation and dysfunction. HIF-1α acts as a potential link between inflammatory signaling pathways and the development of PE.

Evaluation of the Anti-Cancer Potential of Rosa damascena Mill. Callus Extracts against the Human Colorectal Adenocarcinoma Cell Line.

Chemotherapy is an aggressive form of chemical drug therapy aiming to destroy cancer cells. Adjuvant therapy may reduce hazards of chemotherapy and help in destroying these cells when obtained from natural products, such as medical plants. In this study, the potential therapeutic effect of Rosa damascena callus crude extract produced in vitamin-enhanced media is investigated on colorectal cancer cell line Caco-2. Two elicitors, i.e., L-ascorbic acid and citric acid at a concentration of 0.5 g/L were added to the callus induction medium. Callus extraction and the GC-MS analysis of methanolic crude extracts were also determined. Cytotoxicity, clonogenicity, proliferation and migration of Caco-2 colorectal cancer cells were investigated using MTT cytotoxicity, colony-forming, Ki-67 flow cytometry proliferation and Migration Scratch assays, respectively. Our results indicated that L-ascorbic acid treatment enhanced callus growth parameters and improved secondary metabolite contents. It showed the least IC50 value of 137 ug/mL compared to 237 ug/mL and 180 ug/mL in the citric acid-treated and control group. We can conclude that R. damascena callus elicited by L-ascorbic acid improved growth and secondary metabolite contents as well as having an efficient antiproliferative, anti-clonogenic and anti-migratory effect on Caco-2 cancer cells, thus, can be used as an adjuvant anti-cancer therapy.

Exploring 2-Tetradecanoylimino-3-aryl-4-methyl-1,3-thiazolines Derivatives as Alkaline Phosphatase Inhibitors: Biochemical Evaluation and Computational Analysis.

The current study focused on the laboratory approach in conjunction with computational methods for the synthesis and bioactivity assessment of unique 2-tetradecanoylimino-3-aryl-4-methyl-1,3-thiazolines (2a-2k). Processes included cyclizing 1-aroyl-3-arylthioureas with propan-2-one in the presence of trimethylamine and bromine. By using spectroscopic techniques and elemental analyses, structures were elucidated. To assess the electronic properties, density functional theory (DFT) calculations were made, while binding interactions of synthesized derivatives were studied by the molecular docking tool. Promising results were found during the evaluation of bioactivity of synthesized compounds against alkaline phosphatase. The drug likeliness score, an indicator used for any chemical entity posing as a drug, was within acceptable limits. The data suggested that most of the derivatives were potent inhibitors of alkaline phosphatase, which in turn may act as lead molecules to synthesize derivatives having desired pharmacological profiles for the treatment of specific diseases associated with abnormal levels of ALPs.

Evaluation of Phytochemistry and Pharmacological Properties of Alnus nitida.

In the current study, the anti-inflammatory and analgesic potential of Alnus nitida (leaves and fruits) was evaluated in the Sprague-Dawley rat. Traditionally, A. nitida was used for the treatment of inflammatory ailments. However, A. nitida leaves and fruits have not been yet reported regarding any potential medicinal effects. Leaves/fruits of A. nitida were extracted with methanol and fractionated to attain n-hexane, chloroform, ethyl acetate and aqueous fractions. These extracts were then evaluated for in vivo analgesic and anti-inflammatory potential. For in vivo anti-inflammatory activity, carrageenan-induced paw edema assay, Freunds' complete adjuvant-induced edema, xylene-induced ear edema and histamine-induced paw edema models were used in rats, which showed significant (p < 0.01) reduction (70−80%) in edema in comparison of inflammatory controls. On other hand, for the analgesic assessment, hot plate assay and acetic acid-induced writhing tests were used, which showed a significant (p < 0.01) rise in latency time (40−60%) as compared with pain-induced controls. These results were comparable with standard drugs in a concentration-dependent manner and no mortality or toxicity was observed during all experiments. Then, for the identification of chemical constituents gas chromatography−mass spectrometry (GC-MS) analysis was performed, which indicated the presence of neophytadiene, 3,7,11,15-Tetramethyl-2-hexadecen-1-ol, phytol and vitamin E, justifying the use of A. nitida to treat inflammatory disorders.

Phytochemical Analysis and Understanding the Antioxidant and Anticancer Properties of Methanol Extract from Litsea glutinosa: In Vitro and In Vivo Studies.

Litsea glutinosa (L. glutinosa) is considered an evidence-based medicinal plant for the treatment of cancer, the leading cause of death worldwide. In our study, the in vitro antioxidant and in vivo anticancer properties of an essential ethno-medicinal plant, L. glutinosa, were examined using non-toxic doses and a phytochemical analysis was executed using gas-chromatography-mass-spectrometry. The in vitro antioxidant study of the L. glutinosa methanolic extract (LGBME) revealed a concentration-dependent antioxidant property. The bark extract showed promising antioxidant effects in the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay. The strongest antioxidant activity was demonstrated at the maximum concentration (50 µg/mL). The IC50 values of the LGBME and BHT were 5.51 and 5.01 µg/mL, respectively. At the same concentration, the total antioxidant capacity of the LGBME was 0.161 µg/mL and the ferric reducing antioxidant power assay result of the LGBME was 1.783 µg/mL. In the cytotoxicity study, the LD50 of the LGBME and gallic acid were 24.93 µg/mL and 7.23 µg/mL, respectively. In the in vivo anticancer-activity studies, the LGBME, particularly at a dose of 150 mg/kg/bw, showed significant cell-growth inhibition, decreased tumor weight, increased mean survival rate, and upregulated the reduced hematological parameters in EAC (Ehrlich's ascites carcinoma)-induced Swiss albino mice. The highest cell-growth inhibition, 85.76%, was observed with the dose of 150 mg/kg/bw. Furthermore, the upregulation of pro-apoptotic genes (p53, Bax) and the downregulation of anti-apoptotic Bcl-2 were observed. In conclusion, LGBME extract has several bioactive phytoconstituents, which confirms the antioxidant and anticancer properties of L. glutinosa.

Effects of neoadjuvant therapies on genetic regulation of targeted pathways in ER+ primary ductal breast carcinoma: A meta-analysis of microarray datasets.

Breast cancer arises as a result of multiple interactions between environmental and genetic factors. Conventionally, breast cancer is treated based on histopathological and clinical features. DNA technologies like the human genome microarray are now partially integrated into clinical practice and are used for developing new "personalized medicines" and "pharmacogenetics" for improving the efficiency and safety of cancer medications. We investigated the effects of four established therapies-for ER+ ductal breast cancer-on the differential gene expression. The therapies included single agent tamoxifen, two-agent docetaxel and capecitabine, or combined three-agents CAF (cyclophosphamide, doxorubicin, and fluorouracil) and CMF (cyclophosphamide, methotrexate, and fluorouracil). Genevestigator 8.1.0 was used to compare five datasets from patients with infiltrating ductal carcinoma, untreated or treated with selected drugs, to those from the healthy control. We identified 74 differentially expressed genes involved in three pathways, i.e., apoptosis (extrinsic and intrinsic), oxidative signaling, and PI3K/Akt signaling. The treatments affected the expression of apoptotic genes (TNFRSF10B [TRAIL], FAS, CASP3/6/7/8, PMAIP1 [NOXA], BNIP3L, BNIP3, BCL2A1, and BCL2), the oxidative stress-related genes (NOX4, XDH, MAOA, GSR, GPX3, and SOD3), and the PI3K/Akt pathway gene (ERBB2 [HER2]). Breast cancer treatments are complex with varying drug responses and efficacy among patients. This necessitates identifying novel biomarkers for predicting the drug response, using available data and new technologies. GSR, NOX4, CASP3, and ERBB2 are potential biomarkers for predicting the treatment response in primary ER+ ductal breast carcinoma.

Formulation Development and Investigations on Therapeutic Potential of Nanogel from Beta vulgaris L. Extract in Testosterone-Induced Alopecia.

The objective of the present study was to develop a novel nanogel containing Beta vulgaris L. hydroalcoholic extract and assess its efficacy for treating testosterone-induced alopecia. Beta vulgaris L. leaf hydroalcoholic extract nanogel (BVEN) was prepared by ionic gelation method, incorporated in carbopol 934 gel. Optimization of particle size and entrapment efficiency as the responses was carried out by central composite design response surface methodology. Prepared nanoparticles were evaluated for entrapment efficiency, particle size, zeta potential, polydispersity index, Fourier transform infrared spectroscopy, transmission electron microscopy, and differential scanning calorimetry. Nanogel was evaluated for pH, colour, appearance and homogeneity, viscosity, spreadability, in vitro release study, and stability studies. Further, 2.5% and 5% BVEN were also evaluated for antialopecic activity in Swiss albino mice by using parameters as hair growth initiation, testosterone content, total protein, prostate weight measurement, hair follicular density, anagen/telogen ratio, and histopathological studies. The resulting nanoparticles had better entrapment efficiency with particle size of 274 nm, polydispersity index of 0.259, and zeta potential of +28.8. BVEN pH 6.5, drug content, i.e., quercetin 99.84 ± 1.30% and stigmasterol 99.89 ± 1.52%, spreadability 20.3 ± 0.5925 g cm/sec, and viscosity 110 × 105 cps were observed. Stability studies showed that nanogel was stable at 4°C ± 2°C/60% ± 5% RH. It was found that 5% BVEN showed better antialopecic activity as compared to 2.5% BVEN.

New Insight into the Pharmacological Importance of Atropine as the Potential Inhibitor of AKR1B1 via Detailed Computational Investigations: DFTs, ADMET, Molecular Docking, and Molecular Dynamics Studies.

The aim of this research is to investigate the quantum geometric properties and chemical reactivity of atropine, a pharmaceutically active tropane alkaloid. Using density functional theory (DFT) computations with the B3LYP/SVP functional theory basis set, the most stable geometry of atropine was determined. Additionally, a variety of energetic molecular parameters were calculated, such as the optimized energy, atomic charges, dipole moment, frontier molecular orbital energies, HOMO-LUMO energy gap, molecular electrostatic potential, chemical reactivity descriptors, and molecular polarizability. To determine atropine's inhibitory potential, molecular docking was used to analyze ligand interactions within the active pockets of aldo-keto reductase (AKR1B1 and AKR1B10). The results of these studies showed that atropine has greater inhibitory action against AKR1B1 than AKR1B10, which was further validated through molecular dynamic simulations by analyzing root mean square deviation (RMSD) and root mean square fluctuations (RMSF). The results of the molecular docking simulation were supplemented with simulation data, and the ADMET characteristics were also determined to predict the drug likeness of a potential compound. In conclusion, the research suggests that atropine has potential as an inhibitor of AKR1B1 and could be used as a parent compound for the synthesis of more potent leads for the treatment of colon cancer associated with the sudden expression of AKR1B1.

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best.

A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.

Attenuation of hyperglycemia-associated dyslipidemic, oxidative, cognitive, and inflammatory crises via modulation of neuronal ChEs/NF-κB/COX-2/NOx, and hepatorenal functional deficits by the Tridax procumbens extract.

Tridax procumbens (cotton buttons) is a flowering plant with a medicinal reputation for treating infections, wounds, diabetes, and liver and kidney diseases. The present research was conducted to evaluate the possible protective effects of the T. procumbens methanolic extract (TPME) on an experimentally induced type 2 diabetes rat model. Wistar rats with streptozotocin (STZ)-induced diabetes were randomly allocated into five groups of five animals each, viz., a normal glycemic group (I), diabetic rats receiving distilled water group (II), diabetic rats with 150 (III) and 300 mg/kg of TPME (IV) groups, and diabetic rats with 100 mg/kg metformin group (V). All treatments were administered for 21 consecutive days through oral gavage. Results: Administration of the T. procumbens extract to diabetic rats significantly restored alterations in levels of fasting blood glucose (FBG), body weight loss, serum and pancreatic insulin levels, and pancreatic histology. Furthermore, T. procumbens significantly attenuated the dyslipidemia (increased cholesterol, low-density lipoprotein-cholesterol (LDL-C), triglycerides, and high-density lipoprotein (HDL) in diabetic rats), serum biochemical alterations (alanine transaminase (ALT), aspartate transaminase (AST), alanine phosphatase (ALP), blood urea nitrogen (BUN), creatinine, uric acid, and urea) and full blood count distortion in rats with STZ-induced diabetes. The TPME also improved the antioxidant status as evidenced by increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and decreased malondialdehyde (MDA); and decreased levels of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)), and proinflammatory mediators including nuclear factor (NF)-κB, cyclooxygenase (COX)- 2, and nitrogen oxide (NOx) in the brain of rats with STZ-induced diabetes compared to rats with STZ-induced diabetes that received distilled water. However, TPME treatment failed to attenuate the elevated monoamine oxidases and decreased dopamine levels in the brain of rats with STZ-induced diabetes. Extract characterization by liquid chromatography mass spectrometry (LC-MS) identified isorhamnetin (retention time (RT)= 3.69 min, 8.8%), bixin (RT: 25.06 min, 4.72%), and lupeol (RT: 25.25 min, 2.88%) as the three most abundant bioactive compounds that could be responsible for the bioactivity of the plant. In conclusion, the TPME can be considered a promising alternative therapeutic option for managing diabetic complications owing to its antidiabetic, antihyperlipidemic, antioxidant, and anti-inflammatory effects in rats with STZ-prompted diabetes.

Quercetin-3-O-ß-D-Glucopyranoside-Rich Fraction from Spondias mombin Leaves Halted Responses from Oxidative Stress, Neuroinflammation, Apoptosis, and Lipid Peroxidation in the Brain of Dichlorvos-Treated Wistar Rats.

Dichlorvos (2,3-dichlorovinyl dimethyl phosphate or DDVP), is a popular organophosphate (OP) with several domestic, industrial, and agricultural uses and applications in developing countries [...].

Mutivariate optimization strategy for the sonication-based extraction of Nardostachys jatamansi roots and analysis for chemical composition, anti-oxidant and acetylcholinesterase inhibitory potential.

Extracts from medicinal plants are generally obtained by conventional methods like percolation and maceration. Owing to limitations of traditional methods and to meet the rising demand of extracts, the development of new green approaches is need of hour. In the present research, we have developed an ultrasound-assisted extraction (UAE) method for the Nardostachys jatamansi (NJ) D. Don, DC roots and optimized the extraction parameters for possible improved extract yield. A multivariate optimization strategy using the Centre Composite Design coupled with response surface methodology was applied. A numerical optimization approach accurately predicted the extraction conditions (sonication time âˆ¼ 20 min, ethanol âˆ¼ 70 % and a liquid/solid ratio of about 21:1). Scanning electron microscopy of the plant samples after UAE also indicated the cavitation effect due to sound waves. GC-MS analysis of the optimized ultrasound extract (OUNJ) confirmed improvement in the concentration of various secondary metabolites like jatamansone (91.8 % increase), spirojatamol (42.3 % increase), globulol (130.4 % increase), sitosterol (84.6 % increase) as compared to the soxhlet extract (SXNJ). Different anti-oxidant parameters (DPPH, Glutathione, Catalase SOD and NO) were also significantly altered (p < 0.05) in the optimized extracts. The IC50 to inhibit acetylcholinesterase activity (AChE) in vitro and its concentration in brain homogenates were significantly (p < 0.05) improved by OUNJ extract as compared to the SXNJ ones. To conclude, we can say that established optimized conditions for UAE of N. jatamansi roots not only reduce the extraction time but also improved the pharmacological potential of the extracts.

Barhi date (Phoenix dactylifera) extract ameliorates hepatocellular carcinoma in male rats.

Hepatocellular carcinoma (HCC) is a malignant tumor with limited treatment options. Given this fact, it may be important to develop new molecular targeted therapies from natural products, especially those which are primary sources of effective anticancer drugs with distinct mechanisms. Moreover, the complementary use of traditional herbs or fruit may increase the possibility of finding curative options for cancer. Here we explore the anticancer effects and possible molecular mechanism of Barhi date extract using an HCC rat model. Thirty two male albino rats were arbitrarily allocated into four groups: a negative control group (NCG); a positive control group (PCG), which received CCl4 (1 ml/kg b.wt./ i.p.) twice a week for three months; a Barhi date extract (400 mg/kg b.wt./day/orally) treatment group (DTG) during the third month of CCl4 administration; and a cisplatin (1.5 mg/kg b.wt./ i.p.) treatment group ( CTG) during the third month of CCl4 administration. After treatment we performed biochemical analyses of all groups to assess relative eukaryotic initiation factor 2 alpha (eIF2α), extracellular signal-regulated kinases (ERKs), protein kinase RNA-like endoplasmic reticulum kinase (PERK), poly (ADP-ribose) polymerase (PARP), and CASPASE 3 protein content, and examined expression of the genes phosphatase and tensin homolog (PTEN) and protein kinase B (AKT). We also performed an immunohistochemistry assay for alpha-fetoprotein (AFP). Our data showed higher PARP and CASPASE3 levels and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) in the PCG compared to the DTG and the cisplatin treatment group CTG. However, we also found a significant decrease in PTEN in the PCG relative to both the DTG and the CTG. We conclude that the anti-tumor activity of Barhi date extract may be mediated by the inhibition of cell proliferation and apoptosis via the ERK /PARP/caspase3 pathway and the AKT/ PTEN signaling pathways.

Oral supplementation of policosanol alleviates carbon tetrachloride-induced liver fibrosis in rats.

Liver fibrosis is a prevalent liver disease that requires rapid and effective treatment prior to its progression to cirrhosis and liver damage. Recently, several reports have investigated the efficacy of phytotherapy using natural herbal extracts rather than synthetic drugs to treat several liver diseases. Policosanol is a herbal extract used to treat patients with cardiovascular. However, its therapeutic effect on liver fibrosis is still unknown. Therefore, the present study aimed to assess the potential antifibrotic effect of policosanol compared to silymarin and the possible underlying molecular mechanisms. Rats were categorized into four groups; negative control group "NCG", the fibrotic group "FG", silymarin treated group "STG", and policosanol treated group "PTG". Serum liver enzymes, oxidative stress markers, angiogenic growth factors, and pro-inflammatory cytokines were measured biochemically. The relative mRNA expressions of liver caspase-3 and alpha-smooth muscle actin (α-SMA) were assessed. Immunohistochemical staining was carried out using anti- α-SMA, and anti-caspase-3 antibodies. Compared to NCG, the FG group demonstrated a significant decrease in the level of serum liver enzymes "GSH, TAC, and SDF. Nevertheless, it demonstrateda significant increase in the level of pro-inflammatory cytokines "Il-6, TNF"; oxidative stress markers "NO, MDA", and angiogenic growth factors "VEGF and PDGF" and the expression of α-SMA, and Caspase-3. Interestingly, the values of these measurements were restored to normal levels in the treated groups, particularly the PTG. In conclusion, our data revealed the beneficial effects of co-administration of policosanol or silymarin on the fibrotic liver rat model and thus could be a promising natural therapeutic drug.

Ginseng® Alleviates Malathion-Induced Hepatorenal Injury through Modulation of the Biochemical, Antioxidant, Anti-Apoptotic, and Anti-Inflammatory Markers in Male Rats.

This study aims to see if Ginseng® can reduce the hepatorenal damage caused by malathion. Four groups of forty male Wistar albino rats were alienated. Group 1 was a control group that got orally supplied corn oil (vehicle). Group 2 was intoxicated by malathion dissolved in corn oil orally at 135 mg/kg/day. Group 3 orally received both malathion + Panax Ginseng® (300 mg/kg/day). Group 4 was orally given Panax Ginseng® at a 300 mg/kg/day dose. Treatments were administered daily and continued for up to 30 consecutive days. Malathion's toxic effect on both hepatic and renal tissues was revealed by a considerable loss in body weight and biochemically by a marked increase in liver enzymes, LDH, ACP, cholesterol, and functional renal markers with a marked decrease in serum TP, albumin, and TG levels with decreased AchE and Paraoxonase activity. Additionally, malondialdehydes, nitric oxide (nitrite), 8-hydroxy-2-deoxyguanosine, and TNFα with a significant drop in the antioxidant activities were reported in the malathion group. Malathion upregulated the inflammatory cytokines and apoptotic genes, while Nrf2, Bcl2, and HO-1 were downregulated. Ginseng® and malathion co-treatment reduced malathion's harmful effects by restoring metabolic indicators, enhancing antioxidant pursuit, lowering the inflammatory reaction, and alleviating pathological alterations. So, Ginseng® may have protective effects against hepatic and renal malathion-induced toxicity on biochemical, antioxidant, molecular, and cell levels.

Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure.

Type 2 diabetes mellitus (T2DM) is a chronic endocrine disorder due to the reduction of insulin sensitivity and relative deficiency of insulin secretion. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta (TGF-ß) superfamily and was initially identified as macrophage inhibitory cytokine-1 (MIC-1). GDF15 is considered a cytokine with an anti-inflammatory effect and increases insulin sensitivity, reduces body weight, and improves clinical outcomes in diabetic patients. GDF15 acts through stimulation of glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which is highly expressed in the brain stem to induce taste aversion. Metformin belongs to the group of biguanides that are derived from the plant Galega officinalis. It is interesting to note that metformin is an insulin-sensitizing agent used as a first-line therapy for T2DM that has been shown to increase the circulating level of GDF15. Thus, the present review aims to determine the critical association of the GDF15 biomarker in T2DM and how metformin agents affect it. This review illustrates that metformin activates GDF15 expression, which reduces appetite and leads to weight loss in both diabetic and nondiabetic patients. However, the present review cannot give a conclusion in this regard. Therefore, experimental, preclinical, and clinical studies are warranted to confirm the potential role of GDF15 in T2DM patients.

Traditional herbs against COVID-19: back to old weapons to combat the new pandemic.

BACKGROUND: Recently, the coronavirus (COVID-19) pandemic is a chief public health disaster caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are no established effective preventive or therapeutic anti-COVID-19 drugs available except for some recently approved vaccines. Still, countless recent studies recommend various alternative and complementary approaches against COVID-19, which are medicinal herbs employed as traditional remedies to enhance immunity to struggle with viral infections. In addition, physicians worldwide are highly interested in vitamin and mineral supplements to help them combat COVID-19 either through protection or treatment. Dietary supplements specifically vitamin D, vitamin C, and zinc provide good prophylactic and therapeutic support to the presently available treatment regimens. In the present work, we have focused on plant-based remedies with promising anti-COVID-19 activities. AIM: To enable investigators and researchers to identify potential herbal compounds with anti-COVID activity to be used as promising therapies to combat this pandemic. MAIN BODY: This review highlights the recently published studies concerning natural traditional herbs, herbal bioactive metabolites, dietary supplements, and functional foods that could help prevent and/or treat COVID-19. Herein, we explored medicinal herbs as potential inhibitors of SARS-CoV-2 and discussed how these studies help form larger discussions of diet and disease. Moreover, by investigating the herbal bioactive components, we have outlined several medicinal herbs that can fight against COVID-19 by hindering SARS-CoV-2 replication and entry to its host cells, deterring the cytokine storm, and several other means. Finally, we have summarized various herbal products, functional foods, and dietary supplements with potent bioactive compounds which can inhibit and/or prevent COVID-19 disease progression. CONCLUSIONS: Based on the studies reviewed in this work, it was concluded with no doubt that phytochemical components present in various herbs could have a starring role in the deterrence and cure of coronavirus contagion.

Circulating microRNA203 and its target genes' role in psoriasis pathogenesis.

Numerous microRNAs (miRNAs) have been found to have an aberrant expression in the peripheral blood or psoriasis patients' lesions. Psoriasis was shown to have the abnormal expression of microRNA-203 (miR-203). It is a skin-specific signal that governs cellular proliferation in a protein kinase C-dependent manner and is mostly generated by keratinocytes. This work evaluated the expression levels of the circulating miR-203 target genes SOCS3, SOCS6, TP63, TNF-, IL8, and IL24 in psoriasis patients. Using a relative quantitation PCR technique, we determined the expression levels of miR-203 and its target genes (SOCS3, SOCS6, TP63, TNF-, IL8, and IL24) in the plasma of 120 psoriatic patients and matched healthy controls. The disease characteristics of the patients were then correlated with the expression results. We also conducted numerous enrichment analyses for the diseases, functions, and pathways connected to the under-researched biomarkers. Compared to healthy controls, psoriatic patients had significantly increased levels of miR-203 expression; 7.1 (4.4-9.9). In contrast, psoriatic patients had significantly lower expression of all the examined genes compared to healthy controls. Regarding all the study biomarkers, the receiver operating characteristic (ROC) curve analysis demonstrated significant sensitivity and specificity for differentiating between psoriatic patients and healthy controls. According to the results of the disease matching score generated by miR-203 and its target genes, psoriasis was ranked first with a score of 4.45. The third-place finisher with a value of 3.98, it also demonstrated that miR-203 and its target genes are connected to various skin disorders. Our results show that miR-203 contributes to psoriasis pathogenesis not only locally in skin lesions but also in circulation, indicating that it may contribute to the systemic symptoms of the illness. MiR-203 overexpression in psoriasis suggests that miR-203 may be involved in an anti-inflammatory response because it targets both SOCS gene family members and pro-inflammatory cytokines.

Computational Insights into the Structural and Functional Impacts of nsSNPs of Bone Morphogenetic Proteins.

BMPs (bone morphogenetic proteins) are multipurpose (transforming growth factor)TGF-superfamily released cytokines. These glycoproteins, acting as disulfide-linked homo- or heterodimers, are highly potent regulators of bone and cartilage production and repair, cell proliferation throughout embryonic development, and bone homeostasis in the adults. Due to the fact that genetic variation might influence structural functions, this study is aimed to determine the pathogenic effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in BMP genes. The implications of these variations, investigated using computational analysis and molecular models of the mature TGF-ß domain, revealed the impact of modifications on the function of BMP protein. The three-dimensional (3D) structure analysis was performed on the nsSNP Y316S, V386G, E387G, C389G, and C391G nsSNP in the TGF-ß domain of chicken BMP2 and H344P, S347P, V357A nsSNP in the TGF-ß domain of chicken BMP4 protein that was anticipated to be harmful and of high risk. The ability of the proteins to perform variety of tasks interact with other molecules depends on their tertiary structural composition. The current analysis revealed the four most damaging variants (Y316S, V386G, E387G, C389G, and C391G), highly conserved and functional and are located in the TGF-beta domain of BMP2 and BMP4. The amino acid substitutions E387G, C389G, and C391G are discovered in the binding region. It was observed that the mutations in the TGF-beta domain caused significant changes in its structural organization including the substrate binding sites. Current findings will assist future research focused on the role of these variants in BMP function loss and their role in skeletal disorders, and this will possibly help to develop practical strategies for treating bone-related conditions.