The Potential Inhibitory Role of Acetyl-L-Carnitine on Proliferation, Migration, and Gene Expression in HepG2 and HT29 Human Adenocarcinoma Cell Lines.

Malignancies of the liver and colon are the most prevalent forms of digestive system cancer globally. Chemotherapy, one of the most significant treatments, has severe side effects. Chemoprevention using natural or synthetic medications can potentially reduce cancer severity. Acetyl-L-carnitine (ALC) is an acetylated derivative of carnitine essential for intermediate metabolism in most tissues. This study aimed to investigate the effects of ALC on the proliferation, migration, and gene expression of human liver (HepG2) and colorectal (HT29) adenocarcinoma cell lines. The cell viability and half maximal inhibitory concentration of both cancer cell lines were determined using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Wound healing after treatment was assessed using a migration assay. Morphological changes were imaged using brightfield and fluorescence microscopy. Post treatment, apoptotic DNA was detected using a DNA fragmentation assay. The relative mRNA expressions of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor (VEGF) were evaluated using RT-PCR. The results showed that ALC treatment affects the wound-healing ability of HepG2 and HT29 cell lines. Changes in nuclear morphology were detected under fluorescent microscopy. ALC also downregulates the expression levels of MMP9 and VEGF in HepG2 and HT29 cell lines. Our results indicate that the anticancer action of ALC is likely mediated by a decrease in adhesion, migration, and invasion.

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.

Cyanidin-3-Glucoside Modulates hsa_circ_0001345/miRNA106b/ATG16L1 Axis Expression as a Potential Protective Mechanism against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of malignancy in the liver. Autophagy was found to have a significant effect in controlling HCC. Anthocyanins, which are naturally occurring pigments in a variety of fruits and vegetables, have been thoroughly documented to be involved in a variety of bioactive activities and are widely employed for their antioxidant capabilities. Cyanidin-3-glucoside (C3G) extracted from Morus alba L. has promising antioxidant and anti-tumour activities. The current study aims to examine the protective action of C3G against hepatocellular carcinoma through the investigation of the autophagy protein ATG16L1 expression along with its related RNA molecules (hsa_circ_0001345 and miRNA106b) in Wistar rats. In vivo precancerous lesions (PCL) were induced using diethylnitrosamine (DEN) and acetamidofluorene (2-AAF). Rats were treated with C3G (10, 15, and 20 mg/kg; 4 times weekly) for 112 days (16 weeks). Liver function tests, alfa fetoprotein, ATG16L1 expression, hsa_circ_0001345, and miRNA106b differential expression were examined. Liver sections were examined by histological and immunohistochemical approaches. The current study's findings indicated that C3G administration protects against the negative effects of DEN-2-AAF on liver functions and liver histopathological sections, which nominated C3G as a potential prophylactic agent against HCC.

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.

Investigation of the New Inhibitors by Sulfadiazine and Modified Derivatives of α-D-glucopyranoside for White Spot Syndrome Virus Disease of Shrimp by In Silico: Quantum Calculations, Molecular Docking, ADMET and Molecular Dynamics Study.

The α-D-glucopyranoside and its derivatives were as the cardinal investigation for developing an effective medication to treat the highest deadly white spot syndrome virus (WSSV) diseases in Shrimp. In our forthcoming work, both computational tools, such as molecular docking, quantum calculations, pharmaceutical kinetics, ADMET, and their molecular dynamics, as well as the experimental trial against WSSV, were executed to develop novel inhibitors. In the beginning, molecular docking was carried out to determine inhibitors of the four targeted proteins of WSSV (PDB ID: 2ED6, 2GJ2, 2GJI, and 2EDM), and to determine the binding energies and interactions of ligands and proteins after docking. The range of binding affinity was found to be between -5.40 and -7.00 kcal/mol for the protein 2DEM, from -5.10 to 6.90 kcal/mol for the protein 2GJ2, from -4.70 to -6.2 kcal/mol against 2GJI, and from -5.5 kcal/mol to -6.6 kcal/mol for the evolved protein 2ED6 whereas the L01 and L03 display the highest binding energy in the protein 2EDM. After that, the top-ranked compounds (L01, L02, L03, L04, and L05), based on their high binding energies, were tested for molecular dynamics (MD) simulations of 100 ns to verify the docking validation and stability of the docked complex by calculating the root mean square deviation (RMSD) and root mean square fluctuation (RMSF). The molecules with the highest binding energy were then picked and compared to the standard drugs that were been applied to fish experimentally to evaluate the treatment at various doses. Consequently, approximately 40-45% cure rate was obtained by applying the dose of oxytetracycline (OTC) 50% with vitamin C with the 10.0 g/kg feed for 10 days. These drugs (L09 to L12) have also been executed for molecular docking to compare with α-D-glucopyranoside and its derivatives (L01 to L08). Next, the evaluation of pharmacokinetic parameters, such as drug-likeness and Lipinski's principles; absorption; distribution; metabolism; excretion; and toxicity (ADMET) factors, were employed gradually to further evaluate their suitability as inhibitors. It was discovered that all ligands (L01 to L12) were devoid of hepatotoxicity, and the AMES toxicity excluded L05. Additionally, all of the compounds convey a significant aqueous solubility and cannot permeate the blood-brain barrier. Moreover, quantum calculations based on density functional theory (DFT) provide the most solid evidence and testimony regarding their chemical stability, chemical reactivity, biological relevance, reactive nature and specific part of reactivity. The computational and virtual screenings for in silico study reveals that these chosen compounds (L01 to L08) have conducted the inhibitory effect to convey as a possible medication against the WSSV than existing drugs (L09, L10, L11 and L12) in the market. Next the drugs (L09, L10, L11 and L12) have been used in trials.

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.

Design, Synthesis and Cytotoxic Activity Evaluation of Newly Synthesized Amides-Based TMP Moiety as Potential Anticancer Agents over HepG2 Cells.

A novel series of amides based TMP moiety was designed, synthesized and evaluated for their antiproliferative as well as enzyme inhibition activity. Compounds 6a and 6b showed remarkable cytotoxic activity against HepG2 cells with IC50 values 0.65 and 0.92 µM, respectively compared with SAHA and CA-4 as reference compounds. In addition, compound 6a demonstrated good HDAC-tubulin dual inhibition activity as it showed better HDAC activity as well as anti-tubulin activity. Moreover, compound 6a exhibited G2/M phase arrest and pre-G1 apoptosis as demonstrated by cell cycle analysis and Annexin V assays. Further apoptosis studies demonstrated that compound 6a boosted the level of caspase 3/7. Caspase 3/7 activation and apoptosis induction were evidenced by decrease in mitochondrial permeability suggesting that activation of caspase 3/7 may occur via mitochondrial apoptotic pathway.

Chemical and Pharmacological Profiling of Wrightia coccinea (Roxb. Ex Hornem.) Sims Focusing Antioxidant, Cytotoxic, Antidiarrheal, Hypoglycemic, and Analgesic Properties.

The aim of the study was to conduct phytochemical and pharmacological investigations of Wrightia coccinea (Roxb. ex Hornem.) Sims via several in vitro, in vivo, and in silico models. A total of four compounds were identified and isolated from the methanol extract of the bark and the methanol extract of the seed pulp of W. coccinea through successive chromatographic techniques and were characterized as 3ß-acetyloxy-olean-12-en-28-ol (1), wrightiadione (2), 22ß-hydroxylupeol (3), and ß-sitosterol (4) by spectroscopic analysis. The aqueous fraction of the bark and chloroform fraction of the fruits provided the most potent antioxidant capacity (IC50 = 7.22 and 4.5 µg/mL, respectively) in DPPH free radical scavenging assay compared with the standard ascorbic acid (IC50 = 17.45 µg/mL). The methanol bark extract and the methanol fruit coat extract exerted anti-diarrheal activity by inhibiting 74.55 ± 0.67% and 77.78 ± 1.5% (mean ± SEM) of the diarrheal episode in mice, respectively, after four hours of loading the samples. In the hypoglycemic test, the methanol bark extract and the methanol fruit coat extract (400 mg/kg) produced a significant (p < 0.05) reduction in the blood glucose level in mice. Both doses of the plant extracts (200 mg/kg and 400 mg/kg) used in the study induced a significant (p < 0.05) increase in pain reaction time. The in vitro and in vivo findings were supported by the computational studies. The isolated compounds exhibited higher binding affinity compared with the standard drugs towards the active binding sites of glutathione reductase, epidermal growth factor receptor (EGFR), kappa opioid receptor, glucose transporter 3 (GLUT 3), Mu opioid receptor, and cyclooxygenase 2 (COX-2) proteins due to their potent antioxidant, cytotoxic, anti-diarrheal, hypoglycemic, and central and peripheral analgesic properties, respectively. The current findings concluded that W. coccinea might be a potential natural source for managing oxidative stress, diarrhea, hyperglycemia, and pain. Further studies are warranted for extensively phytochemical screening and establishing exact mechanisms of action.

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.

Phenolic Constituents from Wendlandia tinctoria var. grandis (Roxb.) DC. Stem Deciphering Pharmacological Potentials against Oxidation, Hyperglycemia, and Diarrhea: Phyto-Pharmacological and Computational Approaches.

Wendlandia tinctoria var. grandis (Roxb.) DC. (Family: Rubiaceae) is a semi-evergreen shrub distributed over tropical and subtropical Asia. The present research intended to explore the pharmacological potential of the stem extract of W. tinctoria, focusing on the antioxidant, hypoglycemic, and antidiarrheal properties, and to isolate various secondary metabolites as mediators of such activities. A total of eight phenolic compounds were isolated from the dichloromethane soluble fraction of the stem extract of this plant, which were characterized by electrospray ionization (ESI) mass spectrometric and 1H NMR spectroscopic data as liquiritigenin (1), naringenin (2), apigenin (3), kaempferol (4), glabridin (5), ferulic acid (6), 4-hydroxybenzoic acid (7), and 4-hydroxybenzaldehyde (8). The dichloromethane soluble fraction exhibited the highest phenolic content (289.87 ± 0.47 mg of GAE/g of dried extract) and the highest scavenging activity (IC50 = 18.83 ± 0.07 µg/mL) against the DPPH free radical. All of the isolated compounds, except 4-hydroxybenzaldehyde, exerted a higher antioxidant effect (IC50 = 6.20 ± 0.10 to 16.11 ± 0.02 µg/mL) than the standard butylated hydroxytoluene (BHT) (IC50 = 17.09 ± 0.01 µg/mL). Significant hypoglycemic and antidiarrheal activities of the methanolic crude extract at both doses (200 mg/kg bw and 400 mg/kg bw) were observed in a time-dependent manner. Furthermore, the computational modeling study supported the current in vitro and in vivo findings, and the isolated constituents had a higher or comparable binding affinity for glutathione reductase and urase oxidase enzymes, glucose transporter 3 (GLUT 3), and kappa-opioid receptor, inferring potential antioxidant, hypoglycemic, and antidiarrheal properties, respectively. This is the first report of all of these phenolic compounds being isolated from this plant species and even the first demonstration of the plant stem extract's antioxidant, hypoglycemic, and antidiarrheal potentials. According to the current findings, the W. tinctoria stem could be a potential natural remedy for treating oxidative stress, hyperglycemia, and diarrhea. Nevertheless, further extensive investigation is crucial for thorough phytochemical screening and determining the precise mechanisms of action of the plant-derived bioactive metabolites against broad-spectrum molecular targets.

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.

Mutations in the binding site of TNFR1 PLAD reduce homologous interactions but can enhance antagonism of wild-type TNFR1 activity.

The tumour necrosis factor receptor superfamily (TNFRSF) members contain cysteine-rich domains (CRD) in their extracellular regions, and the membrane-distal CRD1 forms homologous interactions in the absence of ligand. The CRD1 is therefore termed a pre-ligand assembly domain (PLAD). The role of PLAD-PLAD interactions in the induction of signalling as a consequence of TNF-TNFR binding led to the development of soluble PLAD domains as antagonists of TNFR activation. In the present study, we generated recombinant wild-type (WT) PLAD of TNFR1 and mutant forms with single alanine substitutions of amino acid residues thought to be critical for the formation of homologous dimers and/or trimers of PLAD (K19A, T31A, D49A and D52A). These mutated PLADs were compared with WT PLAD as antagonists of TNF-induced apoptosis or the activation of inflammatory signalling pathways. Unlike WT PLAD, the mutated PLADs showed little or no homologous interactions, confirming the importance of particular amino acids as contact residues in the PLAD binding region. However, as with WT PLAD, the mutated PLADs functioned as antagonists of TNF-induced TNFR1 activity leading to induction of cell death or NF-κB signalling. Indeed, some of the mutant PLADs, and K19A PLAD in particular, showed enhanced antagonistic activity compared with WT PLAD. This is consistent with the reduced formation of homologous multimers by these PLAD mutants effectively increasing the concentration of PLAD available to bind and antagonize WT TNFR1 when compared to WT PLAD acting as an antagonist. This may have implications for the development of antagonistic PLADs as therapeutic agents.

Assessment of the Efficacy of Olive Leaf (Olea europaea L.) Extracts in the Treatment of Colorectal Cancer and Prostate Cancer Using In Vitro Cell Models.

Cancer is one of the most serious public health issues worldwide, ranking second only to cardiovascular diseases as a cause of death. Numerous plant extracts have extraordinary health benefits and have been used for centuries to treat a variety of ailments with few side effects. Olive leaves have a long history of medicinal and therapeutic use. In this study, the anti-cancer properties of an olive leaf extract were investigated in vitro using colorectal and prostate cancer cell lines (HT29 and PC3, respectively). A high-performance liquid chromatography analysis showed that the olive leaf extract contained a high chlorogenic acid content. Accordingly, chlorogenic acid may be related to the observed effects of the aqueous extract on cancer cells, including increased inhibition of cancer cell growth, migration, DNA fragmentation, cell cycle arrest at the S phase, reactive oxygen species (ROS) production, and altered gene expression. The effects of the extracts were greater in HT29 than in PC3 cells. These results suggest that chlorogenic acid, the main constituent in the olive extract, is a promising new anti-cancer agent. Further analyses should focus on its in vivo effects on colorectal tumor models, both alone and in combination with established agents.

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.

Current approaches used in treating COVID-19 from a molecular mechanisms and immune response perspective.

Coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared by the World Health Organization (WHO) as a global pandemic on March 11, 2020. SARS-CoV-2 targets the respiratory system, resulting in symptoms such as fever, headache, dry cough, dyspnea, and dizziness. These symptoms vary from person to person, ranging from mild to hypoxia with acute respiratory distress syndrome (ARDS) and sometimes death. Although not confirmed, phylogenetic analysis suggests that SARS-CoV-2 may have originated from bats; the intermediary facilitating its transfer from bats to humans is unknown. Owing to the rapid spread of infection and high number of deaths caused by SARS-CoV-2, most countries have enacted strict curfews and the practice of social distancing while awaiting the availability of effective U.S. Food and Drug Administration (FDA)-approved medications and/or vaccines. This review offers an overview of the various types of coronaviruses (CoVs), their targeted hosts and cellular receptors, a timeline of their emergence, and the roles of key elements of the immune system in fighting pathogen attacks, while focusing on SARS-CoV-2 and its genomic structure and pathogenesis. Furthermore, we review drugs targeting COVID-19 that are under investigation and in clinical trials, in addition to progress using mesenchymal stem cells to treat COVID-19. We conclude by reviewing the latest updates on COVID-19 vaccine development. Understanding the molecular mechanisms of how SARS-CoV-2 interacts with host cells and stimulates the immune response is extremely important, especially as scientists look for new strategies to guide their development of specific COVID-19 therapies and vaccines.

Genome-Wide Identification of lncRNA and mRNA for Diagnosing Type 2 Diabetes in Saudi Arabia.

Purpose: According to the World Health Organization, Saudi Arabia ranks seventh worldwide in the number of patients with diabetes mellitus. To our knowledge, no research has addressed the potential of noncoding RNA as a diagnostic and/or management biomarker for patients with type 2 diabetes mellitus (T2DM) living in high-altitude areas. This study aimed to identify molecular biomarkers influencing patients with T2DM living in high-altitude areas by analyzing lncRNA and mRNA. Patients and Methods: RNA sequencing and bioinformatics analyses were used to identify significantly expressed lncRNAs and mRNAs in T2DM and healthy control groups. Coding potential was analyzed using coding-noncoding indices, the coding potential calculator, and PFAM, and the lncRNA function was predicted using Pearson's correlation. Differentially expressed transcripts between the groups were identified, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the biological functions of both lncRNAs and mRNAs. Results: We assembled 1766 lncRNAs in the T2DM group, of which 582 were novel. This study identified three lncRNA target genes (KLF2, CREBBP, and REL) and seven mRNAs (PIK3CD, PIK3R5, IL6R, TYK2, ZAP70, LAMTOR4, and SSH2) significantly enriched in important pathways, playing a role in the progression of T2DM. Conclusion: To the best of our knowledge, this comprehensive study is the first to explore the applicability of certain lncRNAs as diagnostic or management biomarkers for T2DM in females in Taif City, Saudi Arabia through the genome-wide identification of lncRNA and mRNA profiling using RNA seq and bioinformatics analysis. Our findings could help in the early diagnosis of T2DM and in designing effective therapeutic targets.

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.

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.

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.