Unraveling Multicopper [Cu3] and [Cu6] Clusters with Rare µ3-Sulfato and Linear µ2-Oxido-Bridges as Potent Antibiofilm Agents against Multidrug-Resistant Staphylococcus aureus.

In this research article, two multicopper [Cu3] and [Cu6] clusters, [Cu3(cpdp)(µ3-SO4)(Cl)(H2O)2]·3H2O (1) and [Cu6(cpdp)2(µ2-O)(Cl)2(H2O)4]·2Cl (2) (H3cpdp = N,N'-bis[2-carboxybenzomethyl]-N,N'-bis[2-pyridylmethyl]-1,3-diaminopropan-2-ol), have been explored as potent antibacterial and antibiofilm agents. Their molecular structures have been determined by a single-crystal X-ray diffraction study, and the compositions have been established by thermal and elemental analyses, including electrospray ionization mass spectrometry. Structural analysis shows that the metallic core of 1 is composed of a trinuclear [Cu3] assembly encapsulating a µ3-SO42- group, whereas the structure of 2 represents a hexanuclear [Cu6] assembly in which two trinuclear [Cu3] motifs are exclusively bridged by a linear µ2-O2- group. The most striking feature of the structure of 2 is the occurrence of an unusual linear oxido-bridge, with the Cu3-O6-Cu3' bridging angle being 180.00°. Whereas 1 can be viewed as an example of a copper(II)-based compound displaying a rare µ3:η1:η1:η1 bridging mode of the SO42- group, 2 is the first example of any copper(II)-based compound showing an unsupported linear Cu-O-Cu oxido-bridge. Employing variable-temperature SQUID magnetometry, the magnetic susceptibility data were measured and analyzed exemplarily for 1 in the temperature range of 2-300 K, revealing the occurrence of antiferromagnetic interactions among the paramagnetic copper centers. Both 1 and 2 exhibited potent antibacterial and antibiofilm activities against methicillin-resistant Staphylococcus aureus (MRSA BAA1717) and the clinically isolated culture of methicillin-resistant S. aureus (MRSA CI1). The mechanism of antibacterial and antibiofilm activities of these multicopper clusters was investigated by analyzing and determining the intracellular reactive oxygen species (ROS) generation, lipid peroxidation, microscopic observation of cell membrane disruption, membrane potential, and leakage of cellular components. Additionally, 1 and 2 showed a synergistic effect with commercially available antibiotics such as vancomycin with enhanced antibacterial activity. However, 1 possesses higher antibacterial, antibiofilm, and antivirulence actions, making it a potent therapeutic agent against both MRSA BAA1717 and MRSA CI1 strains.

The protective effects of nerol to prevent the toxicity of carbon tetrachloride to the liver in Sprague-Dawley rats.

Introduction: Carbon-tetrachloride (CCl4) is well-known to cause liver damage due to severe oxidative stress. Nerol, on the other hand, is a monoterpene that is antioxidant, antiviral, antibacterial, anti-inflammatory, and anxiolytic. This study set out to determine if nerol may be used as a prophylactic measure against the oxidative stress mediated hepatic injury caused by CCl4. Materials and methods: For the aim of this experiment, 35 male Sprague-Dawley rats ranging in body weight (BW) from 140 to 180 g were split into five separate groups. With the exception of vehicle control group 1, all experimental rats were subjected to carbon tetrachloride exposure through intra-peritoneal injection at a 0.7 mL/kg body weight dose once a week for 4 weeks (28 days). The treatment groups 3 and 4 received oral administration of nerol at 50 and 100 mg/kg BW for 28 days. In the same time period, the standard control group received 100 mg/kg BW silymarin. Results: Serum hepatic markers, lipid profiles, albumin, globulin, bilirubin, and total protein were all substantially improved in nerol-treated rats in a dose-dependent manner that had been exposed to CCl4 compared to the only CCl4-treated group. Carbon tetrachloride-exposed rats had lower glutathione, superoxide dismutase, and catalase levels and higher thio-barbituric acid reactive substances (TBARS) levels than normal rats. In contrast, administration of nerol shown a significant augmentation in the concentrations of these antioxidant compounds, while concurrently inducing a decline in the levels of TBARS in the hepatic tissue. In a similar vein, the histo-pathological examination yielded further evidence indicating that nerol offered protection to the hepatocyte against damage generated by CCl4. Conclusion: According to the findings of our investigation, nerol has potential as a functional element to shield the liver from harm brought on by ROS that are caused by CCL4.

The efficacy of natural bioactive compounds against prostate cancer: Molecular targets and synergistic activities.

Globally, prostate cancer (PCa) is regarded as a challenging health issue, and the number of PCa patients continues to rise despite the availability of effective treatments in recent decades. The current therapy with chemotherapeutic drugs has been largely ineffective due to multidrug resistance and the conventional treatment has restricted drug accessibility to malignant tissues, necessitating a higher dosage resulting in increased cytotoxicity. Plant-derived bioactive compounds have recently attracted a great deal of attention in the field of PCa treatment due to their potent effects on several molecular targets and synergistic effects with anti-PCa drugs. This review emphasizes the molecular mechanism of phytochemicals on PCa cells, the synergistic effects of compound-drug interactions, and stem cell targeting for PCa treatment. Some potential compounds, such as curcumin, phenethyl-isothiocyanate, fisetin, baicalein, berberine, lutein, and many others, exert an anti-PCa effect via inhibiting proliferation, metastasis, cell cycle progression, and normal apoptosis pathways. In addition, multiple studies have demonstrated that the isolated natural compounds: d-limonene, paeonol, lanreotide, artesunate, and bicalutamide have potential synergistic effects. Further, a significant number of natural compounds effectively target PCa stem cells. However, further high-quality studies are needed to firmly establish the clinical efficacy of these phytochemicals against PCa.

Mikania micrantha Kunth: An Ethnopharmacological Treasure Trove of Therapeutic Potential.

Mikania micrantha is utilized as a therapeutic for the treatment of various human ailments including insect bites, rashes and itches of skin, chicken pox, healing of sores and wounds, colds and fever, nausea, jaundice, rheumatism, and respiratory ailments. This study aimed at summarizing the traditional uses, phytochemical profile, and biological activities of M. micrantha based on obtainable information screened from different databases. An up-to-date search was performed on M. micrantha in PubMed, Science Direct, clinicaltrials.gov, and Google Scholar databases with specific keywords. No language restrictions were imposed. Published articles, theses, seminar/conference papers, abstracts, and books on ethnobotany, phytochemistry and pharmacological evidence were considered. Based on the inclusion criteria, this study includes 53 published records from the above-mentioned databases. The results suggest that fresh leaves and whole plant are frequently used in folk medicine. The plant contains more than 150 different phytochemicals under the following groups: essential oils, phenolics and flavonoids, terpenes, terpene lactones, glycosides, and sulfated flavonoids. It contains carbohydrates and micronutrients including vitamins and major and trace minerals. M. micrantha possesses antioxidant, anti-inflammatory, anti-microbial, anti-dermatophytic, anti-protozoal, anthelmintic, cytotoxic, anxiolytic, anti-diabetic, lipid-lowering and antidiabetic, spasmolytic, memory-enhancing, wound-healing, anti-aging, and thrombolytic activities. No clinical studies have been reported to date. M. micrantha might be one of the potential sources of phytotherapeutic compounds against diverse ailments in humans. Studies are required to confirm its safety profile in experimental animals prior to initiating clinical trials. Moreover, adequate investigation is also crucial to clarify exact mechanism of action for each biological effect.

TRPM2-mediated Ca2+ signaling as a potential therapeutic target in cancer treatment: an updated review of its role in survival and proliferation of cancer cells.

The transient receptor potential melastatin subfamily member 2 (TRPM2), a thermo and reactive oxygen species (ROS) sensitive Ca2+-permeable cation channel has a vital role in surviving the cell as well as defending the adaptability of various cell groups during and after oxidative stress. It shows higher expression in several cancers involving breast, pancreatic, prostate, melanoma, leukemia, and neuroblastoma, indicating it raises the survivability of cancerous cells. In various cancers including gastric cancers, and neuroblastoma, TRPM2 is known to conserve viability, and several underlying mechanisms of action have been proposed. Transcription factors are thought to activate TRPM2 channels, which is essential for cell proliferation and survival. In normal physiological conditions with an optimal expression of TRPM2, mitochondrial ROS is produced in optimal amounts while regulation of antioxidant expression is carried on. Depletion of TRPM2 overexpression or activity has been shown to improve ischemia-reperfusion injury in organ levels, reduce tumor growth and/or viability of various malignant cancers like breast, gastric, pancreatic, prostate, head and neck cancers, melanoma, neuroblastoma, T-cell and acute myelogenous leukemia. This updated and comprehensive review also analyzes the mechanisms by which TRPM2-mediated Ca2+ signaling can regulate the growth and survival of different types of cancer cells. Based on the discussion of the available data, it can be concluded that TRPM2 may be a unique therapeutic target in the treatment of several types of cancer. Video Abstract.

Design, Synthesis and Evaluation of a Series of Zinc(II) Complexes of Anthracene-Affixed Multifunctional Organic Assembly as Potential Antibacterial and Antibiofilm Agents against Methicillin-Resistant Staphylococcus aureus.

A novel class of zinc(II)-based metal complexes, i.e., [Zn2(acdp)(µ-Cl)]·2H2O (1), [Zn2(acdp)(µ-NO3)]·2H2O (2), and [Zn2(acdp)(µ-O2CCF3)]·2H2O (3) (Cl- = chloride; NO3- = nitrate; CF3CO2- = trifluoroacetate) of anthracene-affixed multifunctional organic assembly, H3acdp (H3acdp = N,N'-bis[anthracene-2-ylmethyl]-N,N'-bis[carboxymethyl]-1,3-diaminopropan-2-ol), have emerged as promising antibacterial and antibiofilm agents in the domain of medicinal chemistry. Accordingly, complexes 1-3 were synthesized by utilizing H3acdp in combination with ZnCl2, Zn(NO3)2·6H2O, and Zn(CF3CO2)2·H2O respectively, in the presence of NaOH at ambient temperature. The complexation between H3acdp and Zn2+ was delineated by a combined approach of spectrophotometric and spectrofluorometric titration studies. The stoichiometry of acdp3-/Zn2+ in all three complexes is observed to be 1:2, as confirmed by spectrophotometric/spectrofluorometric titration data. Elemental analysis (C, H, N, Zn), molar conductance, FTIR, UV-vis, and thermoanalytical (TGA/DTA) data were effectively used to characterize these complexes. Besides, the structures of 1-3 were established by density functional theory (DFT) calculation using B3LYP/6-311G, specifying a self-assembled compact geometry with average Zn···Zn separation of 3.4629 Å. All three zinc complexes exhibited significantly high antibacterial and antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA BAA1717). However, complex 1 showed a more recognizable activity than 2 and 3, with minimum inhibitory concentration (MIC) values of 200, 350, and 450 µg/mL, respectively. The antimicrobial activity was tested by employing the minimum inhibitory concentration (MIC) and time-kill assay. The crystal violet (CV) assay and microscopic study were performed to examine the antibiofilm activity. As observed, complexes 1-3 had an effect on the production of extracellular polymeric substance (EPS), biofilm cell-viability, and other virulence factors such as staphyloxanthin and hemolysin production, autoaggregation ability, and microbial cell-surface hydrophobicity. Reactive oxygen species (ROS) generated due to inhibition of staphyloxanthin production in response to 1-3 were also analyzed. Moreover, complexes 1-3 showed an ability to damage the bacterial cell membrane due to accumulation of ROS resulting in DNA leakage. In addition, complexes 1-3 displayed a synergistic/additive activity with a commercially available antibiotic drug, vancomycin, with enhanced antibacterial activity. On the whole, our investigation disclosed that complex 1 could be a promising drug lead and attract much attention to medicinal chemists compared to 2 and 3 from therapeutic aspects.

Citrinin as a potential anti-cancer therapy: A comprehensive review.

Citrinin (CIT) is a polyketide-derived mycotoxin, which is produced by many fungal strains belonging to the gerena Monascus, Aspergillus, and Penicillium. It has been postulated that mycotoxins have several toxic mechanisms and are potentially used as antineoplastic agents. Therefore, the present study carried out a systematic review, including articles from 1978 to 2022, by collecting evidence in experimental studies of CIT antiplorifactive activity in cancer. The Data indicate that CIT intervenes in important mediators and cell signaling pathways, including MAPKs, ERK1/2, JNK, Bcl-2, BAX, caspases 3,6,7 and 9, p53, p21, PARP cleavage, MDA, reactive oxygen species (ROS) and antioxidant defenses (SOD, CAT, GST and GPX). These factors demonstrate the potential antitumor drug CIT in inducing cell death, reducing DNA repair capacity and inducing cytotoxic and genotoxic effects in cancer cells.

Therapeutic strategies for rheumatic diseases and disorders: targeting redox imbalance and oxidative stress.

Rheumatic diseases and disorders (RDDs) are a group of chronic autoimmune diseases that are collectively called "multicausal diseases". They have resulted from predisposing genetic profiles and exposure to a range of environmental, occupational and lifestyle risk factors. Other causative factors include bacterial and viral attacks, sexual habits, trauma, etc. In addition, numerous studies reported that redox imbalance is one of the most serious consequences of RDDs. For example, rheumatoid arthritis (RA) as a classic example of chronic RDDs is linked to oxidative stress. This paper summarizes the contributions of redox imbalance to RDDs. The findings suggest that establishing direct or indirect therapeutic strategies for RDDs requires a more in-depth understanding of the redox dysregulation in these diseases. For example, the recent awareness of the roles of peroxiredoxins (Prdxs, e.g. Prdx2, Prdx3) in RDDs provided one potential route of therapeutic intervention of these pathologies. Changes in stressful lifestyles and dietary habits may also provide additional benefits in the management of RDDs. Future studies should be directed to explore molecular interactions in redox regulations associated with RDDS and potential therapeutic interventions.

Hepatoprotective activity of andrographolide possibly through antioxidative defense mechanism in Sprague-Dawley rats.

The aims of this study to assess the efficiency of AGL against acetaminophen (APAP)-induced hepatic toxicity that was generated by mitochondrial oxidative stress and glutathione depletion. Free radical scavenging potentiality was analyzed by using 2, 2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide, nitric oxide, and hydroxyl radical scavenging assays. APAP-induced liver toxicity was formed at a dose level of 640 mg/kg mg/kg BW each, p.o. for 14 days for all experimental rats except the vehicle control group. AGL (5 and 10 mg/kg) were treated orally with negative control and negative control silymarin (50 mg/kg) group. To assess the protective effect, we looked at the levels of serum biochemical markers, liver histoarchitecture, and hepatic antioxidant enzyme activity. AGL showed in vitro anti-oxidant potentialities by scavenging radicals in the respective assays. As evidenced by serum biochemical indicators and relative liver weight, AGL co-administration substantially reduced toxicant-induced hepatic damage. APAP-intoxication increased the malondialdehyde (MDA) level and declined in cellular endogenous antioxidant enzymes such as reduced catalase, superoxide dismutase, and glutathione, where, AGL treatment amended their level. In the same way, histopathological evaluation further verified that AGL protected the hepatocyte from APAP-induced damage. As AGL scavenges toxic free radicals, thereby protects mitochondria and other organelles from reactive oxygen and nitrogen species-mediated stress and its eventual consequence necrosis. Therefore, we propose the hepatoprotective activity of AGL through its antioxidant mechanism.

Anxiolytic-like Effect of Quercetin Possibly through GABA Receptor Interaction Pathway: In Vivo and In Silico Studies.

Scientific evidence suggests that quercetin (QUR) has anxiolytic-like effects in experimental animals. However, the mechanism of action responsible for its anxiolytic-like effects is yet to be discovered. The goal of this research is to assess QUR's anxiolytic effects in mouse models to explicate the possible mechanism of action. After acute intraperitoneal (i.p.) treatment with QUR at a dose of 50 mg/kg (i.p.), behavioral models of open-field, hole board, swing box, and light-dark tests were performed. QUR was combined with a GABAergic agonist (diazepam) and/or antagonist (flumazenil) group. Furthermore, in silico analysis was also conducted to observe the interaction of QUR and GABA (α5), GABA (ß1), and GABA (ß2) receptors. In the experimental animal model, QUR had an anxiolytic-like effect. QUR, when combined with diazepam (2 mg/kg, i.p.), drastically potentiated an anxiolytic effect of diazepam. QUR is a more highly competitive ligand for the benzodiazepine recognition site that can displace flumazenil (2.5 mg/kg, i.p.). In all the test models, QUR acted similar to diazepam, with enhanced effects of the standard anxiolytic drug, which were reversed by pre-treatment with flumazenil. QUR showed the best interaction with the GABA (α5) receptor compared to the GABA (ß1) and GABA (ß2) receptors. In conclusion, QUR may exert an anxiolytic-like effect on mice, probably through the GABA-receptor-interacting pathway.

GC-MS analysis, and evaluation of protective effect of Piper chaba stem bark against paracetamol-induced liver damage in Sprague-Dawley rats: Possible defensive mechanism by targeting CYP2E1 enzyme through in silico study.

The present study attempted to scrutinize the protective effect of the methanolic extract of P. chaba stem bark against paracetamol-induced hepatotoxicity in Sprague-Dawley rats, along with the gas chromatography-mass spectrometry (GC-MS) analysis to identify phytochemicals, which were further docked in the catalytic site of CYP2E1 and the MD simulation for system that plays a major role in the bio-activation of toxic substances that produce reactive metabolites, leading to hepatotoxicity. P. chaba stem methanol extract (250 and 500 mg/kg) were treated orally with the negative control and the negative control silymarin (50 mg/kg) groups. Phytochemical profiling was conducted using GC-MS. In in-silico studies, PyRx software was used for docking analysis and the stability of the binding mode in the target active sites was evaluated through a set of standard MD-simulation protocols using the Charmm 27 force field and Swiss PARAM. Co-administration of P. chaba at both doses with APAP significantly reduced the APAP-augmented liver marker enzymes ALT, AST, ALP, and LDH, along with serum albumin, globulin, hepatic enzymes, histopathological architecture, lipid profiles, total protein, and total bilirubin, and elevated the levels of MDA. The GC-MS analysis indicated that P. chaba extract is enriched in fatty acid methyl esters (46.23 %) and alkaloids (10.91 %) and piperine is represented as a main phytochemical. Among all the identified phytochemicals, piperine (-8.0 kcal/mol) was found to be more interacting and stable with the binding site of CYP2E1. Therefore, all of our findings may conclude that the P. chaba stem extract and its main compound, piperine, are able to neutralize APAP-induced hepatic damage.

Propolis: An update on its chemistry and pharmacological applications.

Propolis, a resinous substance produced by honeybees from various plant sources, has been used for thousands of years in traditional medicine for several purposes all over the world. The precise composition of propolis varies according to plant source, seasons harvesting, geography, type of bee flora, climate changes, and honeybee species at the site of collection. This apiary product has broad clinical applications such as antioxidant, anti-inflammatory, antimicrobial, anticancer, analgesic, antidepressant, and anxiolytic as well asimmunomodulatory effects. It is also well known from traditional uses in treating purulent disorders, improving the wound healing, and alleviating many of the related discomforts. Even if its use was already widespread since ancient times, after the First and Second World War, it has grown even more as well as the studies to identify its chemical and pharmacological features, allowing to discriminate the qualities of propolis in terms of the chemical profile and relative biological activity based on the geographic place of origin. Recently, several in vitro and in vivo studies have been carried out and new insights into the pharmaceutical prospects of this bee product in the management of different disorders, have been highlighted. Specifically, the available literature confirms the efficacy of propolis and its bioactive compounds in the reduction of cancer progression, inhibition of bacterial and viral infections as well as mitigation of parasitic-related symptoms, paving the way to the use of propolis as an alternative approach to improve the human health. However, a more conscious use of propolis in terms of standardized extracts as well as new clinical studies are needed to substantiate these health claims.

Natural Compounds or Their Derivatives against Breast Cancer: A Computational Study.

Background: Breast cancer is one of the most common types of cancer diagnosed and the second leading cause of death among women. Breast cancer susceptibility proteins of type 1 and 2 are human tumor suppressor genes. Genetic variations/mutations in these two genes lead to overexpression of human breast tumor suppressor genes (e.g., BRCA1, BRCA2), which triggers uncontrolled duplication of cells in humans. In addition, multidrug resistance protein 1 (MDR1), an important cell membrane protein that pumps many foreign substances from cells, is also responsible for developing resistance to cancer chemotherapy. Aim of the Study. The aim of this study was to analyze some natural compounds or their derivatives as part of the development of strong inhibitors for breast cancer. Methodology. Molecular docking studies were performed using compounds known in the literature to be effective against BRCA1 and BRCA2 and MDR1, with positive control being 5-fluorouracil, an antineoplastic drug as a positive control. Results: The binding affinity of the compounds was analyzed, and it was observed that they had a better binding affinity for the target proteins than the standard drug 5-fluorouracil. Among the compounds analyzed, α-hederin, andrographolide, apigenin, asiatic acid, auricular acid, sinularin, curcumin, citrinin, hispolon, nerol, phytol, retinol palmitate, and sclareol showed the best binding affinity energy to the BRCA1, BRCA2, and MDR1 proteins, respectively. Conclusions: α-Hederin, andrographolide, apigenin, asiatic acid, auricular acid, hispolon, sclareol, curcumin, citrinin, and sinularin or their derivatives can be a good source of anticancer agents in breast cancer.

Evaluation of mutagenesis, necrosis and apoptosis induced by omeprazole in stomach cells of patients with gastritis.

BACKGROUND: Gastritis is a superficial and prevalent inflammatory lesion that is considered a public health concern once can cause gastric ulcers and gastric cancer, especially when associated with Helicobacter pylori infection. Proton pump inhibitors, such as omeprazole, are the most widely used drugs to treat this illness. The aim of the study was evaluate cytogenetic effects of omeprazole in stomach epithelial cells of patients with gastritis in presence and absence of H. pylori, through cytogenetic biomarkers and catalse and superoxide dismutase analysis. METHODS: The study included 152 patients from the Gastroenterology Outpatient Clinic of Hospital Getúlio Vargas, Teresina-Brazil, that reported continuous and prolonged omeprazole use in doses of 20, 30 and 40 mg/kg. The participants were divided into groups: (1) patients without gastritis (n = 32); (2) patients without gastritis but with OME use (n = 24); (3) patients with gastritis (n = 26); (4) patients with gastritis undergoing OME therapy (n = 26); (5) patients with gastritis and H. pylori (n = 22) and (6) patients with gastritis and H. pylori on OME therapy (n = 22). RESULTS: OME induced cytogenetic imbalance in the stomach epithelium through the formation of micronuclei (group 6 > 1, 2, 3, 4, 5; group 5 > 1, 2, 3; group 4 > 1, 2, 3); bridges (groups 4 and 6 > 1, 2, 3, 5 and group 2 > 3, 5); buds (groups 2,4,6 > , 1, 3, 5); binucleated cells (group 6 > 1, 2, 3, 4, 5; group 4 > 1, 2, 3); (groups 2 and 3 > 1); picnoses (group 6 > 1, 2, 3, 4, 5), groups 2 and 5 > 1, 3; group 4 > 1, 2, 3, 5); cariorrexis (groups 6 and 4 > 1, 2, 3, 5; groups 2, 3, 5 > 1) and karyolysis (groups 2, 4, and 6 > 1, 3, 5; groups 3 and 5 > 1). The OME cytogenetic instability was associated with H. pylori infection, indicating clastogenic/aneugenic effects, chromosomes alterations, gene expression changes, cytotoxicity and apoptosis. CONCLUSIONS: The cytogenetic changescan be attributed to several mechanisms that are still unclear, including oxidative damage, as observed by increased catalase and superoxide dismutase expresion. Positive correlations between antioxidant enzymes were found with micronuclei formation, and were negative for picnoses. Thus, the continuous and prolonged omeprazole use induces genetic instability, which can be monitored through cytogenetic analyzes, as precursor for gastric cancer.

Activities and Molecular Mechanisms of Diterpenes, Diterpenoids, and Their Derivatives in Rheumatoid Arthritis.

Diterpenes and their derivatives have many biological activities, including anti-inflammatory and immunomodulatory effects. To date, several diterpenes, diterpenoids, and their laboratory-derived products have been demonstrated for antiarthritic activities. This study summarizes the literature about diterpenes and their derivatives acting against rheumatoid arthritis (RA) depending on the database reports until 31 August 2021. For this, we have conducted an extensive search in databases such as PubMed, Science Direct, Google Scholar, and Clinicaltrials.gov using specific relevant keywords. The search yielded 2708 published records, among which 48 have been included in this study. The findings offer several potential diterpenes and their derivatives as anti-RA in various test models. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways. In addition, some important derivatives of triptolide and tanshinone IIA have also been shown to have anti-RA effects. Overall, findings suggest that these substances could reduce arthritis score, downregulate oxidative, proinflammatory, and inflammatory biomarkers, modulate various arthritis pathways, and improve joint destruction and clinical arthritic conditions, signs, symptoms, and physical functions in humans and numerous experimental animals, mainly through cytokine and chemokine as well as several physiological protein interaction pathways. Taken all together, diterpenes, diterpenoids, and their derivatives may be promising tools for RA management.

Redox Activity of Flavonoids: Impact on Human Health, Therapeutics, and Chemical Safety.

The cost-effectiveness of presently used therapies is a problem in overall redox-based management, which is posing a significant financial burden on communities across the world. As a result, sophisticated treatment models that provide notions of predictive diagnoses followed by targeted preventive therapies adapted to individual patient profiles are gaining global acclaim as being beneficial to patients, the healthcare sector, and society as a whole. In this context, natural flavonoids were considered due to their multifaceted antioxidant, anti-inflammatory, and anticancer effects as well as their low toxicity and ease of availability. The aim of this review is to focus on the capacity of flavonoids to modulate the responsiveness of various diseases and ailments associated with redox toxicity. The review will also focus on the flavonoids' pathway-based redox activity and the advancement of redox-based therapies as well as flavonoids' antioxidant characteristics and their influence on human health, therapeutics, and chemical safety. Research findings indicated that flavonoids significantly exhibit various redox-based therapeutic responses against several diseases such as inflammatory, neurodegenerative, cardiovascular, and hepatic diseases and various types of cancer by activating the Nrf2/Keap1 transcription system, suppressing the nuclear factor κB (NF-κB)/IκB kinase inflammatory pathway, abrogating the function of the Hsp90/Hsf1 complex, inhibiting the PTEN/PI3K/Akt pathway, and preventing mitochondrial dysfunction. Some flavonoids, especially genistein, apigenin, amentoflavone, baicalein, quercetin, licochalcone A, and biochanin A, play a potential role in redox regulation. Conclusions of this review on the antioxidant aspects of flavonoids highlight the medicinal and folk values of these compounds against oxidative stress and various diseases and ailments. In short, treatment with flavonoids could be a novel therapeutic invention in clinical trials, as we hope.

Ebselen suitably interacts with the potential SARS-CoV-2 targets: an in-silico approach.

Ebselen (SPI-1005) is an active selenoorganic compound that can be found potential inhibitory activity against different types of viral infections such as zika virus, influenza A virus, HCV, and HIV-1; and also be found to exhibit promising antiviral activity against SARS-CoV-2 in cell-based assays but its particular target action against specific non-structural and structural proteins of SARS-CoV-2 is unclear to date. The purpose of this study is to evaluate the anti-SARS-CoV-2 efficacy of Ebselen along with the determination of the specific target among the 12 most common target proteins of SARS-CoV-2. AutoDock Vina in PyRx platform was used for docking analysis against the 12 selected SARS-CoV-2 encoded drug targets. ADME profiling was examined by using SwissADME online server. The stability of binding mode in the target active sites was evaluated using molecular dynamics (MD) simulation studies through NAMD and Desmond package software application. In this docking study, we recognized that Ebselen possesses the highest affinity to N protein (C domain) (PDB ID: 6YUN) and PLpro (PDB ID: 6WUU) among the selected SARS-CoV-2 targets showing -7.4 kcal/mol binding energy. The stability of Ebselen-6YUN and Ebselen-6WUU was determined by a 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of these two complexes displayed stable root mean square deviation (RMSD), while root mean square fluctuations (RMSF) were also found to be consistent. This molecular docking study may propose the efficiency of Ebselen against SARS-CoV-2 to a significant extent which makes it a candidature of COVID-19 treatment.

In Silico Screening of Natural Products as Potential Inhibitors of SARS-CoV-2 Using Molecular Docking Simulation.

OBJECTIVE: To explore potential natural products against severe acute respiratory syndrome coronavirus (SARS-CoV-2) via the study of structural and non-structural proteins of human coronaviruses. METHODS: In this study, we performed an in-silico survey of 25 potential natural compounds acting against SARS-CoV-2. Molecular docking studies were carried out using compounds against 3-chymotrypsin-like protease (3CLPRO), papain-like protease (PLPRO), RNA-dependent RNA polymerase (RdRp), non-structural protein (nsp), human angiotensin converting enzyme 2 receptor (hACE2R), spike glycoprotein (S protein), abelson murine leukemia viral oncogene homolog 1 (ABL1), calcineurin-nuclear factor of activated T-cells (NFAT) and transmembrane protease serine 2. RESULTS: Among the screened compounds, amentoflavone showed the best binding affinity with the 3CLPRO, RdRp, nsp13, nsp15, hACE2R. ABL1 and calcineurin-NFAT; berbamine with hACE2R and ABL1; cepharanthine with nsp10, nsp14, nsp16, S protein and ABL1; glucogallin with nsp15; and papyriflavonol A with PLPRO protein. Other good interacting compounds were juglanin, betulinic acid, betulonic acid, broussooflavan A, tomentin A, B and E, 7-methoxycryptopleurine, aloe emodin, quercetin, tanshinone I, tylophorine and furruginol, which also showed excellent binding affinity towards a number of target proteins. Most of these compounds showed better binding affinities towards the target proteins than the standard drugs used in this study. CONCLUSION: Natural products or their derivatives may be one of the potential targets to fight against SARS-CoV-2.

Plant-derived alkaloids acting on dengue virus and their vectors: from chemistry to pharmacology.

Dengue is a mosquito-borne viral infection, with its prevention and control depending on effective vector control measures. At present, dengue virus (DENV) is an epidemic in more than 100 countries of Southeast Asia, Africa, Eastern Mediterranean, the Americas and the Western Pacific. Several alkaloids isolated from natural herbs can serve as a reservoir for antiDENV drug development. Traditionally, plant extracts rich in alkaloids are used for the treatment of fever and have also revealed antimicrobial activity against various pathogenic bacteria, fungi and virus. The present narrative review collates the literature-based scenario of alkaloids and derivatives acting on DENV. The mechanism of action of such alkaloids with antiDENV and vector activity is also discussed.

Ethnomedicinal Uses, Phytochemistry, and Therapeutic Potentials of Litsea glutinosa (Lour.) C. B. Robinson: A Literature-Based Review.

Litsea glutinosa (Lour.) C. B. Robinson, belonging to the family Lauraceae, is a multipurpose and fast-growing evergreen or deciduous tree that has been traditionally used for numerous purposes such as treatment for diarrhea, dysentery, abdominal pain, indigestion, gastroenteritis, edema, traumatic injuries, colds, arthritis, asthma, diabetes, pain relief, and poignant sexual power. This study aimed to summarize the chemical reports, folk values, and phytopharmacological activities of L. glutinosa, based on available information screened from diverse databases. An up-to-date electronic-based search was accomplished to obtain detailed information, with the help of several databases such as Google Scholar, Scopus, SpringerLink, Web of Science, ScienceDirect, ResearchGate, PubMed, ChemSpider, Elsevier, BioMed Central, and the USPTO, CIPO, INPI, Google Patents, and Espacenet, using relevant keywords. Outcomes advocate that, up to the present time, alkaloids, glycosides, and terpenoids are abundant in, and the most bioactive constituents of, this natural plant. Results demonstrated that L. glutinosa has various remarkable biological activities, including antioxidant, anti-inflammatory, anti-microbial, anticancer, antipyretic, anti-diabetic, analgesic, hepatoprotective, and wound-healing activity. One study revealed that L. glutinosa exhibited significant aphrodisiac and anti-infertility activity. Nevertheless, no clinical studies have been cited. Taken together, L. glutinosa may be one of the significant sources of bioactive constituents that could potentially lead to different effective pharmacological activities. On the other hand, future research should focus on clinical studies and several toxicity evaluations, such as sub-chronic toxicity, teratogenicity, and genotoxicity.