Sclareol antagonizes the sedative effect of diazepam in thiopental sodium-induced sleeping animals: In vivo and in silico studies.

BACKGROUND: Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and diazepam (DZP) in modulating sedation in the thiopental sodium-induced sleeping animal model, supported by in-silico molecular docking analysis. METHODS: The control, sclareol (5, 10 and 20 mg/kg), and the reference drugs [diazepam: 3 mg/kg and Caffeine (CAF): 10 mg/kg] were used in male albino mice. Then, sodium thiopental (40 mg/kg, i.p.) was administrated to induce sleep. The latent period, percentage of sleep incidence and modulation of latency were measured. Further, homology modeling of human γ-aminobutyric acid (GABA) was conducted examine the binding mode of GABA interaction with SCL, DZP, and CAF compounds RESULTS: SCL (low dose) slightly increased the sleep latency, while the higher dose significantly prolonged sleep latency. DZP, a GABAA receptor agonist, exhibited strong sleep-inducing properties, reducing sleep latency, and increasing sleeping time. Caffeine (CAF) administration prolonged sleep latency and reduced sleeping time, consistent with its stimulant effects. The combination treatments involving SCL, DZP, and CAF showed mixed effects on sleep parameters. The molecular docking revealed good binding affinities of SCL, DZP, and CAF for GABAA receptor subunits A2 and A5. CONCLUSIONS: Our findings highlighted the complex interplay between SCL, DZP, and CAF in regulating sleep behaviors and provided insights into potential combination therapies for sleep disorders.

Discovery of potent and selective activity-based probes (ABPs) for the deubiquitinating enzyme USP30.

Ubiquitin-specific protease 30 (USP30) is a deubiquitinating enzyme (DUB) localized at the mitochondrial outer membrane and involved in PINK1/Parkin-mediated mitophagy, pexophagy, BAX/BAK-dependent apoptosis, and IKKß-USP30-ACLY-regulated lipogenesis/tumorigenesis. A USP30 inhibitor, MTX652, has recently entered clinical trials as a potential treatment for mitochondrial dysfunction. Small molecule activity-based probes (ABPs) for DUBs have recently emerged as powerful tools for in-cell inhibitor screening and DUB activity analysis, and here, we report the first small molecule ABPs (IMP-2587 and IMP-2586) which can profile USP30 activity in cells. Target engagement studies demonstrate that IMP-2587 and IMP-2586 engage active USP30 at nanomolar concentration after only 10 min incubation time in intact cells, dependent on the presence of the USP30 catalytic cysteine. Interestingly, proteomics analyses revealed that DESI1 and DESI2, small ubiquitin-related modifier (SUMO) proteases, can also be engaged by these probes, further suggesting a novel approach to develop DESI ABPs.

Use of CRISPR/Cas9 with Homology-Directed Repair to Gene-Edit Topoisomerase IIß in Human Leukemia K562 Cells: Generation of a Resistance Phenotype.

DNA topoisomerase IIß (TOP2ß/180; 180 kDa) is a nuclear enzyme that regulates DNA topology by generation of short-lived DNA double-strand breaks, primarily during transcription. TOP2ß/180 can be a target for DNA damage-stabilizing anticancer drugs, whose efficacy is often limited by chemoresistance. Our laboratory previously demonstrated reduced levels of TOP2ß/180 (and the paralog TOP2α/170) in an acquired etoposide-resistant human leukemia (K562) clonal cell line, K/VP.5, in part due to overexpression of microRNA-9-3p/5p impacting post-transcriptional events. To evaluate the effect on drug sensitivity upon reduction/elimination of TOP2ß/180, a premature stop codon was generated at the TOP2ß/180 gene exon 19/intron 19 boundary (AGAA//GTAA→ATAG//GTAA) in parental K562 cells (which contain four TOP2ß/180 alleles) by CRISPR/Cas9 editing with homology-directed repair to disrupt production of full-length TOP2ß/180. Gene-edited clones were identified and verified by quantitative polymerase chain reaction and Sanger sequencing, respectively. Characterization of TOP2ß/180 gene-edited clones, with one or all four TOP2ß/180 alleles mutated, revealed partial or complete loss of TOP2ß mRNA/protein, respectively. The loss of TOP2ß/180 protein correlated with decreased (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid)-induced DNA damage and partial resistance in growth inhibition assays. Partial resistance to mitoxantrone was also noted in the gene-edited clone with all four TOP2ß/180 alleles modified. No cross-resistance to etoposide or mAMSA was noted in the gene-edited clones. Results demonstrated the role of TOP2ß/180 in drug sensitivity/resistance in K562 cells and revealed differential paralog activity of TOP2-targeted agents. SIGNIFICANCE STATEMENT: Data indicated that CRISPR/Cas9 editing of the exon 19/intron 19 boundary in the TOP2ß/180 gene to introduce a premature stop codon resulted in partial to complete disruption of TOP2ß/180 expression in human leukemia (K562) cells depending on the number of edited alleles. Edited clones were partially resistant to mitoxantrone and XK469, while lacking resistance to etoposide and mAMSA. Results demonstrated the import of TOP2ß/180 in drug sensitivity/resistance in K562 cells and revealed differential paralog activity of TOP2-targeted agents.

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.

In Vitro Antioxidant and In Vivo Hepatoprotective Properties of Wissadula periplocifolia Extract.

Wissadula periplocifolia (L.) Thwaites is a traditional medicinal plant belonging to the family Malvaceae, used in folk medicine for inflamed snake bites and bee stings. The current study was designed to investigate the in vitro antioxidant and in vivo anti-inflammatory and hepatoprotective activities of 80% ethanol extract of W. periplocifolia and its different fractions. The crude ethanolic extract (CEE) was then serially fractionated with petroleum ether fraction (PEF), chloroform fraction (CHF), and aqueous fraction (AQF). The antioxidant activity was assessed using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay, anti-inflammatory activity was determined in the xylene-induced ear edema model, and hepatoprotective activity was measured in the paracetamol-induced hepatic injury model. PEF showed a significant scavenging effect with an IC50 value of 33.5 µg/mL, followed by CEE (IC50 = 42.2 µg/mL), CHF (IC50 = 77 µg/mL), and AQF (IC50 = 80 µg/mL), compared to standard butylated hydroxytoluene (IC50 = 14.8 µg/mL). Both doses of CEE (250 and 500 mg/kg) could reduce ear edema by 41.3 and 50%, respectively, compared to standard diclofenac sodium (76.09%). Moreover, CEE significantly reduces the elevated liver enzymes (ALT, AST, and ALP), compared to control. Nevertheless, it elevated blood protein and reduced the blood bilirubin level (p < 0.01), compared to control. Histopathological studies also indicated significant protection of the liver from paracetamol-induced liver damage. In conclusion, W. periplocifolia could be a good source of antioxidant and hepatoprotective phytochemicals; meanwhile, toxicological and pharmacokinetic studies are recommended.

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.

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.

Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs).

Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

Subchronic Toxicity Study of Alternanthera philoxeroides in Swiss Albino Mice Having Antioxidant and Anticoagulant Activities.

Alternanthera philoxeroides, a tropical herb and edible vegetable, has been popular as a medicinal plant. Applying in vitro approach, we initially attempted to assess the phytochemicals, bioactive chemicals, as well as antioxidant and anticoagulant activities of this plant. Following that, the in vivo toxicological effects of methanolic extracts of A. philoxeroides using different doses on the kidney, heart, lung, liver, stomach, brain, and blood of female Swiss Albino mice were investigated. We estimated phytochemicals content as well as antioxidant activity through DPPH, NO, CUPRAC, and reducing power assays, followed by the anticoagulant activities of PT and aPTT and bioactive compounds using HPLC. To confirm the biocompatibility of A. philoxeroides extracts, histopathological and hematological parameters were examined in a mice model. Total phenol, flavonoid, and tannin content in A. philoxeroides was 181.75 ± 2.47 mg/g, 101.5 ± 3 .53 mg/g, and 68.58 ± 0.80 mg/g, respectively. Furthermore, the HPLC study confirmed the presence of four phenolic compounds: catechin, tannic acid, gallic acid, and vanillic acid. The methanolic extract of A. philoxeroides showed considerable antioxidant activity in all four antioxidant assay methods when compared to the standard. In comparison to ascorbic acid, A. philoxeroides also demonstrated a minor concentration-dependent ferric and cupric reduction activity. In vivo evaluation indicated that A. philoxeroides extracts (doses: 250, 500, and 1000 mg/kg) had no negative effects on the relative organ or body weight, or hematological indicators. Our study concluded that A. philoxeroides had significant antioxidant and anticoagulant activities and demonstrated no negative effects on the body or relative organ weight, histopathological, and hematological indices in the mouse model.

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.

UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology.

Breast cancer has the highest incidence and death rate among cancers in women worldwide. In particular, metastatic estrogen receptor negative (ER-) breast cancer and triple-negative breast cancer (TNBC) subtypes have very limited treatment options, with low survival rates. Ubiquitin carboxyl terminal hydrolase L1 (UCHL1), a ubiquitin C-terminal hydrolase belonging to the deubiquitinase (DUB) family of enzymes, is highly expressed in these cancer types, and several key reports have revealed emerging and important roles for UCHL1 in breast cancer. However, selective and potent small-molecule UCHL1 inhibitors have been disclosed only very recently, alongside chemical biology approaches to detect regulated UHCL1 activity in cancer cells. These tools will enable novel insights into oncogenic mechanisms driven by UCHL1, and identification of substrate proteins deubiquitinated by UCHL1, with the ultimate goal of realising the potential of UCHL1 as a drug target in breast cancer.

Light-mediated discovery of surfaceome nanoscale organization and intercellular receptor interaction networks.

The molecular nanoscale organization of the surfaceome is a fundamental regulator of cellular signaling in health and disease. Technologies for mapping the spatial relationships of cell surface receptors and their extracellular signaling synapses would unlock theranostic opportunities to target protein communities and the possibility to engineer extracellular signaling. Here, we develop an optoproteomic technology termed LUX-MS that enables the targeted elucidation of acute protein interactions on and in between living cells using light-controlled singlet oxygen generators (SOG). By using SOG-coupled antibodies, small molecule drugs, biologics and intact viral particles, we demonstrate the ability of LUX-MS to decode ligand receptor interactions across organisms and to discover surfaceome receptor nanoscale organization with direct implications for drug action. Furthermore, by coupling SOG to antigens we achieved light-controlled molecular mapping of intercellular signaling within functional immune synapses between antigen-presenting cells and CD8+ T cells providing insights into T cell activation with spatiotemporal specificity. LUX-MS based decoding of surfaceome signaling architectures thereby provides a molecular framework for the rational development of theranostic strategies.

Role of Citrus medica L. Fruits Extract in Combatting the Hematological and Hepatic Toxic Effects of Carbofuran.

Citrus medica L. is rich in numerous vital bioactive constituents, though it is an underutilized among the citrus genus. Therefore, the aim of the present investigation was to evaluate the protective role of the C. medica fruit (CMF) methanol extract against carbofuran (CF)-induced toxicity in experimental rats. In addition, this work aims at detecting and measuring polyphenolic compounds by means of high-performance liquid chromatography (HPLC) and evaluation of the antioxidant activity of this extract. For this, studies dealing with serum hematological and biochemical parameters, liver endogenous antioxidants, as well as hepatic histo-architectural features have been carried out to assess the protective ability of CMF against CF-induced toxicity. Additionally, total phenol, flavonoid, and antioxidant capability were measured and the antioxidant action was investigated using DPPH and nitric oxide radical scavenging assays as well as reducing power assessments. HPLC results revealed the presence of benzoic acid, cinnamic acid, gallic acid, quercetin, and salicylic acid in CMF extract. Furthermore, results showed that CMF has considerable total phenol, flavonoid, and antioxidant capability and exhibits significant free radical scavenging and reducing potentialities. On the other hand, CF intoxication of rats significantly altered the hematological and serum biochemical parameters with hepatocytes disruption. Carbofuran also caused an upsurge in malondialdehyde (MDA) level and a decline in hepatic cellular antioxidant enzymes levels in rats compared to the control group. Co-administration of CMF amended the anomalies and improved the histo-architectural arrangement of hepatocytes in treated groups. CMF also inhibited the alteration of endogenous antioxidant enzymes and MDA levels as compared to the carbofuran treated group and returned them to their normal state. Taken all together, results from this investigation highlight the protective role of CMF against CF-induced toxicity which might be attributed to the polyphenolic constituents of the extract.

Antioxidant mediated protective effect of Bridelia tomentosa leaf extract against carbofuran induced oxidative hepatic toxicity.

Bridelia tomentosa (B. tomentosa) is a traditional medicinal plant for treating diverse ailments. Hence, we designed our study to scrutinize the protective effect of the methanol extract of B. tomentosa leaf (BTL) against carbofuran-induced oxidative stress-mediated hepato-toxicity in Sprague-Dawley rats for the first time, along with the identification and quantification of phenolic acids and flavonoids by high-performance liquid chromatography (HPLC) and evaluation of antioxidant and antiradical activities of this extract. HPLC analysis confirmed the existence of tannic acid, gallic acid, salicylic acid, and naringin in B. tomentosa leaf extract which showed in-vitro antioxidant potentialities with DPPH, nitric oxide, hydrogen peroxide, and hydroxyl radical scavenging properties. Co-administration of B. tomentosa leaf extract with carbofuran showed dose-dependent significant protective effects of hepatic toxicity on serum markers such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl-transferase, lactate dehydrogenase, total bilirubin, total protein, albumin, globulin, lipid profile, urea, uric acid, and creatinine. Carbofuran intoxication also revealed an upsurge in malondialdehyde (MDA) and a decline in cellular endogenous antioxidant enzyme levels in rats compared with the control group. However, B. tomentosa leaf extract co-treatment increased the levels of hepatic antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, and amended the MDA level. Similarly, histopathological evaluation further assured that BTL could keep the hepatocyte from carbofuran-induced damage. Therefore, all of our findings may conclude that the phenolic acids and flavonoids of B. tomentosa leaf extract are responsible to neutralize the toxic free radical-mediated oxidative hepatic damages.

Heliotropium indicum L.: From Farm to a Source of Bioactive Compounds with Therapeutic Activity.

This study aimed to summarize the available data on the ethnomedicinal and phytopharmacological activities of Heliotropium indicum L. based on database reports. For this purpose, an up-to-date literature search was carried out in the Google Scholar, Scopus, Springer Link, Web of Science, ScienceDirect, ResearchGate, PubMed, Chem Spider, Elsevier, BioMed Central, and patent offices (e.g., USPTO, CIPO, NPI, Google patents, and Espacenet) for the published materials. The findings suggest that the plant contains many important phytochemicals, including pyrrolizidine alkaloids, indicine, echinitine, supinine, heleurine, heliotrine, lasiocarpine, acetyl indicine, indicinine, indicine N-oxide, cynoglossine, europine N-oxide, heleurine N-oxide, heliotridine N-oxide, heliotrine N-oxide, heliotrine, volatile oils, triterpenes, amines, and sterols. Scientific reports revealed that the herb showed antioxidant, analgesic, antimicrobial, anticancer, antituberculosis, antiplasmodial, anticataract, antifertility, wound healing, antiinflammatory, antinociceptive, antihyperglycemic, anthelmintic, diuretic, antitussive, antiglaucoma, antiallergic, and larvicidal activity. In conclusion, in vitro studies with animal models seem to show the potential beneficial effects of H. indicum against a wide variety of disorders and as a source of phytotherapeutic compounds. However, clinical studies are necessary to confirm the effects observed in animal models, determine the toxicity of the therapeutic dose and isolate the truly bioactive components.

Therapeutic perspectives of the black cumin component thymoquinone: A review.

The dietary phytochemical thymoquinone (TQ), belonging to the family of quinones, mainly obtained from the black and angular seeds of Nigella sativa, is one of the promising monoterpenoid hydrocarbons, which has been receiving massive attention for its therapeutic potential and pharmacological properties. It plays an important role as a chemopreventive and therapeutic agent in the treatment of various diseases and illnesses. The aim of this review is to present a summary of the most recent literature pertaining to the use of TQ for the prevention and treatment of various diseases along with possible mechanisms of action, and the potential use of this natural product as a complementary or alternative medicine. Research findings indicated that TQ exhibits numerous pharmacological activities including antioxidant, anti-inflammatory, cardioprotective, hepatoprotective, antidiabetic, neuroprotective, and anticancer, among others. Conclusions of this review on the therapeutic aspects of TQ highlight the medicinal and folk values of this compound against various diseases and ailments. In short, TQ could be a novel drug in clinical trials, as we hope.

Effects of nerol on paracetamol-induced liver damage in Wistar albino rats.

Nerol, a monoterpene is evident to possess diverse biological activities, including antioxidant, anti-microbial, anti-spasmodic, anthelmintic, and anti-arrhythmias. This study aims to evaluate its hepatoprotective effect against paracetamol-induced liver toxicity in a rat model. Five groups of rats (n = 7) were orally treated (once daily) with 0.05% tween 80 dissolved in 0.9% NaCl solution (vehicle), paracetamol 640 mg/kg (negative control), 50 mg/kg silymarin (positive control), or nerol (50 and 100 mg/kg) for 14 days, followed by the hepatotoxicity induction using paracetamol (PCM). The blood samples and livers of the animals were collected and subjected to biochemical and microscopical analysis. The histological findings suggest that paracetamol caused lymphocyte infiltration and marked necrosis, whereas maintenance of the normal hepatic structural was observed in group pre-treated with silymarin and nerol. The rats pre-treated with nerol significantly and dose-dependently reduced the hepatotoxic markers in animals. Nerol at 100 mg/kg significantly reversed the paracetamol-induced altered situations, including the liver enzymes, plasma proteins, antioxidant enzymes and serum bilirubin, lipid peroxidation (LPO) and cholesterol [e.g., total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c)] levels in animals. Taken together, nerol exerted significant hepatoprotective activity in rats in a dose-dependent manner. PCM-induced toxicity and nerol induced hepatoprotective effects based on expression of inflammatory and apoptosis factors will be future line of work for establishing the precise mechanism of action of nerol in Wistar albino rats.

Photochemical Probe Identification of a Small-Molecule Inhibitor Binding Site in Hedgehog Acyltransferase (HHAT)*.

The mammalian membrane-bound O-acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small-molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small-molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure-activity relationship investigation identified single enantiomer IMP-1575, the most potent HHAT inhibitor reported to-date, and guided design of photocrosslinking probes that maintained HHAT-inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small-molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed by kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP-1575 (Ki =38 nM) and a strategy for mapping small molecule interaction sites in MBOATs.

Evaluation of the Binding Affinity of Anti-Viral Drugs against Main Protease of SARS-CoV-2 Through a Molecular Docking Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a life intimidating viral infection caused by a positive sense RNA virus belonging to the Coronaviridae family, named severe acute respiratory distress syndrome coronavirus 2 (SARA-CoV-2). Since its outbreak in December 2019, the pandemic has spread to more than 200 countries, infected more than 26 million, and claimed the lives of more than 800,000 people. As a disease, COVID-19 can lead to severe and occasionally fatal respiratory problems in humans. Infection with this virus is associated with fever, cough, dyspnea, and muscle aches, and it may progress to pneumonia, multiple organ failure, and death. To date, there is no specific antiviral treatment against this virus. However, the main viral protease has been recently discovered and it is regarded as an appropriate target for antiviral agents in the search for the treatment of COVID-19, due to its pivotal role in polyproteins processing during viral replication. AIM: Consequently, this study intends to evaluate the effectiveness of FDA-approved anti-viral drugs against SARA-CoV-2 through a molecular docking study. METHODS: AutoDock Vina in PyRx platform was used for docking analysis against the main viral protease (Mpro) (PDB ID 6LU7), and Computed Atlas of Surface Topography of proteins (CASTp 3.0) was applied for detecting and characterizing cavities, pockets, and channels of this protein structure. RESULTS: Results revealed that among the conventional antiviral drugs, the protease inhibitors, lopinavir, amprenavir, indinavir, maraviroc, saquinavir, and daclatasvir showed high binding affinity and interacted with amino acid residues of the binding site. CONCLUSION: In conclusion, protease inhibitors may be effective potential antiviral agents against Mpro to combat SARS-CoV-2.