Effects of Acute and Repeated Dose Toxicity Profiling of Chelidonic Acid in Rats: in Silico and in Vivo Evidence.

Chelidonic acid is a phytoconstituent found in rhizomes of the perennial plant celandine. The current study aims to evaluate the acute and repeated dose oral toxicity study of chelidonic acid as per the OECD guidelines 425 and 407. The pharmacokinetic and toxicity profile of chelidonic acid was predicted using online servers and tools. A single dose of chelidonic acid (2000 mg/kg) was administered to female Wistar rats in an acute toxicity study, and the animals were monitored for 14 days. We studied the toxicity profile of chelidonic acid at 10, 20, and 40 mg/kg doses in Wistar rats for repeated dose toxicity (28 days). Clinical biochemistry, haematological, and urine parameters were estimated. A gross necropsy and histopathology were performed. A single oral dose of chelidonic acid (2000 mg/kg) showed no signs of toxicity or mortality. The Administration of chelidonic acid showed no significant alterations in haematological, biochemical, and urine parameters. The histopathology showed normal structure and architecture in all the vital organs. A gross necropsy of vital organs showed no signs of toxicity. The chelidonic acid was found to be safe at all selected dose levels in the acute and repeated dose toxicity study in rats.

In Silico Screening of Some Active Phytochemicals to Identify Promising Inhibitors Against SARS-CoV-2 Targets.

BACKGROUND: There are very few small-molecule drug candidates developed against SARS-CoV-2 that have been revealed since the epidemic began in November 2019. The typical medicinal chemistry discovery approach requires more than a decade of the year of painstaking research and development and a significant financial guarantee, which is not feasible in the challenge of the current epidemic. OBJECTIVE: This current study proposes to find and identify the most effective and promising phytomolecules against SARS-CoV-2 in six essential proteins (3CL protease, Main protease, Papain- Like protease, N-protein RNA binding domain, RNA-dependent RNA polymerase, and Spike receptor binding domain target through in silico screening of 63 phytomolecules from six different Ayurveda medicinal plants. METHODS: The phytomolecules and SARS-CoV-2 proteins were taken from public domain databases such as PubChem and RCSB Protein Data Bank. For in silico screening, the molecular interactions, binding energy, and ADMET properties were investigated. RESULTS: The structure-based molecular docking reveals some molecules' greater affinity towards the target than the co-crystal ligand. Our results show that tannic acid, cyanidin-3-rutinoside, zeaxanthin, and carbolactone are phytomolecules capable of inhibiting SARS-CoV-2 target proteins in the least energy conformations. Tannic acid had the least binding energy of -8.8 kcal/mol, which is better than the binding energy of its corresponding co-crystal ligand (-7.5 kcal/mol) against 3 CL protease. Also, it has shown the least binding energy of -9.9 kcal/mol with a more significant number of conventional hydrogen bond interactions against the RdRp target. Cyanidin-3-rutinoside showed binding energy values of -8.8 and -7.6 kcal/mol against Main protease and Papain-like protease, respectively. Zeaxanthin was the top candidate in the N protein RBD with a binding score of - 8.4 kcal/mol, which is slightly better when compared to a co-crystal ligand (-8.2 kcal/mol). In the spike, carbolactone was the suitable candidate with the binding energy of -7.2 kcal/mol and formed a conventional hydrogen bond and two hydrophobic interactions. The best binding affinity-scored phytomolecules were selected for the MD simulations studies. CONCLUSION: The present in silico screening study suggested that active phytomolecules from medicinal plants could inhibit SARS-CoV-2 targets. The elite docked compounds with drug-like properties have a harmless ADMET profile, which may help to develop promising COVID-19 inhibitors.

An In silico Investigation to Identify Promising Inhibitors for SARS-CoV-2 Mpro Target.

BACKGROUND: A limited number of small molecules against SARS-CoV-2 has been discovered since the epidemic commenced in November 2019. The conventional medicinal chemistry approach demands more than a decade of the year of laborious research and development and a substantial financial commitment, which is not achievable in the face of the current epidemic. OBJECTIVE: This study aims to discover and recognize the most effective and promising small molecules by interacting SARS-CoV-2 Mpro target through computational screening of 39 phytochemicals from five different Ayurvedic medicinal plants. METHODS: The phytochemicals were downloaded from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) PubChem, and the SARS-CoV-2 protein (PDB ID: 6LU7; Mpro) was taken from the PDB. The molecular interactions, binding energy, and ADMET properties were analyzed. RESULTS: The binding affinities were studied using a structure-based drug design of molecular docking, divulging 21 molecules possessing greater to equal affinity towards the target than the reference standard. Molecular docking analysis identified 13 phytochemicals, sennoside-B (-9.5 kcal/mol), isotrilobine (-9.4 kcal/mol), trilobine (-9.0 kcal/mol), serratagenic acid (-8.1 kcal/mol), fistulin (-8.0 kcal/mol), friedelin (-7.9 kcal/mol), oleanolic acid (-7.9 kcal/mol), uncinatone (-7.8 kcal/mol), 3,4-di- O-caffeoylquinic acid (-7.4 kcal/mol), clemaphenol A (-7.3 kcal/mol), pectolinarigenin (-7.2 kcal/mol), leucocyanidin (-7.2 kcal/mol), and 28-acetyl botulin (-7.2 kcal/mol) from ayurvedic medicinal plants phytochemicals possess greater affinity than the reference standard Molnupiravir (-7.0 kcal/mol) against SARS-CoV-2-Mpro. CONCLUSION: Two molecules, namely sennoside-B, and isotrilobine with low binding energies, were predicted as most promising. Furthermore, we carried out molecular dynamics simulations for the sennoside-B protein complexes based on the docking score. ADMET properties prediction confirmed that the selected docked phytochemicals were optimal. These compounds can be investigated further and utilized as a parent core molecule to create novel lead molecules for preventing COVID-19.

Computational Search for Potential COVID-19 Drugs from Ayurvedic Medicinal Plants to Identify Potential Inhibitors against SARS-CoV-2 Targets.

BACKGROUND: To date, very few small drug molecules are used for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has been discovered since the epidemic commenced in November 2019. SARS-CoV-2 RdRp and spike protein are essential targets for drug development amidst whole variants of coronaviruses. OBJECTIVE: This study aims to discover and recognize the most effective and promising small molecules against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and spike protein targets through molecular docking screening of 39 phytochemicals from five different Ayurveda medicinal plants. METHODS: The phytochemicals were downloaded from PubChem, and SARS-CoV-2 RdRp and spike protein were taken from the protein data bank. The molecular interactions, binding energy, and ADMET properties were analyzed. RESULTS: Molecular docking analysis identified some phytochemicals, oleanolic acid, friedelin, serratagenic acid, uncinatone, clemaphenol A, sennosides B, trilobine and isotrilobine from ayurvedic medicinal plants possessing greater affinity against SARS-CoV-2-RdRp and spike protein targets. Two molecules, namely oleanolic acid and sennosides B, with low binding energies, were the most promising. Furthermore, based on the docking score, we carried out MD simulations for the oleanolic acid and sennosides B-protein complexes. CONCLUSION: Molecular ADMET profile estimation showed that the docked phytochemicals were safe. The present study suggested that active phytochemicals from medicinal plants could inhibit RdRp and spike protein of SARS-CoV-2.

Therapeutic antigout and antioxidant activity of Piper betle L. in gout-induced broilers.

1. The following trial investigated the antigout activity and probable mechanism of Piper betle L. herb in gout-induced broiler chickens. The antioxidant and production performance modulating activity of P. betle L. was compared against the standard antigout drug Allopurinol.2. One hundred and sixty, one-day-old female chicks were randomly divided into five treatment groups (control, gout challenged, Allopurinol, P. betle 20 g/kg and P. betle 25 g/kg of feed) with eight birds per group (four replicates) and fed over six weeks. Gout was induced using sodium bicarbonate in water (20 g/l). The clinical signs of gout and production performance were recorded and gross and histopathology was conducted on dead birds. Serum uric acid and creatinine were estimated (on d 10, 14, 17, 19, 21 and 42) and antioxidant and xanthine oxidase enzyme activities were measured from blood samples.3. Uric acid progressively reduced after treatment with P. betle 20 g/kg from d 17 (19.4 ± 0.62 mg/dl) to d 21 (9.81 ± 0.3 mg/dl) and xanthine oxidase activity was likewise suppressed (7.80 ± 0.04 U/mg protein), in a similar manner to Allopurinol (7.75 ± 0.05 U/mg protein), which authenticated the mechanism of antigout activity. Better feed conversion ratios (1.83 ± 0.001) and the restoration of the antioxidants superoxide dismutase, catalase and glutathione to normal levels were observed from birds fed P. betle 20 g/kg than with Allopurinol.4. The data showed that P. betle can be an effective treatment for gout in broiler chicken, as an alternative to Allopurinol.

Potential Role of In Vitro-In Vivo Correlations (IVIVC) for the Development of Plant-Derived Anticancer Drugs.

BACKGROUND: Conventional medicines, along with herbal formulations of Chinese, serve as the primary source and hub of active new drugs where the initial research concentrates on the extraction and isolation of bioactive lead compound(s) to treat several diseases largely for cancer. Plant-derived natural products and their analogs reveal a significant source of several clinically useful anticancer agents. Herbs and herbal derived active compounds play an unavoidable role in the treatment, drug discovery and delivery for decades, as evidenced by numerous existing marked drugs and various cancer-related molecular targets in clinical development. OBJECTIVE: Solubility, resistance and metabolic limitations of the drug can be overcome by suitable molecular modifications. Due to enhancements in tumor targeting technology, some agents who failed in earlier clinical studies are also stimulating renewed interest. In this connection, In Vitro-In Vivo Correlation (IVIVC) plays an important role in the development of dosage forms in the field of pharmaceutical technology. CONCLUSION: IVIVC tool fastens and improves the drug development process and product quality, which is also utilized in internal control for scale-up to improve formulations and alternative production processes. Most importantly, this IVIVC tool lessens the number of human studies during new pharmaceuticals developments. In this review, we would like to grab the attention of readers to the importance and significance of IVIVC for natural products of anticancer drugs examples such as Docetaxel, Etoposide phosphate, 6-Gingerol, Capsaicin, etc.

Larvicidal activity of some medicinal plant extracts against filariasis fever mosquito, Culex quinquefasciatus (Say.) (Diptera: Culicidae).

OBJECTIVES: The present study was aimed to find the larvicidal activity of petroleum ether, chloroform, acetone and methanolic extracts of Dichanthium foveolatum (Del.) Roberty, Leptochloa uniflora Hochst, Pancratium triflorum Roxb and Molineria trichocarpa (Wight) N.P.Balakr against Culex quinquefasciatus. METHODS: The larvicidal potential of selected plant extracts were determined against 4th instar larvae of C. quinquefasciatus with various concentrations viz., 50, 100, 150, 200 and 250 mg/ml. The mortality counts were made after 24 h of incubation and LC50 values were calculated. RESULTS: Chloroform extracts of studied plants were showed highest larvicidal activity with remarkable irritant against the larva of C. quinquefasciatus. Highest larvicidal activity was observed in the chloroform extract of D. foveolatum against the larva of C. quinquefasciatus with LC50 = 277.03 mg/ml. The larvicidal activity of the studied plants as follows chloroform extract of D. foveolatum (LC50 = 277.03 mg/ml) >L. uniflora (LC50 = 300.56 mg/ml) >M. trichocarpa (LC50 = 306.60 mg/ml) >P. triflorum (LC50 318.42 mg/ml). The larvicidal potential of P. triflorum was as follows Chloroform > acetone > methanol > petroleum ether. The larvicidal activities of L. uniflora and M. trichocarpa were as follows Chloroform > petroleum ether > acetone > methanol respectively. The larvicidal potentials of D. foveolatum was as follows Chloroform > methanol > acetone > petroleum ether. CONCLUSION: The chloroform extract of D. foveolatum find use as broad-spectrum larvicidal agent in the near future. It is hoped that more work would be undertaken to evaluate the utility of these plant extracts for field applications considering the promising leads given by the present study.

Hepatoprotective activity of methanolic extract of Syzygium jambos (Linn.) leaf against paracetamol intoxicated Wistar albino rats.

Hepatoprotective activity of methanolic extract of Syzygium jambos (Alston) (Linn.) leaves against Paracetamol-induced hepatic damage in Wistar albino rats was observed at two different doses, 100 and 200 mg/kg body weight. The healthy control, disease control, and standard drug Silymarin-treated groups were also maintained for the comparison. The liver marker enzymes SGOT, SGPT, ALKP, Serum Bilirubin and other metabolic parameters like total cholesterol, HDL-cholesterol were evaluated in all the experimental groups. The changes in liver function parameters were significant in comparison to disease control group and the observed efficacy was comparable to standard drug. The efficacy of the extract was found to be dose dependent. The histopathology study of liver also supports the presence of hepatoprotective activity in S. jambos by showing improved cytoarchitecture of liver cells in the treated groups. The results obtained in this study indicate necessity for further research on isolation and characterization of functional molecules from the extract.

Next generation sequencing and de novo transcriptome analysis of Costus pictus D. Don, a non-model plant with potent anti-diabetic properties.

BACKGROUND: Phyto-remedies for diabetic control are popular among patients with Type II Diabetes mellitus (DM), in addition to other diabetic control measures. A number of plant species are known to possess diabetic control properties. Costus pictus D. Don is popularly known as "Insulin Plant" in Southern India whose leaves have been reported to increase insulin pools in blood plasma. Next Generation Sequencing is employed as a powerful tool for identifying molecular signatures in the transcriptome related to physiological functions of plant tissues. We sequenced the leaf transcriptome of C. pictus using Illumina reversible dye terminator sequencing technology and used combination of bioinformatics tools for identifying transcripts related to anti-diabetic properties of C. pictus. RESULTS: A total of 55,006 transcripts were identified, of which 69.15% transcripts could be annotated. We identified transcripts related to pathways of bixin biosynthesis and geraniol and geranial biosynthesis as major transcripts from the class of isoprenoid secondary metabolites and validated the presence of putative norbixin methyltransferase, a precursor of Bixin. The transcripts encoding these terpenoids are known to be Peroxisome Proliferator-Activated Receptor (PPAR) agonists and anti-glycation agents. Sequential extraction and High Performance Liquid Chromatography (HPLC) confirmed the presence of bixin in C. pictus methanolic extracts. Another significant transcript identified in relation to anti-diabetic, anti-obesity and immuno-modulation is of Abscisic Acid biosynthetic pathway. We also report many other transcripts for the biosynthesis of antitumor, anti-oxidant and antimicrobial metabolites of C. pictus leaves. CONCLUSION: Solid molecular signatures (transcripts related to bixin, abscisic acid, and geranial and geraniol biosynthesis) for the anti-diabetic properties of C. pictus leaves and vital clues related to the other phytochemical functions like antitumor, anti-oxidant, immuno-modulatory, anti-microbial and anti-malarial properties through the secondary metabolite pathway annotations are reported. The data provided will be of immense help to researchers working in the treatment of DM using herbal therapies.

Anticonvulsant and neurotoxicity evaluation of some 6-substituted benzothiazolyl-2-thiosemicarbazones.

Various 6-substituted benzothiazolyl-2-thiosemicarbazones were synthesized and screened for anticonvulsant activity in maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. The 6-methyl benzothiazolyl-2-thiosemicarbazones showed anticonvulsant activity in both mice i.p. and rat oral MES screen. The 6-nitro benzothiazolyl thiosemicarbazone derivative 1a emerged as the most promising one with anti-MES activity in mice i.p., rat i.p. and rat p.o. evaluations. All the compounds exhibited lesser or no neurotoxicity compared to phenytoin. The isatinimino derivatives had shown better activity when compared to the benzylidene or acetophenone derivatives.

Synthesis and anticonvulsant and neurotoxicity evaluation of N4-phthalimido phenyl (thio) semicarbazides.

The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophore were synthesized and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (i.p.), maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (sc STY)-induced seizure threshold tests in mice. Compound 2c afforded protection in all the three screens. Compounds except 1d, 2a and 2d showed no neurotoxicity up to 300 mg/kg. Compounds 1a, 1b, 2c, 2d, 2g and 2i were found to show oral MES activity. The compounds exhibited CNS depression and behavioral despair side effects, lesser than the conventional antiepileptic drugs.

Stansardisation of sringa bhasma.

Sringa Bhasma is an Ayurvedic medicine prescribed mainly for asthma. Physico chemical studies and thin layer chromatography for this medicine was worked out to laydown standards. The evolved parameters can be used for prescribing dependable standards to this medicine.

Insecticidal fatty acids and triglycerides from Dirca palustris.

Five compounds, 1-5, were isolated from the seed hexane extract of Dirca palustris. Compounds 1-3 were triglycerides, and 4 and 5 were linoleic and oleic acids, respectively. Compounds 1-3 were not biologically active; however, 4 (linoleic acid) and 5 (oleic acid) were insecticidal against fourth instar Aedes aegyptii larvae and exhibited potent feeding deterrent activity against neonate larvae of Helicoverpa zea, Lymantria dispar, Orgyia leucostigma, and Malacosoma disstria.