Cardioprotective role of FA against isoproterenol induced cardiac toxicity.

The present study was designed to investigate the protective effect of ferulic acid (FA) against isoproterenol (ISO)-induced cardiac toxicity in rats. Isoproterenol challenged in a dose of 85 mg/kg body weight (b.w.) subcutaneously for two consecutive days in the experimental group resulted in acute cardiac toxicity as evidenced by changes in electrocardiogram (ECG) pattern and marked elevation of serum cardiac enzymes viz aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine kinase (CK-MB) and lactate dehydrogenase (LDH) also increases inflammatory cytokines. Moreover, acute toxicity effect was exhibited by disturbance in the antioxidant system as decrease in activities of superoxide dismutase (SOD) and glutathione (GSH) with the rise in activities of malondialdehyde (MDA) and nitric oxide (NO). Pre-treatment with FA at the increasing dose of (10, 20 and 40 mg/kg b.w.) orally for 28 consecutive days followed by isoproterenol injection for 2 days significantly attenuated changes in serum cardiac enzymes. Furthermore, histopathological evaluation confirmed the restoration of cellular architecture in FA pretreated rats. The cardioprotective effect of FA was comparable with standard drug treatment metoprolol. Taken together, FA demonstrated cardioprotective effect against ISO-induced cardiac toxicity by normalization of serum cardiac biomarkers, alleviating oxidative stress and augmenting endogenous antioxidant system.

Molecular Insights into Coumarin Analogues as Antimicrobial Agents: Recent Developments in Drug Discovery.

A major global health risk has been witnessed with the development of drug-resistant bacteria and multidrug-resistant pathogens linked to significant mortality. Coumarins are heterocyclic compounds belonging to the benzophenone class enriched in different plants. Coumarins and their derivatives have a wide range of biological activity, including antibacterial, anticoagulant, antioxidant, anti-inflammatory, antiviral, antitumour, and enzyme inhibitory effects. In the past few years, attempts have been reported towards the optimization, synthesis, and evaluation of novel coumarin analogues as antimicrobial agents. Several coumarin-based antibiotic hybrids have been developed, and the majority of them were reported to exhibit potential antibacterial effects. In the present work, studies reported from 2016 to 2020 about antimicrobial coumarin analogues are the focus. The diverse biological spectrum of coumarins can be attributed to their free radical scavenging abilities. In addition to various synthetic strategies developed, some of the structural features include a heterocyclic ring with electron-withdrawing/donating groups conjugated with the coumarin nucleus. The suggested structure-activity relationship (SAR) can provide insight into how coumarin hybrids can be rationally improved against multidrug-resistant bacteria. The present work demonstrates molecular insights for coumarin derivatives having antimicrobial properties from the recent past. The detailed SAR outcomes will benefit towards leading optimization during the discovery and development of novel antimicrobial therapeutics.

Therapeutic Outcomes of Isatin and Its Derivatives against Multiple Diseases: Recent Developments in Drug Discovery.

Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016-2020. The structure-activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics.

Recognition of Natural Products as Potential Inhibitors of COVID-19 Main Protease (Mpro): In-Silico Evidences.

SARS-CoV-2 (2019-nCoV) emerged in 2019 and proliferated rapidly across the globe. Scientists are attempting to investigate antivirals specific to COVID-19 treatment. The 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease (Mpro).COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral candidates. So the objective and purpose of this work was to investigate the plants with reported potential antiviral activity. With the aid of in silico techniques such as molecular docking and druggability studies, we have proposed several natural active compounds including glycyrrhizin, bicylogermecrene, tryptanthrine, ß-sitosterol, indirubin, indican, indigo, hesperetin, crysophanic acid, rhein, berberine and ß-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against SARS-CoV-2. Promising docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease.

Disulfiram and Its Copper Chelate Attenuate Cisplatin-Induced Acute Nephrotoxicity in Rats Via Reduction of Oxidative Stress and Inflammation.

The use of cisplatin (CP) in chemotherapy of resistant cancers is limited due to its dose-dependent nephrotoxicity. Disulfiram (DSF), the aversion therapy for alcoholism, has recently emerged as an anticancer and chemopreventive agent. Its anticancer activity is potentiated in the presence of copper. However, such use of copper leads to several adverse effects. In the present study, the protective effect of DSF and its copper chelate (Cu-DEDC) against CP-induced nephrotoxicity in rats was evaluated. Nephrotoxicity was induced by a single intraperitoneal injection of CP (5 mg/kg). The treatment groups included control (vehicle treated), CP (CP-treated), CP + DSF (CP followed by DSF), CP + DSF + Cu (CP followed by DSF and CuCl2), CP + Cu-DEDC (CP followed by Cu-DEDC), and CP + AMF (amifostine pre-treated and CP-treated). The DSF, Cu-DEDC, and CuCl2 were administered orally at 50 mM/kg/day dose for 5 days post CP injection. AMF served as a standard chemo protectant, administered intravenously 30 min prior to CP. The markers of oxidative stress, inflammation, and kidney function estimated on the 6th day revealed that both DSF and Cu-DEDC significantly attenuated the CP-induced rise in the serum/urine creatinine and blood urea nitrogen (BUN). The CP-induced rise in serum alkaline phosphatase (ALPase) was reversed by these drugs. Both drugs reduced the levels of malondialdehyde and nitric oxide (NO) in kidney tissues. These drugs reversed CP-induced depletion of SOD, catalase, and GSH in the kidneys. There was a significant reduction in the CP-induced TNF-α and IL-1ß production along with prevention of histological alterations. Above observations indicate that DSF and Cu-DEDC may have significance as adjuvants to protect against CP-induced nephrotoxicity.

Retraction Note: Ultra-diluted Toxicodendron pubescens attenuates pro-inflammatory cytokines and ROS- mediated neuropathic pain in rats.

This paper has been retracted.

Ultra-diluted Toxicodendron pubescens attenuates pro-inflammatory cytokines and ROS- mediated neuropathic pain in rats.

Despite the availability of multiple therapeutic agents, the search for novel pain management of neuropathic pain is still a challenge. Oxidative stress and inflammatory signaling are prominently involved in clinical manifestation of neuropathic pain. Toxicodendron pubescens, popularly known as Rhus Tox (RT) is recommended in alternative medicines as an anti-inflammatory and analgesic remedy. Earlier, we reported anti-inflammatory, anti-arthritic and immunomodulatory activities of Rhus Tox. In continuation, we evaluated antinociceptive efficacy of Rhus Tox in the neuropathic pain and delineated its underlying mechanism. Initially, in-vitro assay using LPS-mediated ROS-induced U-87 glioblastoma cells was performed to study the effect of Rhus Tox on reactive oxygen species (ROS), anti-oxidant status and cytokine profile. Rhus Tox decreased oxidative stress and cytokine release with restoration of anti-oxidant systems. Chronic treatment with Rhus Tox ultra dilutions for 14 days ameliorated neuropathic pain revealed as inhibition of cold, warm and mechanical allodynia along with improved motor nerve conduction velocity (MNCV) in constricted nerve. Rhus Tox decreased the oxidative and nitrosative stress by reducing malondialdehyde (MDA) and nitric oxide (NO) content, respectively along with up regulated glutathione (GSH), superoxide dismutase (SOD) and catalase activity in sciatic nerve of rats. Notably, Rhus Tox treatment caused significant reductions in the levels of tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) as compared with CCI-control group. Protective effect of Rhus Tox against CCI-induced sciatic nerve injury in histopathology study was exhibited through maintenance of normal nerve architecture and inhibition of inflammatory changes. Overall, neuroprotective effect of Rhus Tox in CCI-induced neuropathic pain suggests the involvement of anti-oxidative and anti-inflammatory mechanisms.

A Chemosensitizer Drug: Disulfiram Prevents Doxorubicin-Induced Cardiac Dysfunction and Oxidative Stress in Rats.

In the present study, the preventive effects of orally administered disulfiram (DS) against the doxorubicin (DOX)-induced cardiotoxicity were investigated in rats. DS was orally administered for 7 days at doses of 2, 10, and 50 mg/kg/day. DOX (30 mg/kg) was intraperitoneally administered on the 5th day of the initiation of DS treatment. Within 48 h of injection, DOX treatment significantly altered ECG, elevated the ST height, and increased the QT and QRS intervals. It reduced the cardiac levels of injury markers like creatine kinase isoenzyme-MB and lactate dehydrogenase. DOX elevated the serum levels of SGOT and nitric oxide. Its injection significantly induced lipid peroxidation in the cardiac tissue and reduced the activities of innate antioxidants like super oxide dismutase, catalase, and reduced glutathione in the cardiac tissue. DOX treatment raised the TNF-α level and caused histological alterations in the myocardium like neutrophil infiltrations, myonecrosis, and edema. Pre-treatment of rats with DS (2, 10, and 50 mg/kg p. o. for 7 days) prevented the ECG changes, minimized oxidative stress, and normalized the biochemical indicators of the DOX-induced cardiotoxicity. DS also protected rat heart from DOX-induced histological alterations. Recently, DS is reported to exert chemosensitization of cancer cells. Our in vitro investigation using MCF7 cell line revealed that DS reverses the DOX-induced suppression of NF-κB and Nrf2 expression. These findings about the protective activity of DS against the DOX-induced cardiotoxicity warrant a detailed investigation on its utility as an adjunct therapy to cancer chemotherapy.