Discovery of novel anticancer flavonoids as potential HDAC2 inhibitors: virtual screening approach based on molecular docking, DFT and molecular dynamics simulations studies.

Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn2+ and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO-LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03912-5.

Light Sensitive Liposomes: A Novel Strategy for Targeted Drug Delivery.

Light-sensitive liposomes have emerged as a promising platform for drug delivery, offering the potential for precise control over drug release and targeted therapy. These lipid-based nanoparticles possess photoresponsive properties, allowing them to undergo structural changes or release therapeutic payloads upon exposure to specific wavelengths of light. This review presents an overview of the design principles, fabrication methods, and applications of light-sensitive liposomes in drug delivery. Further, this article also discusses the incorporation of light-sensitive moieties, such as azobenzene, spiropyran, and diarylethene, into liposomal structures, enabling spatiotemporal control over drug release. The utilization of photosensitizers and imaging agents to enhance the functionality and versatility of light-sensitive liposomes is also highlighted. Finally, the recent advances, challenges, and future directions in the field, emphasizing the potential for these innovative nanocarriers to revolutionize targeted therapeutics, are also discussed.

COVID-19 pandemic effects on the distribution of healthcare services in India: A systematic review.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has brought fundamental changes to our problems and priorities, especially those related to the healthcare sector. India was one of the countries severely affected by the harsh consequences of the COVID-19 pandemic. AIM: To understand the challenges faced by the healthcare system during a pandemic. METHODS: The literature search for this review was conducted using PubMed, EMBASE, Scopus, Web of Science, and Google Scholar. We also used Reference Citation Analysis (RCA) to search and improve the results. We focused on the published scientific articles concerned with two major vital areas: (1) The Indian healthcare system; and (2) COVID-19 pandemic effects on the Indian healthcare system. RESULTS: The Indian healthcare system was suffering even before the pandemic. The pandemic has further stretched the healthcare services in India. The main obstacle in the healthcare system was to combat the rising number of communicable as well as noncommunicable diseases. Besides the pandemic measures, there was a diversion of focus of the already established healthcare services away from the chronic conditions and vaccinations. The disruption of the vaccination services may have more severe short and long-term consequences than the pandemic's adverse effects. CONCLUSION: Severely restricted resources limited the interaction of the Indian healthcare system with the COVID-19 pandemic. Re-establishment of primary healthcare services, maternal and child health services, noncommunicable diseases programs, National Tuberculosis Elimination Program, etc. are important to prevent serious long-term consequences of this pandemic.

Expression of microRNA-21 in saliva and tumor tissue of patients with oral squamous cell carcinoma: a predictor of cervical lymph node metastasis.

OBJECTIVE: Evaluation of diagnostic accuracy of microRNA-21 (miR-21) in saliva and tumor tissue for presurgical assessment of lymph node metastasis in patients with oral squamous cell carcinoma (OSCC). STUDY DESIGN: Unstimulated whole saliva and tumor tissue was obtained from clinically suspected patients with OSCC. A total of 130 patients diagnosed with OSCC were included as study participants. The assessment of cervical lymph node metastasis was done before surgery using imaging scans and post surgically confirmed by histopathologic examination of excised lymph nodes. miR-21 expression was evaluated using real-time polymerase chain reaction. The data was statistically analyzed for correlation analysis, cutoff values, sensitivity, and specificity. The κ statistic was applied to assess the degree of agreement between the lymph node metastasis and miR-21 expression. RESULTS: miR-21 expression showed a statistically significant correlation with cervical lymph node metastasis with a diagnostic accuracy of 65% to 71.54% in saliva and 69% to 81.54% in tumor tissue. Very good agreement was observed between tumor tissue miR-21-3p and cervical lymph node metastasis with a specificity of 80.60% and a sensitivity of 82.40%. CONCLUSIONS: miR-21 expression in saliva and tumor tissue of patients with OSCC showed high diagnostic accuracy for assessment of cervical lymph node metastasis. It can be used as an alternative for assessment of cervical lymph node metastasis before surgery.

Platelet Augmentation Potential of Polyherbal Formulation in Cyclophosphamide-Induced Thrombocytopenia in Wistar Rats.

INTRODUCTION: Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes, also known as platelets, in the blood. Several medicinal plants possess curative and protective effect against thrombocytopenia associated with diseases or drugs. AIM: In the present study, we have investigated the platelet augmentation activity of polyherbal formulation (VITA PLAT Capsule) in cyclophosphamide-induced thrombocytopenic rat model. MATERIALS AND METHODS: Twenty-four albino Wistar rats were divided into four groups. Thrombocytopenia was induced in the rats by administering cyclophosphamide (25 mg/kg, i.p.) for three days to all the groups except normal controls. The test groups were given orally a polyherbal formulation suspended in normal saline for 14 days. Blood was withdrawn from the retro-orbital plexus of the rats on days 1, 7, and 14 of study to determine platelet counts in all groups. Clotting time and bleeding time were determined on the last day of study. Data were collected and analyzed using GraphPad Prism 8. RESULTS: The results showed that the polyherbal formulation treatment could significantly ameliorate platelet count in thrombocyto-penic rats in the initial as well as in the later phase. The total WBC count was also improved during later phase in test groups. However, there is no significant difference between clotting time and bleeding time in all groups. CONCLUSIONS: Our study suggests a potential role of this formulation in the augmentation of platelet counts in various thrombocyto-penic disorders including a role in ameliorating the haemorrhagic complications of dengue fever.

In Silico Discovery of Novel Flavonoids as Poly ADP Ribose Polymerase (PARP) Inhibitors.

BACKGROUND: The concept of synthetic lethality is an emerging field in the treatment of cancer and can be applied for new drug development of cancer as already been represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. OBJECTIVE: In this study, we performed virtual screening of 329 flavonoids obtained from the Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database to identify novel PARP inhibitors. MATERIALS AND METHODS: Virtual screening carried out using different in silico methods which include molecular docking studies, prediction of drug-likeness and in silico toxicity studies. RESULTS: Fifteen out of 329 flavonoids achieved better docking score as compared to rucaparib which is an FDA approved PARP inhibitor. These 15 hits were again rescored using accurate docking mode and drug-likeliness properties were evaluated. The accuracy of the docking method was checked using re-docking. Finally NPACT00183 and NPACT00280 were identified as potential PARP inhibitors with docking score of -139.237 and -129.36, respectively. These two flavonoids also showed no AMES toxicity and no carcinogenicity which was predicted using admetSAR. CONCLUSION: Our finding suggests that NPACT00183 and NPACT00280 have promising potential to be further explored as PARP inhibitors.

Novel therapeutic intervention of coenzyme Q10 and its combination with pioglitazone on the mRNA expression level of adipocytokines in diabetic rats.

AIMS: Aim of the present study was to investigate the effect of co-administration coenzyme Q10 and pioglitazone on the mRNA expression of adipocytokines in white adipose tissues of chemically induced type 2 diabetes mellitus in rats. MAIN METHODS: Diabetes was induced by administration of streptozotocin (65 mg/kg, i.p.), followed by nicotinamide (110 mg/kg, i.p.) 15 min later. The diabetic rats were treated coenzyme Q10 (Q10, 10 mg/kg, p.o.) or pioglitazone (PIO, 20 mg/kg, p.o.) alone and their combination for four weeks. Biochemical parameters like FBS level, insulin and HbA1c along with tissue levels of MDA, SOD, CAT and GSH were estimated. The mRNA levels of ADIPOQ, RBP4, RETN, IL-6 and TNF-α in White Adipose Tissue (WAT) were measured. KEY FINDINGS: Treatment with Q10 + PIO showed a significant reduction in the levels of FBS, HbA1c and a significant increase in insulin levels as compared to normal control group. Additionally, there was a significant change in the levels of biomarkers of oxidative stress after treatment with Q10 + PIO as compared to streptozotocin-nicotinamide group. Treatment with Q10 + PIO also significantly altered the mRNA expression of ADIPOQ, RETN, IL-6 and TNF-α when compared to monotherapy. However, mRNA expression of RBP4 did not alter in Q10 + PIO treated animal as compared to Q10 or PIO alone. SIGNIFICANCE: It is concluded that co-administration of Q10 and PIO has been shown the better therapeutic effect on the mRNA expression of adipocytokines and oxidative stress parameters as compared to either Q10 or PIO.

In Silico Discovery of Novel Phytoconstituents of Amyris pinnata as a Mitotic Spindle Kinase Inhibitor.

BACKGROUND: Despite many successes in the discovery of numerous cancer chemotherapeutic agents from natural sources, some of the moieties were dropped because of its inefficiency or serious toxicity. Mitosis is an ordered series of fundamentally mechanical events in which identical copies of the genome are moved to two discrete locations within the dividing cell. The crucial role of the mitotic spindle in cell division has identified, which is an important target in cancer chemotherapy. In the present study, we are reporting molecular docking studies and in silico pharmacokinetic profiles of selected phytoconstituents obtained from Amyris pinnata. METHODS: Molecular docking studies of selected phytoconstituents were performed using iGEMDOCK. The crystal structure of the protein was exported from the protein data bank (PDB id: 4C4H). In silico pharmacokinetic profile of selected phytoconstituents was performed using the SWISSADME server. RESULTS: Compound AMNP6 showed higher binding affinity as compared to the standard ligand. All the selected phytoconstituents have passed the Lipinski rule of five and shown no violations. CONCLUSION: Good binding affinity and drug likeliness of the AMNP6 suggest that it can be further investigated and explored as mitotic spindle kinase inhibitor in cancer disease.

Anti-anaphylactic and antiasthmatic activity of Euphorbia thymifolia L. on experimental animals.

In Ayurveda, Euphorbia thymifolia L. (Euphorbiaceae) prescribed in the treatment of various ailments like bronchial asthma, cough, diarrhea and bleeding piles. The present study was investigated to evaluate antianaphylactic, mast cell stabilizing and antiasthmatic activity of methanol and aqueous extract of E. thymifolia (ET) on experimental animals. Anaphylaxis was induced by administration of horse serum and triple antigen vaccine intraperitoneal (i.p.) in albino Wistar rats. Extracts of ET were administered to the rats in dose of 250 and 500 mg/kg orally for 14 days. At the end of treatment, asthma score was measured and various blood parameters like differential count (DC), total WBC count and IgE were estimated. Interleukin (IL)-4, IL-5 and TNF-α were measured by ELISA commercial kit from BALF. Histopathological changes of lungs were observed. Antiasthmatic activity of extracts of ET was also studied on histamine-induced bronchospasm in guinea pigs. In vitro mast cell stabilizing activity of extracts was evaluated on compound 48/80 challenged rat intestinal mesenteric mast cells. The treatment with extracts of ET produced significant decrease in asthma score and they also brought to normalcy the increased total WBC, DC counts, serum IgE, TNF-α, IL-4 and IL-5 in BALF. The histopathological study further supported the protective effect of ET extracts. The pretreatment with extracts of ET displayed significant reduction in degranulation of mesenteric mast cell numbers. The treatment with extracts of ET significantly increased in time of PCD. Thus, these findings concluded that E. thymifolia could be effectively used in the treatment of anaphylaxis and asthma.

Antimalarial Phytochemicals Identification from Euphorbia Hirta against Plasmepsin Protease: an In Silico Approach.

BACKGROUND: Aspartic protease found in plasmodium parasites such as plasmepsin I, II and IV plays an important role in the degradation of hemoglobin. The studies have shown that effective drug must be able to inhibit more than one type of plasmepsin to avoid further growth of parasites and to prevent resistance of drug. Therefore, plasmepsins are believed to be excellent drug target for malarial disease. Extract of the plant Euphorbia hirta has been proved to exert antimalarial activity. However, molecular mechanism of this activity was not described. AIM: The aim of present investigation is to identify antimalarial phytochemicals of Euphorbia hirta as plasmepsin protease inhibitors using an in silico approach. MATERIALS AND METHODS: Docking studies were performed on three different protein targets plasmepsin I, II, and IV using iGEMDOCK. ADME and bioactivity predictions were done using molinspiration online tool. Toxicity studies were performed using ProTox-II online tool. RESULTS: In the docking studies seven compounds showed significant inhibitory activity with low docking score as compared to standard drug artemisinin. Six compounds showed no violations as per Lipinski rule. Bioactivity prediction states that all the compounds may act through enzyme inhibition. The results of in silico studies suggest that out of the eleven selected phytochemicals isorhamnetin and pinocembrin have more drug likeliness properties and lesser in silico toxicity with more binding affinity than artemisinin on all receptors. CONCLUSION: These findings indicate that isorhamnetin and pinocembrin have promising potential for development of antimalarial drug as plasmepsin inhibitors.

Comparative assessment of efficacy of two different pretreatment single oral doses of betamethasone on inter-appointment and postoperative discomfort: An in vivo clinical evaluation.

AIM: Study aimed to evaluate the efficacy of two different pretreatment single oral doses of betamethasone on the incidence of inter-appointment flare up and postoperative discomfort. MATERIALS AND METHODS: Fifty-four patients aged 18-59 years requiring endodontic treatment were selected and randomly assigned to three groups; single pretreatment oral dose of placebo or betamethasone in two different oral doses of 0.5 mg and 1 mg, respectively. Endodontic therapy was completed in two visits using triple antibiotic paste as intracanal medicament. Patients were given a questionnaire to record their pain at 1, 2, 3, and 7 days after treatment. In the second visit, obturation was done, and the patients were again instructed to record their pain scores after treatment and discharged. The verbal rating scale was used for recording the pain scores. Statistical analysis was done using ANOVA and the Friedman test. RESULTS: 0.5 mg betamethasone group showed least mean pain scores among all experimental groups; however, there was no statistically significant difference between any of the groups (P > 0.05). CONCLUSION: Pretreatment single oral dose of betamethasone is an effective in managing endodontic flare-ups; however, the results were statistically insignificant.

Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study.

The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 3(2) factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 ± 5.12 nm average particle size and -12.8 ± 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX.