Selective inhibition of peptidyl-arginine deiminase (PAD): can it control multiple inflammatory disorders as a promising therapeutic strategy?

Peptidyl arginine deiminases (PADs) are a family of post-translational modification enzymes that irreversibly citrullinate (deiminate) arginine residues of protein and convert them to a non-classical amino acid citrulline in the presence of calcium ions. It has five isotypes, such as PAD1, PAD2, PAD3, PAD4, and PAD6, found in mammalian species. It has been suggested that increased PAD expression in various tissues contributes to the development of multiple inflammatory diseases, including rheumatoid arthritis (RA), cancer, diabetes, and neurological disorders. Elevation of PAD enzyme expression depends on several factors like rising intracellular Ca2+ levels, oxidative stress, and proinflammatory cytokines. PAD inhibitors originating from natural or synthetic sources can be used as a novel therapeutic approach concerning inflammatory disorders. Here, we review the pathological role of PAD in several inflammatory disorders, factors that trigger PAD expression, epigenetic role and finally, decipher the therapeutic approach of PAD inhibitors in multiple inflammatory disorders.

Phyto-pharmacological perspective of Silymarin: A potential prophylactic or therapeutic agent for COVID-19, based on its promising immunomodulatory, anti-coagulant and anti-viral property.

Coronavirus disease 2019 (COVID-19) triggered by a new viral pathogen, named severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), is now a global health emergency. This debilitating viral pandemic not only paralyzed the normal daily life of the global community but also spread rapidly via global travel. To date there are no effective vaccines or specific treatments against this highly contagious virus; therefore, there is an urgent need to advocate novel prophylactic or therapeutic interventions for COVID-19. This brief opinion critically discusses the potential of Silymarin, a flavonolignan with diverse pharmacological activity having antiinflammatory, antioxidant, antiplatelet, and antiviral properties, with versatile immune-cytokine regulatory functions, that able to bind with transmembrane protease serine 2 (TMPRSS2) and induce endogenous antiviral cytokine interferon-stimulated gene 15, for the management of COVID-19. Silymarin inhibits the expression of host cell surface receptor TMPRSS2 with a docking binding energy corresponding to -1,350.61 kcal/mol and a full fitness score of -8.11. The binding affinity of silymarin with an impressive virtual score exhibits significant potential to interfere with SARS-CoV-2 replication. We propose in-depth pre-clinical and clinical review studies of silymarin for the development of anti-COVID-19 lead, based on its clinical manifestations of COVID-19 and multifaceted bioactivities.

Osteoarthritis: Prognosis and emerging therapeutic approach for disease management.

Osteoarthritis (OA), a disorder of joints, is prevalent in older age. The contemporary cure for OA is aimed to confer symptomatic relief, consisting of temporary pain and swelling relief. In this paper, we discuss various modalities responsible for the onset of OA and associated with its severity. Inhibition of chondrocytes receptors such as DDR2, SDF-1, Asporin, and CXCR4 by specific pharmacological inhibitors attenuates OA, a critical step for finding potential disease modifying drugs. We critically analyzed recent OA studies with an emphasis on intermediate target molecules for OA intervention. We also explored some novel and safe treatments for OA by considering disease prognosis crosstalk with cellular signaling pathways.

The urgent need for integrated science to fight COVID-19 pandemic and beyond.

The COVID-19 pandemic has become the leading societal concern. The pandemic has shown that the public health concern is not only a medical problem, but also affects society as a whole; so, it has also become the leading scientific concern. We discuss in this treatise the importance of bringing the world's scientists together to find effective solutions for controlling the pandemic. By applying novel research frameworks, interdisciplinary collaboration promises to manage the pandemic's consequences and prevent recurrences of similar pandemics.

Attenuation of nociceptive pain and inflammatory disorders by total steroid and terpenoid fraction of Euphorbia tirucalli Linn root in experimental in vitro and in vivo model.

The plant Euphorbia tirucalli Linn has been successfully used as a tribal folk medicine in India and Africa for the management of acute inflammatory, arthritic, nociceptive pain and asthmatic symptoms. The present study was conducted to assess the anti-inflammatory, analgesic, anti-asthmatic and anti-arthritic role of the total steroid and terpenoid rich fractions of the hydro-alcoholic extract of E. tirucalli root (STF-HAETR). STF-HAETR fraction demonstrated 71.25 ± 2.5 and 74.25 ± 5.1% protection against acetic acid-induced pain and central neuropathic pain at 75 and 100 mg/kg doses, respectively. It showed 96.97% protection against acute inflammation at 100 mg/kg with 1.6-fold better activity than the standard drug. The fraction exhibited such efficacy via inhibition of proinflammatory cytokines TNF-α, IFN-γ, by 61.12 and 65.18%, respectively, at 100 µg/mL. Inhibition of cyclooxygenase and Nitric oxide synthase in a dose-dependent manner affirms its analgesic and anti-inflammatory activity. The spectrophotometric analysis reveals that STF-HAETR induces ameliorative effect against heat-induced denaturation of Bovine serum albumin (BSA) and exhibits significant anti-proteinase activity. The plant fraction also demonstrated anti-asthmatic activity by displaying 62.45% protection against histamine induced bronchoconstriction or dyspnoea. Our findings suggest that STF-HAETR could be an effective safe therapeutic agent to treat nociceptive pain, acute inflammation, asthma, and arthritis which may authenticate its traditional use.

Leishmania donovani Aurora kinase: A promising therapeutic target against visceral leishmaniasis.

BACKGROUND: Aurora kinases are key mitotic kinases executing multiple aspects of eukaryotic cell-division. The apicomplexan homologs being essential for survival, suggest that the Leishmania homolog, annotated LdAIRK, may be equally important. METHODS: Bioinformatics, stage-specific immunofluorescence microscopy, immunoblotting, RT-PCR, molecular docking, in-vitro kinase assay, anti-leishmanial activity assays, flow cytometry, fluorescence microscopy. RESULTS: Ldairk expression is seen to vary as the cell-cycle progresses from G1 through S and finally G2M and cytokinesis. Kinetic studies demonstrate their enzymatic activity exhibiting a Km and Vmax of 6.12µM and 82.9pmoles·min(-1)mg(-1) respectively against ATP using recombinant Leishmania donovani H3, its physiological substrate. Due to the failure of LdAIRK-/+ knock-out parasites to survive, we adopted a chemical knock-down approach. Based on the conservation of key active site residues, three mammalian Aurora kinase inhibitors were investigated to evaluate their potential as inhibitors of LdAIRK activity. Interestingly, the cell-cycle progressed unhindered, despite treatment with GSK-1070916 or Barasertib, inhibitors with greater potencies for the ATP-binding pocket compared to Hesperadin, which at nanomolar concentrations, severely compromised viability at IC50s 105.9 and 36.4nM for promastigotes and amastigotes, respectively. Cell-cycle and morphological studies implicated their role in both mitosis and cytokinesis. CONCLUSION: We identified an Aurora kinase homolog in L. donovani implicated in cell-cycle progression, whose inhibition led to aberrant changes in cell-cycle progression and reduced viability. GENERAL SIGNIFICANCE: Human homologs being actively pursued drug targets and the observations with LdAIRK in both promastigotes and amastigotes suggest their potential as therapeutic-targets. Importantly, our results encourage the exploration of other proteins identified herein as potential novel drug targets.

Cationic liposomal sodium stibogluconate (SSG), a potent therapeutic tool for treatment of infection by SSG-sensitive and -resistant Leishmania donovani.

Pentavalent antimonials have been the first-line treatment for leishmaniasis for decades. However, the development of resistance to sodium stibogluconate (SSG) has limited its use, especially for treating visceral leishmaniasis (VL). The present work aims to optimize a cationic liposomal formulation of SSG for the treatment of both SSG-sensitive (AG83) and SSG-resistant (GE1F8R and CK1R) Leishmania donovani infections. Parasite killing was determined by the 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (MTT) assay and microscopic counting of Giemsa-stained macrophages. Macrophage uptake studies were carried out by confocal microscopic imaging. Parasite-liposome interactions were visualized through transmission electron microscopy. Toxicity tests were performed using assay kits. Organ parasite burdens were determined by microscopic counting and limiting dilution assays. Cytokines were measured by enzyme-linked immunosorbent assays (ELISAs) and flow cytometry. Although all cationic liposomes studied demonstrated leishmanicidal activity, phosphatidylcholine (PC)-dimethyldioctadecylammonium bromide (DDAB) vesicles were most effective, followed by PC-stearylamine (SA) liposomes. Since entrapment of SSG in PC-DDAB liposomes demonstrated enhanced ultrastructural alterations in promastigotes, PC-DDAB-SSG vesicles were further investigated in vitro and in vivo. PC-DDAB-SSG could effectively alleviate SSG-sensitive and SSG-resistant L. donovani infections in the liver, spleen, and bone marrow of BALB/c mice at a dose of SSG (3 mg/kg body weight) not reported previously. The parasiticidal activity of these vesicles was attributed to better interactions with the parasite membranes, resulting in direct killing, and generation of a strong host-protective environment, necessitating a very low dose of SSG for effective cures.

Comprehensive review on recent trends and perspectives of natural exo-polysaccharides: Pioneering nano-biotechnological tools.

Exopolysaccharides (EPSs), originating from various microbes, and mushrooms, excel in their conventional role in bioremediation to showcase diverse applications emphasizing nanobiotechnology including nano-drug carriers, nano-excipients, medication and/or cell encapsulation, gene delivery, tissue engineering, diagnostics, and associated treatments. Acknowledged for contributions to adsorption, nutrition, and biomedicine, EPSs are emerging as appealing alternatives to traditional polymers, for biodegradability and biocompatibility. This article shifts away from the conventional utility to delve deeply into the expansive landscape of EPS applications, particularly highlighting their integration into cutting-edge nanobiotechnological methods. Exploring EPS synthesis, extraction, composition, and properties, the discussion emphasizes their structural diversity with molecular weight and heteropolymer compositions. Their role as raw materials for value-added products takes center stage, with critical insights into recent applications in nanobiotechnology. The multifaceted potential, biological relevance, and commercial applicability of EPSs in contemporary research and industry align with the nanotechnological advancements coupled with biotechnological nano-cleansing agents are highlighted. EPS-based nanostructures for biological applications have a bright future ahead of them. Providing crucial information for present and future practices, this review sheds light on how eco-friendly EPSs derived from microbial biomass of terrestrial and aquatic environments can be used to better understand contemporary nanobiotechnology for the benefit of society.

Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point?

Breast cancer ranks second among the causes of cancer-related deaths in women. In spite of the recent advances achieved in the diagnosis and treatment of breast cancer, further study is required to overcome the risk of cancer resistance to treatment and thereby improve the prognosis of individuals with advanced-stage breast cancer. The existence of a hypoxic microenvironment is a well-known event in the development of mutagenesis and rapid proliferation of cancer cells. Tumor cells, purposefully cause local hypoxia in order to induce angiogenesis and growth factors that promote tumor growth and metastatic characteristics, while healthy tissue surrounding the tumor suffers damage or mutate. It has been found that these settings with low oxygen levels cause immunosuppression and a lack of immune surveillance by reducing the activation and recruitment of tumor infiltrating leukocytes (TILs). The immune system is further suppressed by hypoxic tumor endothelium through a variety of ways, which creates an immunosuppressive milieu in the tumor microenvironment. Non responsiveness of tumor endothelium to inflammatory signals or endothelial anergy exclude effector T cells from the tumor milieu. Expression of endothelial specific antigens and immunoinhibitory molecules like Programmed death ligand 1,2 (PDL-1, 2) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) by tumor endothelium adds fuel to the fire by inhibiting T lymphocytes while promoting regulatory T cells. The hypoxic microenvironment in turn recruits Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and T regulatory cells (Treg). The structure and function of newly generated blood vessels within tumors, on the other hand, are aberrant, lacking the specific organization of normal tissue vasculature. Vascular normalisation may work for a variety of tumour types and show to be an advantageous complement to immunotherapy for improving tumour access. By enhancing immune response in the hypoxic tumor microenvironment, via immune-herbal therapeutic and immune-nutraceuticals based approaches that leverage immunological evasion of tumor, will be briefly reviewed in this article. Whether these tactics may be the game changer for emerging immunological switch point to attenuate the breast cancer growth and prevent metastatic cell division, is the key concern of the current study.

Investigation of bio-active Amaryllidaceae alkaloidal small molecules as putative SARS-CoV-2 main protease and host TMPRSS2 inhibitors: interpretation by in-silico simulation study.

The novel coronavirus disease 2019 (Covid-19) outburst is still threatening global health. This highly contagious viral disease is caused by the infection of SARS-CoV-2 virus. Covid-19 and post-Covid-19 complications induce noteworthy mortality. Potential chemical hits and leads against SARS-CoV-2 for combating Covid-19 are urgently required. In the present study, a virtual-screening protocol was executed on potential Amaryllidaceae alkaloids from a pool of natural compound library against SARS-CoV-2 main protease (Mpro) and transmembrane serine protease (TMPRSS2). For the collected 1016 alkaloids from the curated library, initially, molecular docking using AutoDock Vina (ADV), and thereafter 100 ns molecular-dynamic (MD) simulation has been executed for the best top-ranked binding affinity compounds for both the viral and host proteins. Comprehensive intermolecular-binding interactions profile of Amaryllidaceae alkaloids suggested that phyto-compounds Galantamine, Lycorenine, and Neronine as potent modulators of SARS-CoV-2 Mpro and host TMPRSS2 protein. All atomistic long range 100 ns MD simulation studies of each top ranked complex in triplicates also illustrated strong binding affinity of three compounds towards Mpro and TMPRSS2. Identified compounds might be recommended as prospective anti-viral agents for future drug development selectively targeting the SARS-CoV-2 Mpro or blocking host TMPRSS2 receptor, subjected to pre-clinical and clinical assessment for a better understanding of in-vitro molecular interaction and in-vivo validation.Communicated by Ramaswamy H. Sarma.

Discovery of safe and orally effective 4-aminoquinaldine analogues as apoptotic inducers with activity against experimental visceral leishmaniasis.

Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 µM). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.

Structure-based virtual screening, molecular dynamics and binding affinity calculations of some potential phytocompounds against SARS-CoV-2.

COVID-19 caused by a positive-sense single stranded RNA virus named as severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the global pandemic. This virus has infected about 10.37 Crores and taken lives of 2.24 Crores people of 213 countries to date. To cope-up this emergency clinical trials are undergoing with some existing drugs like remdesivir, flavipiravir, lopinavir-ritonavir, nafamostat, doxycycline, hydroxy-chloroquine, dexamethasone, etc., despite their severe toxicity and health hazards among diabetics, hypertensive, cardiac patients or normal individuals. The lack of safe and approved treatment for COVID-19 has forced the scientific community to find novel and safe compounds with potential efficacy. This study evaluates a few selective herbal compounds like glucoraphanin, vitexin, niazinin, etc., as a potential inhibitor of the spike protein and 3-chymotrypsin-like protease (3CLpro) or main protease (Mpro) of SARS-COV-2 through in-silico virtual studies such as molecular docking, target analysis, toxicity prediction and ADME prediction and supported by a Molecular-Dynamic simulation. Selective phytocompounds were docked successfully in the binding site of spike glycoprotein and 3CLpro (Mpro) of SARS-CoV-2. In-silico approaches also predict this molecule to have good solubility, pharmacodynamic property and target accuracy through MD simulation and ADME studies. These hit molecules niazinin, vitexin, glucoraphanin also obey Lipinski's rule along with their stable binding towards target protein of the virus, which makes them suitable for further biochemical and cell-based assays followed by clinical investigations to highlight their potential use in COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

Validation of antioxidant, antiproliferative, and in vitro anti-rheumatoid arthritis activities of epigallo-catechin-rich bioactive fraction from Camellia sinensis var. assamica, Assam variety white tea, and its comparative evaluation with green tea fraction.

The epigallocatechin-rich polyphenolic fraction of Assam variety white tea, traditionally used for the management of diverse inflammatory ailments and health drink, was investigated through eco-friendly green aqueous extraction, TLC, and HPLC characterization, phytochemical screening, in vitro DPPH assay, anti-proteinase, MTT assay on synovial fibroblast and colon cancer cells, apoptotic FACS analysis, cytokine ELISA, p-STAT3 western blotting, and in silico docking analysis. HPLC-TLC standardized white tea fraction (WT-F) rendered higher extractive-yield (21%, w/w), than green tea fraction(GT-F) (12%, w/w). WT-F containing flavonoids and non-hydrolysable polyphenols showed better antioxidant activity, rather than equivalent GT-F. WT-F demonstrated remarkable anti-rheumatoid-arthritis activity via killing of synovial fibroblast cells (66.1%), downregulation of TNF-α (93.33%), IL-6 (87.97%), and p-STAT3 inhibition (77.75%). Furthermore, WT-F demonstrated better anti-proliferative activity against colon cancer cells (HCT-116). Collectively, our study revealed that the white tea fraction has boundless potential as anti-rheumatoid arthritis and anti-proliferative agent coupled with apoptotic, antioxidant anti-proteinase, and anti-inflammatory properties. PRACTICAL APPLICATIONS: Our eco-friendly extracted bioactive aqueous fraction of white tea, characterized by TLC-HPLC study and phytochemical screening have demonstrated remarkable anti-rheumatoid arthritis property and anti-proliferative action on colon cancer cells including potential anti-oxidant, anti-inflammatory, and anti-proteinase efficacy. The test WT-F sample has shown impressive safety on normal mammalian cells. WT-F has demonstrated better efficacy against rheumatoid arthritis and cancer model compared to equivalent green tea fraction. Traditionally, it is extensively used for boosting immunity, and energy, with cosmetic, and agricultural applications by the native inhabitants. So, the aqueous fraction of WT is suggested to be used as a prophylactic nutraceutical supplement and or therapeutic agent in commercial polyherbal formulation to attenuate and management of auto-inflammatory rheumatoid arthritis and carcinogenesis of colon. It is additionally suggested to establish in vivo rheumatoid arthritis animal and clinical study to validate their pharmacokinetic stability and dose optimization coupled with anti-inflammatory, cytotoxicity, and anti-oxidant property.

The chimera of S1 and N proteins of SARS-CoV-2: can it be a potential vaccine candidate for COVID-19?

INTRODUCTION: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as one of the biggest global health issues. Spike protein (S) and nucleoprotein (N), the major immunogenic components of SARS-CoV-2, have been shown to be involved in the attachment and replication of the virus inside the host cell. AREAS COVERED: Several investigations have shown that the SARS-CoV-2 nucleoprotein can elicit a cell-mediated immune response capable of regulating viral replication and lowering viral burden. However, the development of an effective vaccine that can stop the transmission of SARS-CoV-2 remains a matter of concern. Literature was retrieved using the keywords COVID-19 vaccine, role of nucleoprotein as vaccine candidate, spike protein, nucleoprotein immune responses against SARS-CoV-2, and chimera vaccine in PubMed, Google Scholar, and Google. EXPERT OPINION: We have focussed on the use of chimera protein, consisting of N and S-1 protein components of SARS-CoV-2, as a potential vaccine candidate. This may act as a polyvalent mixed recombinant protein vaccine to elicit a strong T and B cell immune response, which will be capable of neutralizing the wild and mutated variants of SARS-CoV-2, and also restricting its attachment, replication, and budding in the host cell.

Phytopharmaceuticals mediated Furin and TMPRSS2 receptor blocking: can it be a potential therapeutic option for Covid-19?

BACKGROUND: Currently, novel coronavirus disease (Covid-19) outbreak creates global panic across the continents, as people from almost all countries and territories have been affected by this highly contagious viral disease. The scenario is deteriorating due to lack of proper & specific target-oriented pharmacologically safe prophylactic agents or drugs, and or any effective vaccine. drug development is urgently required to back in the normalcy in the community and to combat this pandemic. PURPOSE: Thus, we have proposed two novel drug targets, Furin and TMPRSS2, as Covid-19 treatment strategy. We have highlighted this target-oriented novel drug delivery strategy, based on their pathophysiological implication on SARS-CoV-2 infection, as evident from earlier SARS-CoV-1, MERS, and influenza virus infection via host cell entry, priming, fusion, and endocytosis. STUDY DESIGN &  METHODS: An earlier study suggested that Furin and TMPRSS2 knockout mice had reduced level of viral load and a lower degree of organ damage such as the lung. The present study thus highlights the promise of some selected novel and potential anti-viral Phytopharmaceutical that bind to Furin and TMPRSS2 as target. RESULT: Few of them had shown promising anti-viral response in both preclinical and clinical study with acceptable therapeutic safety-index. CONCLUSION: Hence, this strategy may limit life-threatening Covid-19 infection and its mortality rate through nano-suspension based intra-nasal or oral nebulizer spray, to treat mild to moderate SARS-COV-2 infection when Furin and TMPRSS2 receptor may initiate to express and activate for processing the virus to cause cellular infection by replication within the host cell and blocking of host-viral interaction.

Scavenging Properties of Plant-Derived Natural Biomolecule Para-Coumaric Acid in the Prevention of Oxidative Stress-Induced Diseases.

Para-coumaric acid (p-CA) is a plant derived secondary metabolite belonging to the phenolic compounds. It is widely distributed in the plant kingdom and found mainly in fruits, vegetables, and cereals. Various in vivo and in vitro studies have revealed its scavenging and antioxidative properties in the reduction of oxidative stress and inflammatory reactions. This evidence-based review focuses on the protective role of p-CA including its therapeutic potential. p-CA and its conjugates possesses various bioactivities such as antioxidant, anti-inflammatory, anti-cancer, anti-diabetic, and anti-melanogenic properties. Due to its potent free radical scavenging activity, it can mitigate the ill effects of various diseases including arthritis, neurological disorders, and cardio-vascular diseases. Recent studies have revealed that p-CA can ameliorate the harmful effects associated with oxidative stress in the reproductive system, also by inhibiting enzymes linked with erectile function.

Discoidin domain receptor 2: An emerging pharmacological drug target for prospective therapy against osteoarthritis.

Discoidin domain receptor2 (DDR2), a cell membrane tyrosine kinase on chondrocytes surface plays main role in cell-ECM interaction during the progressive degeneration of articular cartilage in osteoarthritis. The degraded component of ECM, type II collagen upon DDR2 binding provokes synthesis of matrix metalloproteinases (MMPs), responsible for severe destruction of joint tissues. DDR2 knockout has been investigated to decline the expression of MMP-1 and 13. Previously, various molecules were effective in preclinical level against different targets in OA, but found to be collapsed in clinical trial due to insufficient target specificity and clinical toxicity. Review emphasizes the role of DDR2 in the degeneration of cartilage in osteoarthritis (OA) and its blocking by DDR2 antagonist attenuates the disease severity. DDR2 in chondrocytes contributes paramount role in degradation of cartilage at early stage of osteoarthritis via collagen 2 binding through the felicitation of TGF-ß signaling molecule and other triggering factors. DDR2 involvement in regulation of matrix metalloproteinase (MMP), cross talking interaction in maintenance of ECM-chondrocytes, bone developments, interference RNA and designing the DDR2 antagonists have been critically investigated. The exploration may conclude that the DDR2 could be the novel pharmacological target to prevent the progression of osteoarthritis at early stage because of over expression of DDR2 and MMP which further promotes severe cartilage degeneration. Owing to pharmacological specificity of DDR2 in OA as drug target, it is to be hypothesized that development of safe molecules as DDR2 antagonist could be the good option in the treatment of OA with promising landmark.

Oral therapy with sertraline, a selective serotonin reuptake inhibitor, shows activity against Leishmania donovani.

OBJECTIVES: This study was executed to investigate the efficacy of oral therapy and preliminary leishmanicidal mechanism of sertraline, a selective serotonin reuptake inhibitor widely used for the management of depression, against Leishmania donovani, a causative agent of visceral leishmaniasis (VL). METHODS: The effect of the drug was determined for: (i) direct promastigote killing by inhibition of MTT reduction and (ii) killing activity against intracellular amastigotes in mouse peritoneal macrophages by microscopic evaluation of surviving amastigotes in macrophages in Giemsa-stained slides. Furthermore, the oral therapy of sertraline against established VL in BALB/c mice was evaluated through estimation of splenic and liver parasite burdens by Leishman Donovan units. Moreover, the preliminary mechanism of action of the drug against promastigotes was assessed by measuring the intracellular ATP levels and oxygen consumption of treated cells. RESULTS: Sertraline killed L. donovani promastigotes and intracellular amastigotes with 50% inhibitory concentrations (IC(50)s) of 2.2 and 2.3 mg/L, respectively. The drug was also effective in eliminating splenic (72%) and liver (70%) parasite loads in infected BALB/c mice through oral therapy. A sertraline-induced fall in cytoplasmic ATP levels and oxygen consumption rate in promastigotes suggests the involvement of an apoptosis mode of cell death in the treated parasites. CONCLUSIONS: Sertraline could be a promising pharmacological tool for the oral treatment of VL.

Ichnocarpus frutescens (L.) R. Br. root derived phyto-steroids defends inflammation and algesia by pulling down the pro-inflammatory and nociceptive pain mediators: An in-vitro and in-vivo appraisal.

Ichnocarpus frutescens, a climber plant, is distributed all over India. As its different parts are used as anti-inflammatory agent, so we re-investigated the roots to isolate compounds and evaluate its biological efficacy. Also, in-silico molecular docking was carried out to elucidate the structure activity relationship (SAR) of isolated compounds toward identifies the drug target enzyme with validation, which was further supported by anti-inflammatory in-vitro and in-vivo experimental models. The compounds have been undertaken mainly to investigate the anti-inflammatory and analgesic efficacy along with molecular docking investigation followed by anti-proteinase, anti-denaturation and cyclooxygenase (COX) inhibition studies. Inflammatory cytokines like TNF-α and IL-6 were assayed from lipopolysaccharides (LPS) and Concavallin (CON A) stimulated human PBMC derived macrophages by Enyme linked immune sorbent assay (ELISA) method. The purity index of the lead compound was determined by HPLC. The compounds were illustrated as 2-hydroxy tricosanoic acid (1), stigmasterol glucoside (2), stigmasterol (3), ß-sitosterol (4) and ß-sitosterol glucoside (5). The test molecules showed significant anti-denaturation, anti-proteinase and analgesic effect validated with docking study. Compounds exhibited anti-inflammatory and pain killing action due to dexamethasone like phytosterol property. Promising anti-denaturation and anti-proteinase activity offered by the compound 5, may hold its promise to fight against arthritis by rejuvenating the osteoblast cells and destroying the bone-resorpting complex of hydrated protein, bone minerals by secreting the acid and an enzyme collagenase along with pain management. The lead bioactive compound i.e. ß-sitosterol glucoside (compound 5) demonstrated considerable anti-inflammatory activity showing more than 90% protection against the inflammatory cytokines at 50 µM dose. The anti-denaturation and COX-2 inhibition shown by the compound 5 was also noteworthy with the significant IC50 (ranging from 0.25 to 2.56 µM) that also supporting its future promise for developing as anti-inflammatory agent. Since the most bio-active compound (5) elicit promising acute anti-inflammatory action and peripheral anti-nociceptive pain killing action with a significant ED50 dose of 3.95 & 2.84 mg/kg i.p. respectively in the in-vivo animal model. It could suggest its potentiality as a good in-vivo bio available agent to be an emerging anti-inflammatory drug regimen scaffold in the future. It also establishes significant in-vitro and in-vivo result co-relation. Therefore, the compound 5 could be believed as a potent lead for designing anti-inflammatory, anti-arthritic drug or pain killer without showing any untoward effect.

Total steroid and terpenoid enriched fraction from Euphorbia neriifolia Linn offers protection against nociceptive-pain, inflammation, and in vitro arthritis model: An insight of mechanistic study.

The plant Euphorbia neriifolia Linn has been successfully used for the management of acute inflammatory, arthritic, nociceptive pain and relieves the asthmatic symptom as a tribal folk medicine in India. The present study was conducted to evaluate the anti-inflammatory, analgesic, anti-arthritic activity from total steroid and terpenoid rich fractions derived from hydro-alcoholic extract of Euphorbia neriifolia stem (STF-HAENS). STF-HAENS fraction demonstrated 68.58±2.5% and 75.25±5.1% protection against acetic acid-induced pain and central neuropathic pain at 80mg/kg. It also showed 98.47% protection against acute inflammation at 100mg/kg with 1.7 fold higher protective activity than the standard drug. The fraction exhibited this efficacy via inhibition of proinflammatory cytokines TNF-α, IFN-γ, IL-12 and IL-6 by 74%, 81.26%, 92.10% and 93.4% respectively at 100µg/ml. It also showed dual inhibition of cyclooxygenase (COX) and lipooxygenase (LOX) activity in a dose-dependent manner that elicited the desired pharmacological action. The fraction downregulated nitric-oxide production from lipopolysaccharide (LPS) stimulated PBMC derived macrophages. The spectrophotometric analysis reveals the STF-HAENS induced ameliorative effect against heat-induced denaturation of BSA protein and exhibited significant antiproteinase activity. Our findings suggest that STF-HAENS could be used as an effective safe therapeutic agent for treatment of nociceptive pain, acute inflammation and arthritis.