Prospects for the convergence of polyphenols with pharmaceutical drugs in Type 2 Diabetes: challenges, risks, and strategies.

Type 2 diabetes mellitus (T2DM) is a complex disease that can lead to a variety of life-threatening secondary health conditions. Current treatment strategies primarily revolve around tight glucose control that is difficult to achieve and often turns out to be dangerous due to possible hypoglycemic events. Numerous long-term studies have demonstrated that complex pathways, including low-grade inflammation due to fluctuating glucose levels, are involved in the progression of the disease and the development of secondary health conditions. Growing clinical evidence supports the effectiveness of using multiple medications, possibly in combination with insulin, to effectively manage T2DM. On the other hand, despite the huge, largely untapped potential therapeutic benefit of 'polyphenols', there remains a general skepticism of the practice. However, for any evidence-based clinical intervention, the balance of benefits and risks takes center stage and is governed by biopharmaceutics principles. In this article, we outline the current clinical perspectives on pharmaceutical drug combinations, rationale for early initiation of insulin, and the advantages of novel dosage forms to meet the pathophysiological changes of T2DM, emphasizing the need for further clinical studies to substantiate these approaches. We also make the case for traditional medicines and their combinations with pharmaceutical drugs and outline the inherent challenges in doing so, while also providing recommendations for future research and clinical practice. Significance Statement Type 2 diabetes is associated with life-threatening secondary health conditions that are often difficult to treat. This review provides an in-depth account of preventing/delaying secondary health conditions through combination therapies and emphasizes the role of effective delivery strategies in realizing the translation of such combinations. We will build the case for the importance of polyphenols in diabetes, determine the reasons for skepticism, and potential combinations with pharmaceutical drugs.

Evaluation of Antidepresant Activity and Phytochemical Screening of Plant Cordia Dichotoma.

INTRODUCTION: The traditional medicinal system of India, Ayurveda, has mentioned Cordia Dichotoma as a potential treatment for various ailments. In the current research, the extracts of Cordia Dichotoma was examined to evaluate their antidepressant potential. MATERIALS AND METHODS: Here, green leaves of Cordia Dichotoma were used to prepare chloroform, ethanol, and aqueous extracts (referred to as CdCe, CdEe, and CdAe respectively). The research focused on investigating the antidepressant effects of these extracts using behavioral models in experimental animals. Additionally, locomotor activity was assessed as part of the evaluation process. RESULTS: Immobility time was reduced with CdEe Cordia Dichotoma rFST & mTST when at 200 mg/kg and 400 mg/kg body weight. The CdAe showed reduction in immobility time in the repeated rFST) at 400 mg/kg, while in the mTST, significant effects were observed at 200 and 400 mg/kg. Regarding the chloroform extract, it only exhibited a significant reduction in immobility time in the modified Tail Suspension Test (mTST) at a low dose of 200 mg/kg. However, no noticeable change in motor dysfunction was observed with CCl4 and aqueous extracts at doses of 200 and 400 mg/kg. It is worth noting that the chloroform extract (CdCe) did lead to a significant decrease in locomotor activity at the same dosage level. Taken together, these findings suggest that extracts obtained from Cordia Dichotoma leaves may possess antidepressant properties.

Nanotechnology-Enhanced Naloxone and Alternative Treatments for Opioid Addiction.

Opioids are commonly prescribed to address intense, ongoing pain associated with cancer, as well as long-lasting noncancer-related pain when alternative methods have proven ineffective. Individuals who exhibit both chronic pain and misuse of opioids face a significant danger of experiencing adverse health outcomes and the potential loss of life related to opioid use. Thus, there is a current movement to prescribe naloxone to those considered high-risk for opioid overdose. Naloxone has been explored as an antidote to reverse acute respiratory depression. Conversely, naloxone can give rise to other problems, including hypertension and cardiac arrhythmias. Thus, the importance of nanotechnology-enabled drug delivery strategies and their role in mitigating naloxone side-effects are significant. In this review, we explore the latest advancements in nanotechnology-enabled naloxone and alternative methods for addressing the opioid crisis through the utilization of non-opioid natural alternatives for chronic pain management.

Performance analysis of base-isolated structures in mitigating underground blast-induced ground motion effects: A parametric study.

This study delves into mitigating ground motion induced by underground blasts on superstructures. A parametric analysis is conducted to assess the performance of base isolated structures under different blast scenarios. The analysis is conducted using Newmark's time step integration method, and the absolute acceleration of the structure and displacement of the isolator bearing are calculated to evaluate the response. Results demonstrate the significant effectiveness of base isolation in reducing blast-induced vibrations. The parameters of the base isolator, including damping ratio and time period, are systematically varied to understand their impact on the response. Key findings include the significant influence of the ground medium on both fixed base and base isolated superstructures, with soil-rock interface locations reducing floor acceleration under various blast load intensities. The N-Z bearing system is shown to effectively reduce the dynamic response in both rock and soil media. This study recommends specific combinations of ground medium and site location for optimal protection against blast threats. Ultimately, this study facilitates a better understanding of the dynamic interaction between underground blasts and superstructures, paving the way for more effective blast-resistant structural designs.

Lymph node targeting of cyclosporine ameliorates ocular manifestations in a mouse model of systemic lupus erythematosus (SLE) via PD-L1.

One-third of systemic lupus erythematosus (SLE) patients experience various degrees of ocular manifestations, with immunosuppressants recommended as a treatment option. Targeted immune suppression via oral administration is challenging due to the harsh gastrointestinal tract environment combined with complex physiological barriers. Here, we report the efficacy of orally administered cyclosporine (CsA)-laden polymer nanoparticles decorated with the ligand - Gambogic Acid (P2Ns-GA-CsA) in sustained lymph node delivery. This is the first report demonstrating the CD71 specificity of P2Ns-GA-CsA in the CD71 knockout mouse model and the influence of spacer length in achieving target tissue bioavailability in a lupus mouse model. P2Ns-GA-CsA effectively regulates T-cell chemotaxis by PD-L1 at a 50 % lower dose compared to conventional CsA in a mouse model exhibiting lupus-associated corneal inflammation. Collectively, these results suggest the possibility for further development of P2Ns-GA to target a diverse range of lymphatic disorders.

Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein.

Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the in vitro, ex vivo and in vivo performance of a drug, and if there exists a correlation between in vitro and in vivo, as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C). The in vitro, ex vivo and in vivo in healthy models validate the hypothesis that 4C has better reach and binding to the receptors. The results indicate that 4C offered better performance over 2C in vivo in improving the oral bioavailability of insulin (INS) by 1.1-fold (3.5-fold compared to unfunctionalized nanoparticles) in a healthy rat model. Similar observations were made in pathophysiological models; however, the effects were less prominent compared to those in healthy models. Throughout, ligand decorated nanoparticles outperformed unfunctionalized nanoparticles. Finally, a semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed using the experimental data sets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability and efficacy of insulin. The study presents a sophisticated oral delivery system for INS or hydrophilic therapeutic cargo, highlighting the significant impact on bioavailability that minor adjustments to the surface chemistry can have.

ZnPP-laden nanoparticles improve glucose homeostasis and chronic inflammation during obesity.

BACKGROUND AND PURPOSE: Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity. EXPERIMENTAL APPROACH: We delivered DMSO-dissolved ZnPP (DMSO-ZnPP) and ZnPP-laden nanoparticles (Nano-ZnPP) to diet-induced obese male mice for 6 weeks. Glucose and insulin tolerance tests were carried out, liver and adipose tissue gene expression profiles analysed, and systemic inflammation analysed using flow cytometry. KEY RESULTS: Nanoparticles significantly increased the delivery efficiency of ZnPP in both cells and mice. In mice with diet-induced obesity, inhibition of HO-1 by Nano-ZnPP significantly decreased adiposity, increased insulin sensitivity, and improved glucose tolerance. Moreover, Nano-ZnPP treatment attenuated both local and systemic inflammatory levels during obesity. Mechanistically, Nano-ZnPP significantly attenuated glucagon, TNF, and fatty acid synthesis signalling pathways in the liver. In white adipose tissue, the oxidative phosphorylation signalling pathway was enhanced and the inflammation signalling pathway diminished by Nano-ZnPP. Our results show that Nano-ZnPP has better effects on the improvement of glucose homeostasis and attenuation of chronic inflammation, than those of DMSO-dissolved ZnPP. CONCLUSIONS AND IMPLICATIONS: These findings indicate that ZnPP-laden nanoparticles are potential therapeutic agents for treating T2DM.

Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes.

The role of advanced drug delivery strategies in drug repositioning and minimizing drug attrition rates, when applied early in drug discovery, is poised to increase the translational impact of various therapeutic strategies in disease prevention and treatment. In this context, drug delivery to the lymphatic system is gaining prominence not only to improve the systemic bioavailability of various pharmaceutical drugs but also to target certain specific diseases associated with the lymphatic system. Although the role of the lymphatic system in lupus is known, very little is done to target drugs to yield improved clinical benefits. In this review, we discuss recent advances in drug delivery strategies to treat lupus, the various routes of drug administration leading to improved lymph node bioavailability, and the available technologies applied in other areas that can be adapted to lupus treatment. Moreover, this review also presents some recent findings that demonstrate the promise of lymphatic targeting in a preclinical setting, offering renewed hope for certain pharmaceutical drugs that are limited by efficacy in their conventional dosage forms. These findings underscore the potential and feasibility of such lymphatic drug-targeting approaches to enhance therapeutic efficacy in lupus and minimize off-target effects of the pharmaceutical drugs. SIGNIFICANCE STATEMENT: The World Health Organization estimates that there are currently 5 million humans living with some form of lupus. With limited success in lupus drug discovery, turning to effective delivery strategies with existing drug molecules, as well as those in the early stage of discovery, could lead to better clinical outcomes. After all, effective delivery strategies have been proven to improve treatment outcomes.

Magnon bands in pyrochlore slabs with Heisenberg exchange and anisotropies.

The pyrochlore lattice is a versatile venue to probe the properties of magnetically ordered states induced or perturbed by anisotropic terms like the Dzyaloshinskii-Moriya interactions or single-ion anisotropy. Several such ordered states have been investigated recently as precursors of topological magnons and the associated surface states. In parallel, there has been recent progress in growing thin films of magnetic materials with this lattice structure along high symmetry directions of the lattice. In both cases, an account of the magnetic excitations of relevant Hamiltonians for finite slabs is a necessary step in the analysis of the physics of these systems. While the analysis of bulk magnons for these systems is quite common, a direct evaluation of the magnon spectra in the slab geometry, though required, is less frequently encountered. We study here magnon bands in the slab geometry for a class of spin models on the pyrochlore lattice with Heisenberg exchange, Dzyaloshinskii-Moriya interaction and spin-ice anisotropy. For a range of model parameters, for both ferromagnetic and antiferromagnetic exchange, we compute the classical ground states for different slab orientations and determine the spin wave excitations above them. We analyze the ferromagnetic splay phase, the all-in-all-out (AIAO) phase and a coplanar phase and evaluate magnon dispersions for slabs oriented perpendicular to the [111], [100] and [110] directions. For all the phases considered, depending on the slab orientation, magnon band structures can be non-reciprocal and we highlight the differences in the three orientations from this point-of-view. Finally, we present details of the surface localized magnons for all the three slab orientations in the phases we study. For the ferromagnetic splay phase and the AIAO phase we analyze surface states associated with point degeneracies or nodal lines in the bulk spectrum by computing the magnonic Berry curvature and Weyl charges or Chern numbers associated with it.

Rationally Designed Naringenin-Conjugated Polyester Nanoparticles Enable Folate Receptor-Mediated Peroral Delivery of Insulin.

Receptor-mediated transcytosis of nanoparticles is paramount for the effective delivery of various drugs. Here, we report the design and synthesis of highly functional nanoparticles with specific targeting toward the folate receptor (FR) for the peroral delivery of insulin. In doing so, we demonstrate naringenin (NAR), a citrous flavonoid, as a targeting ligand to FR, with a similar affinity as folic acid. The NAR-decorated nanoparticles indicated a 4-fold increase in FR colocalization compared to unfunctionalized nanoparticles. The NAR-conjugated precision polyester allows for high insulin loading and entrapment efficiencies. As a result, insulin-laden NAR-functional nanoparticles offered a 3-fold higher bioavailability in comparison to unfunctionalized nanoparticles. This work generated a promising contribution to folate-receptor-mediated peroral delivery of insulin, utilizing polymeric nanoparticles decorated with a natural ligand, NAR.

Normative Data on Dehydroepiandrosterone Sulphate (DHEAS) and its Attributes in Healthy Indian Children and Adolescents.

Dehydroepiandrosterone sulphate (DHEAS), the biochemical indicator of adrenarche and pubarche, is of paramount importance in the evaluation of puberty-related disorders. The reference range of DHEAS should be ethnicity, age, sex, pubarche and Tanner stage specific. Anthropometry, puberty assessment and hormonal parameters were estimated using electrochemiluminescence assay. Bone age was estimated using the BoneXpert software. Of 2191 healthy Indian children aged 5-18 y screened at Chandigarh, 1919 were included in the final analysis (994 boys). The median DHEAS levels at pubarche stage P2 were 82.10 (55.0-129.0) g/dl in girls and 132.50 (95.12-205.50) g/dl in boys. By ROC analysis, the level of DHEAS at pubarche was 63.7 g/dl (sensitivity 72.6%, specificity 64.4%) in girls and 82.2 g/dl (sensitivity 81.8%, specificity 68.8%) in boys. The median age at adrenarche was 9.5 y in both sexes. On multivariate regression analysis; bone age, body mass index (BMI), gonadal steroids, and insulin-like growth factor-1 (IGF-1) significantly correlated with serum DHEAS levels in either sex.

Potential of Y. lipolytica epoxide hydrolase for efficient production of enantiopure (R)-1,2-octanediol.

The recombinant Yleh from a tropical marine yeast Yarrowia lipolytica NCIM 3589 exhibited a high epoxide hydrolase activity of 9.34 ± 1.80 µmol min-1 mg-1 protein towards 1,2-epoxyoctane (EO), at pH 8.0 and 30 °C. The reaction product was identified as 1,2-Octanediol (OD) by GC-MS using EO and H2O18 as substrate, affirming the functionality of Yleh as an epoxide hydrolase. For EO, the Km, Vmax, and kcat/Km values were 0.43 ± 0.017 mM, 0.042 ± 0.003 mM min-1, and 467.17 ± 39.43 mM-1 min-1, respectively. To optimize the reaction conditions for conversion of racemic EO by Yleh catalyst to enantiopure (R)-1,2-octanediol, initially, Response Surface Methodology was employed. Under optimized reaction conditions of 15 mM EO, 150 µg purified Yleh at 30 °C a maximal diol production of 7.11 mM was attained in a short span of 65 min with a yield of 47.4%. Green technology using deep eutectic solvents for the hydrophobic substrate (EO) were tested as co-solvents in Yleh catalyzed EO hydrolysis. Choline chloride-Glycerol, produced 9.08 mM OD with an increased OD yield of 60.5%. Thus, results showed that deep eutectic solvents could be a promising solvent for Yleh-catalyzed reactions making Yleh a potential biocatalyst for the biosynthesis of enantiopure synthons.

Room Temperature Curable Copper Nanowire-Based Transparent Heater.

Copper nanowires (Cu NWs) are a promising alternative to silver NWs to develop transparent conducting films (TCFs) due to their comparable electrical conductivity and relative abundance. Postsynthetic modifications of the ink and high-temperature postannealing processes for obtaining conducting films are significant challenges that need to be addressed before commercial deployment of these materials. In this work, we have developed an annealing-free (room temperature curable) TCF with Cu NW ink that requires minimal postsynthetic modifications. Organic acid pretreated Cu NW ink is used for spin-coating to obtain a TCF with a sheet resistance of 9.4 Ω/sq. and optical transparency of 67.4% at 550 nm. For oxidation protection, the Cu NW TCF is encapsulated with polydimethylsiloxane (PDMS). The encapsulated film is tested as a transparent heater at various voltages and shows good repeatability. These results demonstrate the potential of Cu NW-based TCFs as a replacement for Ag-NW based TCFs for a variety of optoelectronic applications, such as transparent heaters, touch screens, and photovoltaics.

Systemic Anti-Inflammatory Therapy Aided by Curcumin-Laden Double-Headed Nanoparticles Combined with Injectable Long-Acting Insulin in a Rodent Model of Diabetes Eye Disease.

Therapeutic interventions that counter emerging targets in diabetes eye diseases are lacking. We hypothesize that a combination therapy targeting inflammation and hyperglycemia can prevent diabetic eye diseases. Here, we report a multipronged approach to prevent diabetic cataracts and retinopathy by combining orally bioavailable curcumin-laden double-headed (two molecules of gambogic acid conjugated to terminal carboxyl groups of poly(d,l-lactide-co-glycolide)) nanoparticles and injectable basal insulin. The combination treatment led to a significant delay in the progression of diabetic cataracts and retinopathy, improving liver function and peripheral glucose homeostasis. We found a concurrent reduction in lens aggregate protein, AGEs, and increased mitochondrial ATP production. Importantly, inhibition of Piezo1 protected against hyperglycemia-induced retinal vascular damage suggesting possible involvement of Piezo1 in the regulation of retinal phototransduction. Histologic evaluation of murine small intestines revealed that chronic administration of curcumin-laden double-headed nanoparticles was well tolerated, circumventing the fear of nanoparticle toxicity. These findings establish the potential of anti-inflammatory and anti-hyperglycemic combination therapy for the prevention of diabetic cataracts and retinopathy.

Urolithin A Nanoparticle Therapy for Cisplatin-Induced Acute Kidney Injury.

Cisplatin continues to be one of the frontline cytotoxic drugs. However, cisplatin-induced acute kidney injury (AKI) remains a major unmet medical need without any approved pharmacological interventions. The involvement of reactive oxygen species generation and activation of inflammatory and apoptotic pathways in the pathogenesis of cisplatin-induced AKI prompts the use of natural anti-inflammatory compounds. In this context, resolution of inflammation using natural antioxidant and anti-inflammatory such as urolithin A (UA) could prove beneficial. In the end, testing such combinations in models to eliminate the possibility that UA stimulates tumor growth or compromises the potency of cisplatin could prove useful for clinical translation of adjuvant therapies.

Nanocurcumin combined with insulin alleviates diabetic kidney disease through P38/P53 signaling axis.

Treatments for diabetic kidney disease (DKD) mainly focus on managing hyperglycemia and hypertension, but emerging evidence suggests that inflammation also plays a role in the pathogenesis of DKD. This 10-week study evaluated the efficacy of daily oral nanoparticulate-curcumin (nCUR) together with long-acting insulin (INS) to treat DKD in a rodent model. Diabetic rats were dosed with unformulated CUR alone, nCUR alone or together with INS, or INS alone. The progression of diabetes was reflected by increases in plasma fructosamine, blood urea nitrogen, creatinine, bilirubin, ALP, and decrease in albumin and globulins. These aberrancies were remedied by nCUR+INS or INS but not by CUR or nCUR. Kidney histopathological results revealed additional abnormalities characteristic of DKD, such as basement membrane thickening, tubular atrophy, and podocyte cytoskeletal impairment. nCUR and nCUR+INS mitigated these lesions, while CUR and INS alone were far less effective, if not ineffective. To elucidate how our treatments modulated inflammatory signaling in the liver and kidney, we identified hyperactivation of P38 (MAPK) and P53 with INS and CUR, whereas nCUR and nCUR+INS deactivated both targets. Similarly, the latter interventions led to significant downregulation of renal NLRP3, IL-1ß, NF-ĸB, Casp3, and MAPK8 mRNA, indicating a normalization of inflammasome and apoptotic pathways. Thus, we show therapies that reduce both hyperglycemia and inflammation may offer better management of diabetes and its complications.

Oral Nanocurcumin Alone or in Combination with Insulin Alleviates STZ-Induced Diabetic Neuropathy in Rats.

Diabetes mellitus (DM), a multifaceted metabolic disorder if not managed properly leads to secondary complications. Diabetic peripheral neuropathy (DPN) is one such complication caused by nerve damage that cannot be reversed but can be delayed. Recently, diabetes patients are using dietary supplements, although there remains a general skepticism about this practice. Curcumin (CUR), one such supplement can help prevent underlying low-grade inflammation in diabetes, but it is plagued by poor oral bioavailability. To better understand the role of bioavailability in clinical outcomes, we have tested double-headed nanosystems containing curcumin (nCUR) on DPN. Because CUR does not influence glucose levels, we have also tested the effects of nCUR combined with long-acting subcutaneous insulin (INS). nCUR with or without INS alleviates DPN at two times lower dose than unformulated CUR, as indicated by qualitative and quantitative analysis of the hind paw, sciatic nerve, spleen, and L4-6 spinal cord. In addition, nCUR and nCUR+INS preserve hind paw nerve axons as evident by the Bielschowsky silver stain and intraepidermal nerve fibers (IENF) density measured by immunofluorescence. The mechanistic studies further corroborated the results, where nCUR or nCUR+INS showed a significant decrease in TUNEL positive cells, mRNA expression of NLRP3, IL-1ß, and macrophage infiltration while preserving nestin and NF200 expression in the sciatic nerve. Together, the data confirms that CUR bioavailability is proportional to clinical outcomes and INS alone may not be one of the solutions for DM. This study highlights the potential of nCUR with or without INS in alleviating DPN and warrants further investigation.

Identification, virtual screening and molecular dynamic analysis of novel TMPRSS2 inhibitors from natural compound database as potential entry-blocking agents in SARS-CoV-2 therapy.

Scientific insights gained from the severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) outbreaks have been assisting scientists and researchers in the quest of antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses and influenza viruses both rely on the host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation. Recent studies report SARS-CoV-2 also uses TMPRSS2 to enter cells. In the current study, we employed structure-based virtual screening of 1,82,651 natural compounds downloaded from the zin database against the homology model of the TMPRSS2 protein, followed by a molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening yielded 110 hits with docking scores ranging from -8.654 to -6.775 and glide energies ranging from -55.714 to -29.065 kcal/mol. The binding mode analysis revealed that the hit molecules made H-bond, Pi-Pi stacking and salt bridge contacts with the TMPRSS2 active site residues. MD simulations of the top two hits (ZINC000095912839 and ZINC000085597504) revealed to form a stable complex with TMPRSS2, with a minimal RMSD and RMSF fluctuation. Both the hit structures interacted strongly with the Asp180, Gln183, Gly184, Ser186, Gly207 and Gly209, as predicted by Glide XP docking, and formed a significant H-bond interaction with Ser181 in MD simulation. Among these two, ZINC000095912839 was having the most stable binding interaction with TMPRSS2 of the two molecules. The present study successfully identified TMPRSS2 ligands from a database of zinc natural molecules as potential leads for novel SARs-CoV-2 treatment. Supplementary Inform: The online version contains supplementary material available at 10.1007/s11224-022-01991-3.

Paclitaxel and Urolithin A Prevent Histamine-Induced Neurovascular Breakdown Alike, in an Ex Vivo Rat Eye Model.

Neurovascular eye problems are better prevented than managed or treated. Despite growing concern of occurrence in aging populations and development secondary to diseases such as diabetes and hypertension, we currently have very few options to tackle this global problem. Creating effective and high-throughput screening strategies is as important as the intervention itself. Here, we present for the first time a robust ex vivo rat eye model of histamine-induced vascular damage for investigating the therapeutic potential of paclitaxel (PTX) and urolithin A (UA) as alternatives to dexamethasone for preventing vascular damage in the retina. Extensive loss of vascularization and apoptosis were observed in the histamine-challenged group and successfully prevented in the intervention groups, more significantly in the PTX and UA. These important early results indicate that PTX and UA could be developed as potential preventive strategies for a wide variety of retinal diseases.

Identification of novel TMPRSS2 inhibitors against SARS-CoV-2 infection: a structure-based virtual screening and molecular dynamics study.

The scientific insights gained from the severe acute respiratory syndrome (SARS) and the middle east respiratory syndrome (MERS) outbreaks are helping scientists to fast-track the antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses, as well as influenza viruses, depend on host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation in the human cell. Recent studies show that SARS-CoV-2 also uses TMPRSS2 for its cell entry. In the present study, a structure-based virtual screening of 52,337, protease ligands downloaded from the Zinc database was carried out against the homology model of TMPRSS2 protein followed by the molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening has identified 13 hits with a docking score range of -10.447 to -9.863 and glide energy range of -60.737 to -40.479 kcal/mol. The binding mode analysis shows that the hit molecules form H-bond (Asp180, Gly184 & Gly209), Pi-Pi stacking (His41), and salt bridge (Asp180) type of contacts with the active site residues of TMPRSS2. In the MD simulation of ZINC000013444414, ZINC000137976768, and ZINC000143375720 hits show that these molecules form a stable complex with TMPRSS2. The complex equilibrates well with a minimal RMSD and RMSF fluctuation. All three structures, as predicted in Glide XP docking, show a prominent interaction with the Asp180, Gly184, Gly209, and His41. Further, MD simulation also identifies a notable H-bond interaction with Ser181 for all three hits. Among these hits, ZINC000143375720 shows the most stable binding interaction with TMPRSS2. The present study is successful in identifying TMPRSS2 ligands from zinc data base for a possible application in the treatment of COVID-19.