In vitro and in vivo studies reveal α-Mangostin, a xanthonoid from Garcinia mangostana, as a promising natural antiviral compound against chikungunya virus.

BACKGROUND: Chikungunya virus (CHIKV), a serious health problem in several tropical countries, is the causative agent of chikungunya fever. Approved antiviral therapies or vaccines for the treatment or prevention of CHIKV infections are not available. As diverse natural phenolic compounds have been shown to possess antiviral activities, we explored the antiviral activity of α-Mangostin, a xanthanoid, against CHIKV infection. METHODS: The in vitro prophylactic and therapeutic effects of α-Mangostin on CHIKV replication in Vero E6 cells were investigated by administering it under pre, post and cotreatment conditions. The antiviral activity was determined by foci forming unit assay, quantitative RT-PCR and cell-based immune-fluorescence assay. The molecular mechanism of inhibitory action was further proposed using in silico molecular docking studies. RESULTS: In vitro studies revealed that 8 µM α-Mangostin completely inhibited CHIKV infectivity under the cotreatment condition. CHIKV replication was also inhibited in virus-infected mice. This is the first in vivo study which clearly showed that α-Mangostin is effective in vivo by significantly reducing virus replication in serum and muscles. Molecular docking indicated that α-Mangostin can efficiently interact with the E2-E1 heterodimeric glycoprotein and the ADP-ribose binding cavity of the nsP3 macrodomain. CONCLUSIONS: The findings suggest that α-Mangostin can inhibit CHIKV infection and replication through possible interaction with multiple CHIKV target proteins and might act as a prophylactic/therapeutic agent against CHIKV.

In Vitro Antiviral Activity of α-Mangostin against Dengue Virus Serotype-2 (DENV-2).

Dengue virus (DENV), a member of the family Flaviviridae, is a threat for global health as it infects more than 100 million people yearly. Approved antiviral therapies or vaccines for the treatment or prevention of DENV infections are not available. In the present study, natural compounds were screened for their antiviral activity against DENV by in vitro cell line-based assay. α-Mangostin, a xanthanoid, was observed to exert antiviral activity against DENV-2 under pre-, co- and post-treatment testing conditions. The antiviral activity was determined by foci forming unit (FFU) assay, quantitative RT-PCR and cell-based immunofluorescence assay (IFA). A complete inhibition of DENV-2 was observed at 8 µM under the co-treatment condition. The possible inhibitory mechanism of α-Mangostin was also determined by docking studies. The molecular docking experiments indicate that α-Mangostin can interact with multiple DENV protein targets such as the NS5 methyltransferase, NS2B-NS3 protease and the glycoprotein E. The in vitro and in silico findings suggest that α-Mangostin possesses the ability to suppress DENV-2 production at different stages of its replication cycle and might act as a prophylactic/therapeutic agent against DENV-2.

Perspectives for repurposing drugs for the coronavirus disease 2019.

The newly emerged 2019 novel coronavirus (CoV), named as severe acute respiratory syndrome CoV-2 (SARS-CoV-2), like SARS-CoV (now, SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV), has been associated with high infection rates with over 36,405 deaths. In the absence of approved marketed drugs against coronaviruses, the treatment and management of this novel CoV disease (COVID-19) worldwide is a challenge. Drug repurposing that has emerged as an effective drug discovery approach from earlier approved drugs could reduce the time and cost compared to de novo drug discovery. Direct virus-targeted antiviral agents target specific nucleic acid or proteins of the virus while host-based antivirals target either the host innate immune responses or the cellular machineries that are crucial for viral infection. Both the approaches necessarily interfere with viral pathogenesis. Here we summarize the present status of both virus-based and host-based drug repurposing perspectives for coronaviruses in general and the SARS-CoV-2 in particular.

Full-genome sequences of the first two SARS-CoV-2 viruses from India.

Background & objectives: Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has globally affected 195 countries. In India, suspected cases were screened for SARS-CoV-2 as per the advisory of the Ministry of Health and Family Welfare. The objective of this study was to characterize SARS-CoV-2 sequences from three identified positive cases as on February 29, 2020. Methods: Throat swab/nasal swab specimens for a total of 881 suspected cases were screened by E gene and confirmed by RdRp (1), RdRp (2) and N gene real-time reverse transcription-polymerase chain reactions and next-generation sequencing. Phylogenetic analysis, molecular characterization and prediction of B- and T-cell epitopes for Indian SARS-CoV-2 sequences were undertaken. Results: Three cases with a travel history from Wuhan, China, were confirmed positive for SARS-CoV-2. Almost complete (29,851 nucleotides) genomes of case 1, case 3 and a fragmented genome for case 2 were obtained. The sequences of Indian SARS-CoV-2 though not identical showed high (~99.98%) identity with Wuhan seafood market pneumonia virus (accession number: NC 045512). Phylogenetic analysis showed that the Indian sequences belonged to different clusters. Predicted linear B-cell epitopes were found to be concentrated in the S1 domain of spike protein, and a conformational epitope was identified in the receptor-binding domain. The predicted T-cell epitopes showed broad human leucocyte antigen allele coverage of A and B supertypes predominant in the Indian population. Interpretation & conclusions: The two SARS-CoV-2 sequences obtained from India represent two different introductions into the country. The genetic heterogeneity is as noted globally. The identified B- and T-cell epitopes may be considered suitable for future experiments towards the design of vaccines and diagnostics. Continuous monitoring and analysis of the sequences of new cases from India and the other affected countries would be vital to understand the genetic evolution and rates of substitution of the SARS-CoV-2.

Angiosarcoma of the Eyelid With Superimposed Enterobacter Infection.

Angiosarcoma is a rare, aggressive, malignant endothelial neoplasm with a variable clinical presentation. The authors describe a case of angiosarcoma involving the eyelid that was complicated by a superimposed Enterobacter infection. Following positive cultures for E. aerogenes and multiple biopsies suspicious but not definitive for angiosarcoma, a final biopsy was consistent with angiosarcoma.

Cytotoxicity of Manganese (III) Complex in Human Breast Adenocarcinoma Cell Line Is Mediated by the Generation of Reactive Oxygen Species Followed by Mitochondrial Damage.

Manganese (Mn) complexes are widely studied because of their important catalytic properties in synthetic and biochemical reactions. A Mn (III) complex of an amidoamine ligand was synthesized using a tetradentate amidoamine ligand. In this study, the Mn (III) complex was evaluated for its biological activity by measuring its cytotoxicity in human breast adenocarcinoma cell line (MCF-7). Cytotoxic effects of the Mn (III) complex were determined using established biomarkers in an attempt to delineate the mechanism of action and the utility of the complex as a potential anticancer drug. The Mn (III) complex induces cell death in a dose- and time-dependent manner as shown by microculture tetrazolium assay, a measure of cytotoxic cell death. Our results demonstrated that cytotoxic effects were significantly increased at higher concentrations of Mn (III) complex and with longer time of treatment. The IC50 (Inhibitor concentration that results in 50% cell death) value of Mn (III) complex in MCF-7 cells was determined to be 2.5 mmol/L for 24 hours of treatment. In additional experiments, we determined the Mn (III) complex-mediated cell death was due to both apoptotic and nonspecific necrotic cell death mechanisms. This was assessed by ethidium bromide/acridine orange staining and flow cytometry techniques. The Mn (III) complex produced reactive oxygen species (ROS) triggering the expression of manganese superoxide dismutase 1 and ultimately damaging the mitochondrial function as is evident by a decline in mitochondrial membrane potential. Treatment of the cells with free radical scavenger, N, N-dimethylthiourea decreased Mn (III) complex-mediated generation of ROS and attenuated apoptosis. Together, these results suggest that the Mn (III) complex-mediated MCF-7 cell death utilizes combined mechanism involving apoptosis and necrosis perhaps due to the generation of ROS.

Natural polyphenols based new therapeutic avenues for advanced biomedical applications.

Polyphenols are naturally occurring, synthetic or semisynthetic organic compounds that offer a vast array of advanced biomedical applications. The mostly researched polyphenolic compounds are resveratrol and flavanols, notably (-)-epicatechin. The ongoing research on clinically important resveratrol and flavanols has revealed their potentials as extremely efficient drug agents that can be leveraged for new therapeutic designs for combating stroke related injuries, cancer and renal failures. Here, we have highlighted recent developments in this area with an emphasis on the biomedical applications of polyphenols. Also, a perspective on the future research directions has been discussed. We believe that this review would facilitate further research and development of polyphenols as a therapeutic avenue in medical science.

Psychological language on Twitter predicts county-level heart disease mortality.

Hostility and chronic stress are known risk factors for heart disease, but they are costly to assess on a large scale. We used language expressed on Twitter to characterize community-level psychological correlates of age-adjusted mortality from atherosclerotic heart disease (AHD). Language patterns reflecting negative social relationships, disengagement, and negative emotions-especially anger-emerged as risk factors; positive emotions and psychological engagement emerged as protective factors. Most correlations remained significant after controlling for income and education. A cross-sectional regression model based only on Twitter language predicted AHD mortality significantly better than did a model that combined 10 common demographic, socioeconomic, and health risk factors, including smoking, diabetes, hypertension, and obesity. Capturing community psychological characteristics through social media is feasible, and these characteristics are strong markers of cardiovascular mortality at the community level.

Chronic Conjunctivitis due to Nocardia nova Complex Formation on a Silicone Stent: A Case Report and Review of the Literature.

Nocardial conjunctivitis associated with silicone tubing is an extremely rare finding. The authors present a case of a 52-year-old woman with previous dacryocystorhinostomy and silicone tube placement 3 years prior who presented with OD redness and discharge for 1 week. On examination, the patient was noted to have mucoid discharge and crusting surrounding the silicone tube. The tube debris was sampled, and the culture was positive for Nocardia nova complex sensitive to trimethoprim/sulfamethoxazole and amikacin. Silicone tube colonization and N. nova complex conjunctivitis are both rare but should be considered in the differential diagnosis of patients with indwelling silicone tubes presenting with chronic conjunctivitis resistant to fluoroquinolones and tobramycin.

Oral administration of the flavanol (-)-epicatechin bolsters endogenous protection against focal ischemia through the Nrf2 cytoprotective pathway.

Consumption of flavan-3-ols, notably (-)-epicatechin (EC), has been highly recommended in complementary and alternative medicine (CAM) due to reports that flavan-3-ols boost antioxidant activity, support vascular function, and prevent cardiovascular disease. To date, in vivo efficacy and mechanisms of action for many CAM therapies, including EC, remain elusive in brain ischemia. In contrast to its purported direct antioxidant role, we hypothesized protection through activation of the endogenous transcriptional factor Nrf2. To screen cellular protection and investigate Nrf2 activation, we adopted a pretreatment paradigm using enriched primary neuronal cultures from mice and washed out EC prior to oxygen glucose deprivation to attenuate direct antioxidant effects. EC protected primary neurons from oxygen glucose deprivation by increasing neuronal viability (40.2 ± 14.1%) and reducing protein oxidation, effects that occurred concomitantly with increased Nrf2-responsive antioxidant protein expression. We also utilized wildtype and Nrf2 C57BL/6 knockout mice in a permanent model of focal brain ischemia to evaluate glial cell regulation and complex sensorimotor functioning. EC-treated wildtype mice displayed a reduction or absence of forelimb motor coordination impairments that were evident in vehicle-treated mice. This protection was associated with reduced anatomical injury (54.5 ± 8.3%) and microglia/macrophage activation/recruitment (56.4 ± 13.0%). The protective effects elicited by EC in both model systems were abolished in tissues and neuronal cultures from Nrf2 knockout mice. Together, these data demonstrate EC protection through Nrf2 and extend the benefits to improved performance on a complex sensorimotor task, highlighting the potential of flavan-3-ols in CAM approaches in minimizing subsequent stroke injury.

A Comparative Study to Explore Static and Dynamic Lung Functions in Users and Non-Users of Air Conditioners in Bengaluru.

Background: Air conditioners (AC) have become indispensable in the contemporary World. However, their effects on respiratory health need to be explored further using dynamic and static lung functions. Objectives: The objectives were: 1. To evaluate and compare dynamic parameters (FEV1, FVC, FEV1/FVC, PEFR, and FEF25-75) in AC users and non-users of Bengaluru. 2. To evaluate and compare airway resistance and specific airway conductance as additional parameters. Materials and Methods: After applying ATS-ERS criteria for lung disorders, 30 AC users and non-users of Bengaluru, aged 18-40 yrs were assessed using body plethysmography. A significant association of restrictive pattern was seen in AC users (9 AC users out of 60 participants, Chi-square 8.37, P = 0.0038) having an Odd's ratio of 26.95 (CI: 1.4876 to 488.3558, Z = 2.229, P = 0.0258). Airway resistance (Raw) was comparable in both groups further indicating a non-obstructive pathology. Conclusion: AC users had a significant decrease in flow rates (PEFR and FEF25-75) as well as an association with restrictive lung disorder suggesting the need for proper ventilation and hygiene. It is crucial to develop policies to maintain indoor air quality.

Comparative evaluation of circumferential crestal bone loss after 1 year of implant placement with flapless versus flap surgery using surgical template after immediate loading in the posterior mandibular region using cone-beam computed tomography: A randomized controlled trial.

Aim: The study was aimed to evaluate circumferential crestal bone level after one year of implant placement with flapless versus flap surgery using surgical template after immediate loading in the posterior mandibular region using CBCT. Setting and Design: The study was designed as a Randomized controlled trial. Material and Methods: 32 implants were placed in single edentulous spaces in the mandibular posterior region after random allocation into two groups: Flap surgery (Group A) and Flapless surgery (Group B). Virtual implant planning was performed using Blue Sky Bio software, and static CBCT guided 3D printed surgical templates were fabricated for all participants of both the groups. Immediate non-functional temporization was performed. Circumferential crestal bone levels were assessed after surgery and one-year follow-up using CBCT and XELIS software. Vertical bone loss (VBL) and horizontal bone loss (HBL) was assessed on four sides: buccal, lingual, mesial and distal. Statistical Analysis Used: Data was analyzed using Statistical Package for Social Sciences IBM Corp. Released 2017, IBM SPSS Statistics for Windows, Version 25.0. (Armonk, NY: IBM Corp.) and Graph Pad Prism 7.0 version. The level of significance was chosen <0.05. Chi square test was performed to assess the difference in the age in the two groups. Mann-Whitney U test was performed to compare the two groups for outcome measure. Graphically, quantile-quantile (Q-Q) plot was made using mean and standard deviation for normality verification of data. Results: 100% survival rate and patient compliance was observed along the one-year follow-up duration. By using Mann-Whitney U test, statistically significant difference was found in the vertical bone loss among participants of Flap surgery (Group A) and Flapless surgery (Group B) on all the four sides after one year of implant placement. However, significant results were not obtained for the difference in the horizontal bone level. Conclusion: Within the limitations of this study, vertical bone loss measured circumferentially was more positively correlated with the implants placed with flap surgery compared to flapless surgery after immediate loading in the posterior mandibular region after one year.

Growing concerns on male reproductive health amidst COVID-19 pandemic.

Blood-testis barrier is body's innate mechanism to defend germ cells by creating a physical and immunological barrier. But some viral infections are known to evade it. As ACE2 and TMPRSS2 are present all over the body including male reproductive tract, it is worth exploring how coronavirus disease (COVID-19) could possibly affect male fertility. A review of literature was done using search engines like PubMed, Medline, Google Scholar, etc., and all the latest articles up to May 2021 were considered. Some studies have substantiated the presence of orchitis in COVID patients using semen and tissue samples. Though most studies report the absence of virus in testis, involvement of seminiferous tubules has been seen in pathological analysis suggesting defective spermatogenesis. This can be primarily attributed to inflammation and increased vascular permeability. Other factors that could affect male fertility are fever, autoimmune response, drugs, and erectile dysfunction. Male fertility is an important aspect of health care and must be looked into. Further studies can be done to understand host immunity towards SARS-CoV-2 in the testis. It will be worthwhile to know whether viral orchitis and its sequelae are acute or chronic in nature, and if they are reversible. Effect of the virus on female reproductive tract can also be assessed further. Counselling can be given to affected/recovering patients along with correct selection of drugs to prevent these long-term complications.

Delineation of an epitope recognized by a chikungunya virus anti-capsid monoclonal antibody on the protease domain using an immuno-informatics approach.

The capsid-protein (CP) of chikungunya virus (CHIKV) is reported to generate a primary immune response in infected individuals during disease progression. CP-specific monoclonal antibodies (mAbs) developed in our laboratory, exhibited promising potential in diagnosing recent CHIKV infection in IgM capture ELISA. In this study we focused on the molecular and structural characterization of one such representative mAb ClVE4/D9 to delineate the epitope recognized by it using an immuno-informatics approach. The antigen-antibody interacting residues were found to lie within the dimer interface region of the CP, also predicted as a conformational epitope. This implies that the mAb could interfere during the process of nucleocapsid assembly, ultimately preventing budding and egress of the virus particle. The binding specificity of the mAb highlights the possibility of using this anti-CP antibody for therapeutic or prophylactic treatment against CHIKV.Communicated by Ramaswamy H. Sarma.

Cardiovascular Autonomic Function Tests in Patients of Obsessive-Compulsive Disorder: A Cross-Sectional Study.

Background: Patients with psychiatric disorders are at an increased risk of developing cardiovascular disease, reducing life expectancy. Autonomic dysfunction has been linked to this increased risk; many studies have found reductions in heart rate variability (HRV). Only a few studies have systematically explored the relationship between obsessive-compulsive disorder (OCD) and autonomic function, and they have found contradicting results. The present study is intended to explore comprehensive autonomic functions in OCD patients and compare them with healthy controls. Methods: A total of 18 OCD patients meeting Diagnostic and Statistical Manual of Mental Disorders - 5 (DSM-5) criteria were enrolled to undergo comprehensive autonomic function testing, and the results were compared with 25 age- and sex-matched healthy controls. Results: Time-domain parameters of HRV such as standard deviation of the RR intervals, coefficient of variance of RR intervals, standard deviation of differences between adjacent RR intervals, root square of the mean of the sum of the squares of differences between adjacent RR intervals, and percentage of number of RR interval differences ≥ 50 ms were significantly lower in OCD patients, indicating lesser parasympathetic tone. Frequency-domain parameters such as total power and very low frequency were significantly lower in OCD patients, indicating a significant decrease in autonomic tone. Nonlinear parameters such as dispersion of points perpendicular to the line of identity and dispersion of points along the line of identity were significantly lower in OCD patients, indicating altered vagal and sympathetic tone. In autonomic reactivity tests, the fall in systolic blood pressure during the lying to standing test and change in diastolic blood pressure during the cold pressor test were significantly altered in OCD patients, indicating abnormal sympathetic reactivity. There was no significant correlation between autonomic parameters and the severity of OCD. Conclusion: OCD is characterized by a decreased parasympathetic tone and abnormal sympathetic reactivity compared to normal controls.

Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers.

Plasma transfusions are standard treatments to replace missing proteins in people with rare genetic diseases. Prior studies have demonstrated that heterochronic parabiosis has beneficial effects on several tissues of old animals receiving young blood. Human clinical trials are currently underway to investigate whether the infusion of plasma or plasma-derived factors from young donors can be used to mitigate human age-related conditions. Here, we use data from a safety study (n = 18, mean age 74) to investigate whether human umbilical cord plasma concentrate (hereinafter Plasma Concentrate) injected weekly (1 ml intramuscular) into elderly human subjects over a 10-week period affects different biomarkers, including epigenetic age measures, standard clinical biomarkers of organ dysfunction, mitochondrial DNA copy number (mtDNA-CN), and leukocyte telomere length. This study shows that treatment with plasma concentrate is safe. More than 20 clinical biomarkers were significantly and beneficially altered following the treatments. For example, creatinine was significantly decreased (p = 0.0039), while estimated glomerular filtration rate (eGFR) was increased (p = 0.0044), indicating the treatment may improve biomarkers of kidney function. Three of four immunoglobulin biomarkers decreased, while telomere length and mtDNA-CN were not significantly affected by the treatment. The treatment reduced DNA methylation-based GrimAge by an average of 0.82 years (p = 0.0093), suggests a reduction in morbidity and mortality risk. By contrast, no significant results could be observed for epigenetic clocks that estimate chronological age. Our results support the view that plasma concentrate contains youth-promoting factors.

Comparative evaluation of crestal bone level by flapless and flap techniques for implant placement: Systematic review and meta-analysis.

Aim: :To compare the crestal bone level of flapless technique of dental implant placement with the flap technique. Setting and Design: This Systematic review and Meta-analysis was conducted according to the Preferred Reporting Items For Systematic Review and Meta-Analyses (PRISMA) Guidelines and registered with PROSPERO. Materials and Methods: Electronic search of Medline and Google scholar databases for articles from 2010 till March 2020 was performed. Studies comparing the crestal bone level with both the techniques were included. After the collection of data, the risk of bias was assessed for each study. Statistical Analysis Used: Meta-analysis was executed using RevMan 5 software version 5.3. Results: 23 studies were included. Statistically significant difference in crestal bone level was found between flapless and flap surgery with mean difference of -0.14 (flapless placement versus flap surgery; 95% CI: -0.24 to -0.03; P = 0.01FNx01). The difference in crestal bone level between the 2 groups was not statistically significant with a mean difference of -0.05(Guided flapless placement versus flap surgery; 95% CI: -0.10 to 0.00; P=0.06). Meta-analysis of the freehand flapless surgery with flap surgery generated a mean difference of -0.20 which was found to be statistically significant (Freehand flapless placement versus flap surgery; 95% CI: -0.37 to -0.03; P=0.02FNx01). Conclusions: Flapless placement of implant can positively influence crestal bone loss in comparison with conventional flap technique.

Ligand sensing enhances bacterial flagellar motor output via stator recruitment.

It is well known that flagellated bacteria, such as Escherichia coli, sense chemicals in their environment by a chemoreceptor and relay the signals via a well-characterized signaling pathway to the flagellar motor. It is widely accepted that the signals change the rotation bias of the motor without influencing the motor speed. Here, we present results to the contrary and show that the bacteria is also capable of modulating motor speed on merely sensing a ligand. Step changes in concentration of non-metabolizable ligand cause temporary recruitment of stator units leading to a momentary increase in motor speeds. For metabolizable ligand, the combined effect of sensing and metabolism leads to higher motor speeds for longer durations. Experiments performed with mutant strains delineate the role of metabolism and sensing in the modulation of motor speed and show how speed changes along with changes in bias can significantly enhance response to changes in its environment.

Author Correction: Molecular Mechanism of Switching of TrkA/p75NTR Signaling in Monocrotophos Induced Neurotoxicity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel PMMA bone cement nanocomposites containing magnesium phosphate nanosheets and hydroxyapatite nanofibers.

Lack of bioactivity and monomer toxicity are limiting factors of polymethyl methacrylate (PMMA) bone cement in orthopedic applications. Herein, we address these shortcomings by proposing two-dimensional magnesium phosphate (MgP) nanosheets and hydroxyapatite (HA) nanofibers as novel fillers in PMMA bone cement nanocomposites. Two-dimensional MgP nanosheets and one-dimensional HA nanofibers were synthesized by tuning the crystallization of the sodium-magnesium-phosphate ternary system and hydrothermal homogeneous precipitation, respectively. We show that MgP nanosheets exhibit antibacterial properties against Escherichia coli (E. coli). In addition, HA nanofibers with high level of bioactivity are the proper choice to induce cell viability in the nanocomposite. Results indicate that the combination of both fillers can act as deformation locks enhancing the compressive strength of the nanocomposites. The synthesized nanocomposite possesses excellent bioactivity, mechanical properties, and cytocompatibility potentially opening new paradigm in the design of next generation bone cement composites.