Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration.

EFEMP1 R345W is a dominant mutation causing Doyne honeycomb retinal dystrophy/malattia leventinese (DHRD/ML), a rare blinding disease with clinical pathology similar to age-related macular degeneration (AMD). Aged Efemp1  R345W/R345W knock-in mice (Efemp1ki/ki) develop microscopic deposits on the basal side of retinal pigment epithelial cells (RPE), an early feature in DHRD/ML and AMD. Here, we assessed the role of alternative complement pathway component factor B (FB) in the formation of these deposits. RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3 months of age) and increased inflammatory pathways in both neural retina and posterior eyecups (at 17 months of age) of Efemp1ki/ki mice compared with wild-type littermate controls. Proteomics analysis of eye lysates confirmed similar dysregulated pathways as detected by RNA-seq. Complement activation was increased in aged Efemp1ki/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P < 0.05). Deletion of the Cfb gene in female Efemp1ki/ki mice partially normalized the above dysregulated biological pathway changes and oral dosing of a small molecule FB inhibitor from 10 to 12 months of age reduced sub-RPE deposits by 65% (P = 0.029). In contrast, male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females, no elevation of ocular complement activation and no effect of FB inhibition on sub-RPE deposits. The effects of FB deletion or inhibition on Efemp1ki/ki mice supports systemic inhibition of the alternative complement pathway as a potential treatment of dry AMD and DHRD/ML.

Potential of phytocompounds from Brassica oleracea targeting S2-domain of SARS-CoV-2 spike glycoproteins: Structural and molecular insights.

By 24th Sep. 2021, there are more than 229 million COVID-19 cases worldwide, the researchers are tirelessly working to discover and develop an efficient drug molecule against this devastative viral infection. This study aims to evaluate the inhibitory efficiency of the organic acids and phenolic compounds present in Brassica oleracea (Tronchuda Cabbage) against spike glycoprotein in SARS-CoV-2. Thirty-seven phytocompounds are screened on the basis of their molecular weight (<500 g/mol) and 14 ligands are docked using Autodock Vina and Autodock4 (version 4.2.6). The stability of the top five docked complexes was analyzed using classical molecular dynamics (MD) simulation. ADMET analysis is performed for the top five compounds and their targets are identified using SwissTargetPrediction. Phytoactives from B. oleracea namely Astragalin, 3-p-coumaroylquinic acid, 4-p-coumaroylquinic acid and sinapoyl-D-glucoside showed high binding affinities and free energy of binding during molecular docking and MD simulation studies (∼ 8.5-9.0 kcal/mol) for the spike glycoprotein trimer of SARS-CoV2. The ADMET analysis revealed that these phytocompounds have good solubility in the aqueous phase and that they don't penetrate the blood brain barrier. Moreover, there is no P-gp substrate inhibition, CYP1A2 inhibition, CYP2C19 inhibition, CYP2C9 inhibition, CYP2D6 inhibition and CYP3A4 inhibition observed for these compounds. Additionally, zero PAINS alerts were reported. These findings from molecular docking and MD simulation studies suggest that astragalin and coumaroylquinic acids from Tronchuda cabbage possess potential inhibitory capacity against spike glycoprotein trimer of SARS-CoV-2 and could be further taken up as lead targets for drug discovery.

Elements in trace amount with a significant role in human physiology: a tumor pathophysiological and diagnostic aspects.

Cancer has a devastating impact globally regardless of gender, age, and community, which continues its severity to the population due to the lack of efficient strategy for the cancer diagnosis and treatment. According to the World Health Organisation report, one out of six people dies due to this deadly cancer and we need effective strategies to regulate it. In this context, trace element has a very hidden and unexplored role and require more attention from investigators. The variation in concentration of trace elements was observed during comparative studies on a cancer patient and a healthy person making them an effective target for cancer regulation. The percentage of trace elements present in the human body depends on environmental exposure, food habits, and habitats and could be instrumental in the early diagnosis of cancer. In this review, we have conducted inclusive analytics on trace elements associated with the various types of cancers and explored the several methods involved in their analysis. Further, intricacies in the correlation of trace elements with prominent cancers like prostate cancer, breast cancer, and leukaemia are represented in this review. This comprehensive information on trace elements proposes their role during cancer and as biomarkers in cancer diagnosis.

Copper transporter protein (MctB) as a therapeutic target to elicit antimycobacterial activity against tuberculosis.

Tuberculosis (TB) is a prehistoric infection and major etiologic agent of TB, Mycobacterium tuberculosis, which is considered to have advanced from an early progenitor species found in Eastern Africa. By the 1800s, there were approximately 800 to 1000 fatality case reports per 100,000 people in Europe and North America. This research suggests an In-silico study to identify potential inhibitory compounds for the target Mycobacterial copper transport protein (Mctb). ADME-based virtual screening, molecular docking, and molecular dynamics simulations were conducted to find promising compounds to modulate the function of the target protein. Four chemical compounds, namely Anti-MCT1, Anti-MCT2, Anti-MCT3 and Anti-MCT4 out of 1500 small molecules from the Diverse-lib of MTiOpenScreen were observed to completely satisfy Lipinski rule of five and Veber's rule. Further, significantly steady interactions with the MctB target protein were observed. Docking experiments have presented 9 compounds with less than -9.0 kcal/mol free binding energies and further MD simulation eventually gave 4 compounds having potential interactions and affinity with target protein and favorable binding energy ranging from -9.2 to -9.3 kcal/mol. We may propose these compounds as an effective candidate to reduce the growth of M. tuberculosis and may also assist present a novel therapeutic approach for Tuberculosis. In vivo and In vitro validation would be needed to proceed further in this direction.Communicated by Ramaswamy H. Sarma.

Repurposing FDA-approved drugs as FXR agonists: a structure based in silico pharmacological study.

Farnesoid X receptor (FXR) modulates the expression of genes involved in lipid and carbohydrate homeostasis and inflammatory processes. This nuclear receptor is likely a tumor suppressor in several cancers, but its molecular mechanism of suppression is still under study. Several studies reported that FXR agonism increases the survival of colorectal, biliary tract, and liver cancer patients. In addition, FXR expression was shown to be down-regulated in many diseases such as obesity, irritable bowel syndrome, glomerular inflammation, diabetes, proteinuria, and ulcerative colitis. Therefore, development of novel FXR agonists may have significant potential in the prevention and treatment of these diseases. In this scenario, computer-aided drug design procedures can be resourcefully applied for the rapid identification of promising drug candidates. In the present study, we applied the molecular docking method in conjunction with molecular dynamics (MD) simulations to find out potential agonists for FXR based on structural similarity with the drug that is currently used as FXR agonist, obeticholic acid. Our results showed that alvimopan and montelukast could be used as potent FXR activators and outperform the binding affinity of obeticholic acid by forming stable conformation with the protein in silico. However, further investigational studies and validations of the selected drugs are essential to figure out their suitability for preclinical and clinical trials.

Influence of the patients' sex, type of dental prosthesis and antagonist on residual bone resorption at the level of the premaxilla.

OBJECTIVES: To analyze the height and width of the ridge at the level of the premaxilla in edentulous patients, evaluating whether the sex of the patient, type of prosthetic rehabilitation and antagonist have an influence. MATERIAL AND METHOD: We randomly selected a total of 89 patients, having an average age of 66.21 years old. A total of 308 measurements were made, all of them at the level of the premaxilla, in the intercanine area. As dependent variables, we analyzed the patients' sex, age and the antagonist: removable (dental) prostheses (RP), fixed (dental) prostheses (FD), natural dentition (ND). As independent variables, we measured the height and residual width in sagittal sections provided by tomographic studies using Dentascan®. RESULTS: We observed a significantly smaller ridge in women versus in men, and in patients whose antagonist was a fixed prosthesis; whereas for the type of prosthesis, we did not observe significant differences between the two categories analyzed. CONCLUSIONS: Bone resorption at the level of the premaxilla is a variable process in which a smaller size is observed (height and width) in women and when the antagonist is a fixed prosthesis.

Enzyme immobilization on biomass-derived carbon materials as a sustainable approach towards environmental applications.

Enzymes with their environment-friendly nature and versatility have become highly important 'green tools' with a wide range of applications. Enzyme immobilization has further increased the utility and efficiency of these enzymes by improving their stability, reusability, and recyclability. Biomass-derived matrices when used for enzyme immobilization offer a sustainable solution to environmental pollution and fuel depletion at low costs. Biochar and other biomass-derived carbon materials obtained are suitable for the immobilization of enzymes through different immobilization strategies. Environmental pollution has become an utmost topic of research interest due to an ever-increasing trend being observed in anthropogenic activities. This has widely contributed to the release of various toxic effluents into the environment in their native or metabolized forms. Therefore, more focus is being directed toward the utilization of immobilized enzymes in the bioremediation of water and soil, biofuel production, and other environmental applications. In this review, up-to-date literature concerning the immobilization and potential uses of enzymes immobilized on biomass-derived carbon materials has been presented.

Phytochemical constituents of Inula britannica as potential inhibitors of dihydrofolate reductase: A strategic approach against shigellosis.

Shigella dysenteriae type 1 is considered as an epidemic in different developing countries, which is responsible for the most severe form of bacterial dysentery. It habitually can develop to the most severe form of dysentery with deadly complications. Development of drugs against this disease is still ongoing. Therefore, we used in silico studies to screen the Inula britannica phytocompounds that are used in traditional Chinese and Kampo Medicines and have activities against different diseases. Spinacetin, eupatin, chrysoeriol and diosmetin were successfully passed through the docking-based screening and absorption, distribution, metabolism, excretion and toxicity (ADMET) filtration. The estimated docking affinities of eupatin, diosmetin, chrysoeriol and spinacetin with Dihydrofolate reductase type 1 (DHFR-1), were -6.5, -6.5, -6.3 and -6.1 kcal/mol, respectively. Which were selected for further investigations based on their favorable ADME/Tox characteristics. Then, the 100 ns molecular dynamics (MD) simulations of apo DHFR, spinacetin-DHFR, eupatin-DHFR, chrysoeriol-DHFR and diosmetin-DHFR complexes were carried out. The RMSD fluctuations of the spinacetin, eupatin, chrysoeriol and diosmetin inside the binding site were explored. Subsequently, the effect of binding Spinacetin, eupatin, chrysoeriol and diosmetin upon the dynamic stability of protein was assessed. Additionally, Principal Component Analysis (PCA) and Hydrogen bond analysis was performed for the apo protein and the protein ligand complexes. The results revealed that chrysoeriol and eupatin has good inhibitory effects against DHFR-1 as treatment for Shigella dysenteriae type when compared to other compounds under study. Hence this study implies that eupatin and chrysoeriol are a significantly potential drug like molecule for the treatment of Shigellosis and must undergo validation through in vivo and in vitro experiments.Communicated by Ramaswamy H. Sarma.

Targeting Nuclear Receptors in Lung Cancer-Novel Therapeutic Prospects.

Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.

Differential Expression of Genes Regulating Store-operated Calcium Entry in Conjunction With Mitochondrial Dynamics as Potential Biomarkers for Cancer: A Single-Cell RNA Analysis.

Regulation of intracellular concentration of calcium levels is crucial for cell signaling, homeostasis, and in the pathology of diseases including cancer. Agonist-induced entry of calcium ions into the non-excitable cells is mediated by store-operated calcium channels (SOCs). This pathway is activated by the release of calcium ions from the endoplasmic reticulum and further regulated by the calcium uptake through mitochondria leading to calcium-dependent inactivation of calcium-release activated calcium channels (CARC). SOCs including stromal interaction molecules (STIM) and ORAI proteins have been implicated in tumor growth, progression, and metastasis. In the present study, we analyzed the mRNA and protein expression of genes mediating SOCs-STIM1, STIM2, ORAI1, ORAI2, ORAI3, TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPC7, TRPV1, TRPV2, TRPM1, and TRPM7 in head and neck squamous cell cancer (HNSC) patients using TCGA and CPTAC analysis. Further, our in silico analysis showed a significant correlation between the expression of SOCs and genes involved in the mitochondrial dynamics (MDGs) both at mRNA and protein levels. Protein-protein docking results showed lower binding energy for SOCs with MDGs. Subsequently, we validated these results using gene expression and single-cell RNA sequencing datasets retrieved from Gene Expression Omnibus (GEO). Single-cell gene expression analysis of HNSC tumor tissues revealed that SOCs expression is remarkably associated with the MDGs expression in both cancer and fibroblast cells.

Nuclear receptors in oral cancer-Emerging players in tumorigenesis.

Oral cancer has been a global concern for decades, with an estimated 377,713 new cases and 177,757 deaths worldwide, according to the GLOBOCAN 2020. Despite extensive research over the years, there is still a need to establish therapeutic targets to improve patient survival in oral tumorigenesis. Nuclear receptors (NRs) are transcription factors that regulate various biological processes such as growth, differentiation, development, and metabolism, and their aberrant expression has been reported in many diseases, including cancers. Deregulation of different NRs has been linked to various alterations such as mutations, epigenetic changes, and impaired signaling cascades by other proteins and molecules. Very few studies have shown the diagnostic and prognostic potential of NRs in oral cancer. These receptors have been targeted using a plethora of agonists and antagonists, leading to inhibition of tumor proliferation, migration and invasion, and inducing apoptosis, suggesting that NRs could serve as plausible targets for treating oral malignancies. In this review, we focus on the involvement of NRs in oral tumor pathogenesis and highlight the importance of targeting NRs using various agonists and antagonists that could serve as a potential strategy for the prevention and treatment of oral malignancies.

A proteogenomic signature of age-related macular degeneration in blood.

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.

Clinician Adherence to Hypertension Screening and Care Guidelines.

This quality improvement study assesses opportunistic blood pressure measurement, communication of blood pressure reading to adult patients, and recommendation for a follow-up visit at health care facilities in 2 major cities in India.