Exploring the Potential of Exosomes as Biomarkers in Tuberculosis and Other Diseases.

Tuberculosis (TB) is a major cause of morbidity and mortality and remains an important public health issue in developing countries worldwide. The existing methods and techniques available for the diagnosis of TB are based on combinations of laboratory (chemical and biological), radiological, and clinical tests. These methods are sophisticated and laborious and have limitations in terms of sensitivity, specificity, and accuracy. Clinical settings need improved diagnostic biomarkers to accurately detect biological changes due to pathogen invasion and pharmacological responses. Exosomes are membrane-bound vesicles and mediators of intercellular signaling processes that play a significant role in the pathogenesis of various diseases, such as tuberculosis, and can act as promising biomarkers for the monitoring of TB infection. Compared to conventional biomarkers, exosome-derived biomarkers are advantageous because they are easier to detect in different biofluids, are more sensitive and specific, and may be useful in tracking patients' reactions to therapy. This review provides insights into the types of biomarkers, methods of exosome isolation, and roles of the cargo (proteins) present in exosomes isolated from patients through omics studies, such as proteomics. These findings will aid in developing new prognostic and diagnostic biomarkers and could lead to the identification of new therapeutic targets in the clinical setting.

Thuja occidentalis: An Unexplored Phytomedicine with Therapeutic Applications.

BACKGROUND: The recent outbreak of SARS-CoV-2 has received global attention. Due to a lack of recommended treatment regimens, the world faced various limitations resulting in improper management of the disease. Phytomedicines have played a prominent role in the prevention of various epidemics and pandemics in the past. OBJECTIVE: Here, we attempt to focus on safe and feasible use of Thuja occidentalis to manage and alleviate the panic of viral respiratory infections, including COVID-19, by strengthening an individual's immunity. The relevant information was collected from the web-based databases PubMed, Google Scholar, and MEDLINE, as well as other internet sources to review the applicability of T. occidentalis as a phytomedicine in managing respiratory infections and strengthening immunity. CONCLUSION: As important phytomedicine, and antipsychotic, T. occidentalis possesses a plethora of immunological properties that can be used effectively in the management of viral respiratory infections and has the potential to prevent further progression of the disease. Importantly, this could be only a part of the approach for treatment during the current outbreak that should be considered along with other measures.

BESFA: bioinformatics based evolutionary, structural & functional analysis of prostrate, Placenta, Ovary, Testis, and Embryo (POTE) paralogs.

The POTE family comprises 14 paralogues and is primarily expressed in Prostrate, Placenta, Ovary, Testis, Embryo (POTE), and cancerous cells. The prospective function of the POTE protein family under physiological conditions is less understood. We systematically analyzed their cellular localization and molecular docking analysis to elucidate POTE proteins' structure, function, and Adaptive Divergence. Our results suggest that group three POTE paralogs (POTEE, POTEF, POTEI, POTEJ, and POTEKP (a pseudogene)) exhibits significant variation among other members could be because of their Adaptive Divergence. Furthermore, our molecular docking studies on POTE protein revealed the highest binding affinity with NCI-approved anticancer compounds. Additionally, POTEE, POTEF, POTEI, and POTEJ were subject to an explicit molecular dynamic simulation for 50ns. MM-GBSA and other essential electrostatics were calculated that showcased that only POTEE and POTEF have absolute binding affinities with minimum energy exploitation. Thus, this study's outcomes are expected to drive cancer research to successful utilization of POTE genes family as a new biomarker, which could pave the way for the discovery of new therapies.

Phytochemicals: A potential next generation agent for radioprotection.

BACKGROUND: Radiation hazards are accountable for extensive damage in the biological system and acts as a public health burden. Owing to the rapid increasing in radiation technology, both Ionizing radiation (IR) from natural and man made source poses detrimental outcome to public health. IR releases free radicals which induces oxidative stress and deleterious biological damage by modulating radiation induced signalling intermediates. The efficacy of existing therapeutic approach and treatment strategy are limited owing to their toxicity and associated side effects. Indian system of traditional medicine is enriched with prospective phytochemicals with potential radioprotection ability. PURPOSE: The present review elucidated and summarized the potential role of plant derived novel chemical compound with prospective radioprotective potential. METHOD: So far as the traditional system of Indian medicine is concerned, plant kingdom is enriched with potential bioactive molecules with diverse pharmacological activities. We reviewed several compounds mostly secondary metabolites from plant origin using various search engines. RESULTS: Both compounds from land plants and marine source exhibited antioxidant antiinflammatory, free radical scavenging ability. These compounds have tremendous potential in fine-tuning of several signalling intermediates, which are actively participated in the progression and development of a pathological condition associated with radiation stress. CONCLUSION: Development and explore of an operational radioprotective agent from originated from plant source that can be used as a novel molecular tool to eliminate the widespread damage caused by space exploration, ionizing radiation, nuclear war and radiotherapy has been significantly appreciated. Through extensive literature search we highlighted several compounds from both land plant and marine origin can be implemented for a better therapeutic potential against radiation induced injury. Furthermore, extensive clinical trials must be carried out in near future for better therapeutic modality and clinical efficacy.

Host-mycobacteria conflict: Immune responses of the host vs. the mycobacteria TLR2 and TLR4 ligands and concomitant host-directed therapy.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the most grievous infectious diseases with long-term morbidity and unpredicted mortality rates globally. Thus, understanding the host-pathogen interactions to develop potential drugs is the most focused area of research. Mtb has many antigens communicating with host cells via various pattern recognition receptors (PRRs). From which, toll-like receptors-2 and 4 (TLR2 and 4) are two major PRRs that provide the primary immune response to Mtb infection of the respiratory tract. As a result, the TLR-mycobacterium antigen interaction triggers a variety of crucial innate immune signalling mechanisms such as phagosome maturation, oxidative stress, elicitation of cell deaths, production of proinflammatory cytokines, and eventually associates with the adaptive immune response to establish infection. Despite the extensive investigations on TLR2 and 4 Mtb ligands that have a significant role in the immune defence system, there are still many unsolved concerns driving researchers to explore the obscures. This review focuses on the host immune modulation due to Mtb-TLR2 and 4 ligand interaction. Subsequently, the host TLR2 and 4 immune signals in cooperation with other PRRs and successive cytokine expressions are discussed. Also highlighted are some recent findings on host-directed therapy related to TLRs that aid in developing novel immunotherapeutic prospects for the better control of Mtb infection.

Leveraging epigenetics to enhance the efficacy of cancer-testis antigen: a potential candidate for immunotherapy.

Ovarian cancer is the most lethal gynecological malignancy in women. The phenotype is characterized by delayed diagnosis, recurrence and drug resistance. Inherent immunogenicity potential, oncogenic function and expression of cancer-testis/germline antigen (CTA) in ovarian cancer render them a potential candidate for immunotherapy. Revolutionary clinical findings indicate that tumor antigen-mediated T-cell and dendritic cell-based immunotherapeutic approaches provide an excellent strategy for targeting tumors. Currently, dendritic cell vaccination for the treatment of B-cell lymphoma and CTA-based T-cell receptor transduced T-cell therapy involving MAGE-A4 and NY-ESO-1 are well documented and shown to be effective. This review highlighted the mechanical aspects of epigenetic drugs that can elicit a CTA-based humoral and cellular immune response and implicate T-cell and dendritic cell-based immunotherapeutic approaches.

Despite substantial advancements in prognosis and diagnostic approaches, epithelial ovarian cancer is still the most lethal gynecological malignancy worldwide. In addition to radiotherapy, chemotherapy, hormonal therapy, and surgery, immunotherapy in the clinical setting is promising. Tumor-restricted expression and strong immunogenic potential make cancer-testis/germline antigen (CTA) a potential candidate for efficient T-cell and dendritic cell-mediated cancer immunotherapy. The expression of CTAs is shown to be modulated by a specific epigenetic fine-tuning mechanism. However, the expression and role of CTA in epithelial ovarian cancer immunotherapy are poorly understood. Therefore, in the current work, the authors thoroughly highlight and explore the possible epigenetic mechanisms associated with CTA expression and their implication in T-cell and dendritic cell-based immunotherapy approaches to ovarian cancer. Understanding such a paradigm is essential to adopting a precision medicine approach for better therapeutic options.

Low-dose priming of gamma radiation enhanced cadmium tolerance in Chlamydomonas reinhardtii by modulating physio-biochemical pathways.

Microalgae are natural biotic models for exploring the genotoxic effect of heavy metals, irradiation, other external stimuli and the toxicant elimination. The effective removal of heavy metals from the aquatic environment using microalgae has gained considerable attention. However, limited research was carried out on cadmum toxicity in microalgae and their use as bio-accumulants. Previous research suggested that low-dose priming with non-ionizing radiations, such as gamma radiation, increased heavy metal tolerance in plants and aquatic photosynthetic microalgae. In the present study, we have hypothesized the growth inhibitory physiochemical properties of cadmium (Cd) in Chlamydomonas reinhardtii, and analyzed the protective role of low-dose gamma radiations priming against Cd-induced growth inhibition by emphasizing mechanism of cell survival by antioxidant defence system. Experimentally, the gamma-primed C. reinhardtii exhibited higher cell survival and Cd tolerance with effective modulation of biochemical responses such as antioxidant enzymes. The current investigation revealed that low-dose priming of gamma radiation masks Cd-mediated oxidative stress and enhances cellular detoxification via intracellular antioxidant enzymes in C. reinhardtii.

Inactivated whole-virion vaccine BBV152/Covaxin elicits robust cellular immune memory to SARS-CoV-2 and variants of concern.

BBV152 is a whole-virion inactivated vaccine based on the Asp614Gly variant. BBV152 is the first alum-imidazoquinolin-adjuvanted vaccine authorized for use in large populations. Here we characterized the magnitude, quality and persistence of cellular and humoral memory responses up to 6 months post vaccination. We report that the magnitude of vaccine-induced spike and nucleoprotein antibodies was comparable with that produced after infection. Receptor binding domain-specific antibodies declined against variants in the order of Alpha (B.1.1.7; 3-fold), Delta (B.1.617.2; 7-fold) and Beta (B.1.351; 10-fold). However, pseudovirus neutralizing antibodies declined up to 2-fold against the Delta followed by the Beta variant (1.7-fold). Vaccine-induced memory B cells were also affected by the Delta and Beta variants. The SARS-CoV-2-specific multicytokine-expressing CD4+ T cells were found in ~85% of vaccinated individuals. Only a ~1.3-fold reduction in efficacy was observed in CD4+ T cells against the Beta variant. We found that antigen-specific CD4+ T cells were present in the central memory compartment and persisted for at least up to 6 months post vaccination. Vaccine-induced CD8+ T cells were detected in ~50% of individuals. Importantly, the vaccine was capable of inducing follicular T helper cells that exhibited B-cell help potential. These findings show that inactivated vaccine BBV152 induces robust immune memory to SARS-CoV-2 and variants of concern that persists for at least 6 months after vaccination.

An efficient immunoassay for the B cell help function of SARS-CoV-2-specific memory CD4+ T cells.

The B cell "help" function of CD4+ T cells is an important mechanism of adaptive immunity. Here, we describe improved antigen-specific T-B cocultures for quantitative measurement of T cell-dependent B cell responses, with as few as ∼90 T cells. Utilizing M. tuberculosis (Mtb), we show that early priming and activation of CD4+ T cells is important for productive interaction between T and B cells and that similar effects are achieved by supplementing cocultures with monocytes. We find that monocytes promote survivability of B cells via BAFF and stem cell growth factor (SCGF)/C-type lectin domain family 11 member A (CLEC11A), but this alone does not fully recapitulate the effects of monocyte supplementation. Importantly, we demonstrate improved activation and immunological output of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific memory CD4+ T-B cell cocultures with the inclusion of monocytes. This method may therefore provide a more sensitive assay to evaluate the B cell help quality of memory CD4+ T cells, for example, after vaccination or natural infection.

Preliminary Investigation of the Antioxidant, Anti-Diabetic, and Anti-Inflammatory Activity of Enteromorpha intestinalis Extracts.

Marine algae are a promising source of potent bioactive agents against oxidative stress, diabetes, and inflammation. However, the possible therapeutic effects of many algal metabolites have not been exploited yet. In this regard, we explored the therapeutic potential of Enteromorpha intestinalis extracts obtained from methanol, ethanol, and hexane, in contrasting oxidative stress. The total phenolic (TPC) and flavonoids (TFC) content were quantified in all extracts, with ethanol yielding the best values (about 60 and 625 mg of gallic acid and rutin equivalents per gram of extract, respectively). Their antioxidant potential was also assessed through DPPH•, hydroxyl radical, hydrogen peroxide, and superoxide anion scavenging assays, showing a concentration-dependent activity which was greater in the extracts from protic and more polar solvents. The α-amylase and α-glucosidase activities were estimated for checking the antidiabetic capacity, with IC50 values of about 3.8 µg/mL for the methanolic extract, almost as low as those obtained with acarbose (about 2.8 and 3.3 µg/mL, respectively). The same extract also showed remarkable anti-inflammatory effect, as determined by hemolysis, protein denaturation, proteinase and lipoxygenase activity assays, with respectable IC50 values (about 11, 4, 6, and 5 µg/mL, respectively), also in comparison to commercially used drugs, such as acetylsalicylic acid.

Eosinophil: a central player in modulating pathological complexity in asthma.

Eosinophils are the major inflammatory cells which play a crucial role in the development of allergic and non-allergic asthma phenotypes. Eosinophilic asthma is the most heterogeneous phenotype where activated eosinophils are reported to be significantly associated with asthma severity. Activated eosinophils display an array of cell adhesion molecules that not only act as an activation marker, suitable for assessing severity, but also secrete several tissue factors, cytokines and chemokines which modulate the clinical severity. Eosinophil activations are also strictly associated with activation of other hetero cellular populations like neutrophils, macrophages, mast cells, and platelets which culminate in the onset and progression of abnormal phenotypes such as bronchoconstriction, allergic response, fibrosis instigated by tissue inflammation, epithelial injury, and oxidative stress. During the activated state, eosinophils release several potent toxic signaling molecules such as major basic proteins, eosinophil peroxidase, eosinophil cationic protein (ECP), and lipid mediators, rendering tissue damage and subsequently leading to allergic manifestation. The tissue mediators render a more complex manifestation of a severe phenotype by activating prominent signaling cross-talk. Here, in the current review with the help of search engines of PubMed, Medline, etc, we have tried to shed light and explore some of the potent determinants regulating eosinophil activation leading to asthma phenotype.

Phytochemicals: Potential Therapeutic Modulators of Radiation Induced Signaling Pathways.

Ionizing radiation results in extensive damage to biological systems. The massive amount of ionizing radiation from nuclear accidents, radiation therapy (RT), space exploration, and the nuclear battlefield leads to damage to biological systems. Radiation injuries, such as inflammation, fibrosis, and atrophy, are characterized by genomic instability, apoptosis, necrosis, and oncogenic transformation, mediated by the activation or inhibition of specific signaling pathways. Exposure of tumors or normal cells to different doses of ionizing radiation could lead to the generation of free radical species, which can release signal mediators and lead to harmful effects. Although previous FDA-approved agents effectively mitigate radiation-associated toxicities, their use is limited due to their high cellular toxicities. Preclinical and clinical findings reveal that phytochemicals derived from plants that exhibit potent antioxidant activities efficiently target several signaling pathways. This review examined the prospective roles played by some phytochemicals in altering signal pathways associated with radiation response.

Bioactive Metabolites from Marine Algae as Potent Pharmacophores against Oxidative Stress-Associated Human Diseases: A Comprehensive Review.

In addition to cancer and diabetes, inflammatory and ROS-related diseases represent one of the major health problems worldwide. Currently, several synthetic drugs are used to reduce oxidative stress; nevertheless, these approaches often have side effects. Therefore, to overcome these issues, the search for alternative therapies has gained importance in recent times. Natural bioactive compounds have represented, and they still do, an important source of drugs with high therapeutic efficacy. In the ''synthetic'' era, terrestrial and aquatic photosynthetic organisms have been shown to be an essential source of natural compounds, some of which might play a leading role in pharmaceutical drug development. Marine organisms constitute nearly half of the worldwide biodiversity. In the marine environment, algae, seaweeds, and seagrasses are the first reported sources of marine natural products for discovering novel pharmacophores. The algal bioactive compounds are a potential source of novel antioxidant and anticancer (through modulation of the cell cycle, metastasis, and apoptosis) compounds. Secondary metabolites in marine Algae, such as phenolic acids, flavonoids, and tannins, could have great therapeutic implications against several diseases. In this context, this review focuses on the diversity of functional compounds extracted from algae and their potential beneficial effects in fighting cancer, diabetes, and inflammatory diseases.

Influence of rs1042713 and rs1042714 polymorphisms of ß2-adrenergic receptor gene with erythrocyte cAMP in sickle cell disease patients from Odisha State, India.

The vaso-occlusive crisis (VOCs) in sickle cell disease (SCD) is often associated with stress. Epinephrine released during stress acts via beta 2-adrenergic receptors (ß2-AR or ADRB2) to stimulate the synthesis of cyclic adenosine monophosphate (cAMP) in the red blood cells (RBCs). Higher cAMP levels promote adhesion of sickled RBCs to vascular endothelium, a major contributor for VOCs. Several single-nucleotide polymorphisms (SNPs) of the ß2-AR gene have been reported; two of them at codon 16 (rs1042713) and codon 27 (rs1042714) have been extensively studied for their clinical relevance. Therefore, we assessed the influence of polymorphism at these two sites of the ß2-AR gene on the RBC cAMP concentrations with and without epinephrine stimulation in SCD subjects. We determined the frequency distribution of different genotypes of codon 16 and codon 27 of the ß2-AR gene using the Sanger sequencing method in the SCD subjects. We measured the RBC-cAMP levels at baseline and after stimulation with epinephrine, to ascertain the influence of different genotypes in determining cAMP levels. There was no difference in the socio-demographic and hematological indicators in different genotypes of both codon 16 and 27. In the sham-treated erythrocytes, the cAMP levels were significantly different with three genotypes of codon 16 (F = 3.39, P = 0.036; one way ANOVA) but not with different genotypes of codon 27. A significant increase in cAMP levels was noticed with epinephrine treatment in all genotypes of codons 16 and 27 (P = 0.001; Wilcoxon signed-rank test). However, the extent of increase in the epinephrine-treated cAMP values from the sham-treated (baseline) cAMP values was significantly different between the three genotypes of codon 16 (H = 8.74; P = 0.012; Kruskal-Wallis test) but not in codon 27 genotypes. Polymorphism in codon 16 (rs1042713) of the ß2-AR gene influences cAMP concentrations in the RBC both before and after epinephrine treatment. Higher cAMP levels may lead to increased adhesion of sickle cell RBCs to vascular endothelium and may increase the frequency of VOCs.

Association of plasma homocysteine level with vaso-occlusive crisis in sickle cell anemia patients of Odisha, India.

Vascular complications of sickle cell anemia (SCA) are influenced by many factors. Elevated plasma homocysteine (Hcy) is supposed to be an independent risk factor and is either genetic or nutritional origin. The present study evaluated the plasma Hcy level, MTHFR C677T gene polymorphism, effect of folic acid (FA) supplementation' and hemato-biochemical parameters in SCA and their effect on the vaso-occlusive crisis (VOC) in SCA patients of an Asian-Indian haplotype population. One hundred twenty cases of SCA (HbSS) and 50 controls with normal hemoglobin(HbAA) were studied. It was found that the plasma Hcy level is significantly higher (p < 0.0001) in patients with SCA (22.41 ± 7.8 µmol/L) compared to controls (13.2 ± 4.4 µmol/L). Moreover, patients without FA supplementation had a significantly (p < 0.001) higher Hcy level (27 ± 7 µmol/L) compared to those with supplementation (17.75 ± 5.7 µmol/L). Turkey-Kramer multiple comparison tests show that there is a significant difference (p < 0.05) in HbF percent, hemoglobin (Hb), platelet count, serum bilirubin (direct:Bil-D and total:Bil-T), aspartate transaminase (AST), lactate dehydrogenase (LDH), and plasma Hcy levels between mild and severe VOC. Between moderate VOC and severe VOC, there was a significant difference (p < 0.05) in HbF%, Bil-D, AST, Hcy. Pearson correlation revealed that plasma Hcy had a significantly (p < 0.05) positive correlation with AST, serum bilirubin (indirect and total), LDH, jaundice, stroke, VOC per year, and hospitalization per year whereas it was inversely correlated with HbF percentage, Hb level, and FA treatment. In the study population, increased plasma Hcy level, hemolysis, and platelet activation were found to influence VOC in SCA.

Association of fetal hemoglobin level with frequency of acute pain episodes in sickle cell disease (HbS-only phenotype) patients.

BACKGROUND: Sickle cell disease (SCD) is a Mendelian single gene disorder with highly variable phenotypic expression. In the present study, we analyzed the influence of HbF, alpha thalassemia and other hematological indices to determine their association with acute pain episodes. METHOD: This case control study consisted of SCD subjects with HbS phenotype experiencing three or more acute pain episodes in last twelve months (cases) and without any episode of acute pain during last twelve months (controls). Hematological parameters, HbF, and presence of alpha thalassemia were assessed in all subjects. RESULTS: A statistically significant difference between HbF levels (P < 0.025, χ2 test) and alpha thalassemia (P < 0.008, χ2 test) was observed between controls and cases group. Univariate analysis indicated that increased HbF levels > 25% (OR: 0.37, 95% CI: 0.18-0.77, P < 0.008) and presence of alpha thalassemia (OR: 0.53, 95% CI: 0.33-0.85, P < 0.009) provided protection, while multivariate analysis revealed significant protection was attributable only by higher HbF levels (OR: 0.39, 95% CI: 0.17-0.88, P < 0.025). Significantly higher HbF levels were observed only in the 11-20 age group of cases in comparison to controls (Student's t-test, P < 0.001). CONCLUSION: Higher concentrations of HbF are associated with protection against frequent episodes of acute pain crisis in SCD patients.