Lactobacillus as probiotics: opportunities and challenges for potential benefits in female reproductive health.

The growing interest of the scientific community in the study of probiotics has gathered valuable data about its beneficial effects for multiple clinical conditions. This data also provides evidence for the functions and properties of probiotics and how they contribute to health benefits by influencing normal microbiota. Lactobacillus is an important genus which has long been utilized in the food industry and is also found as normal oral, intestinal and vaginal microbiota. Lactobacillus has shown multiple health benefits but its relative importance as a probiotic is majorly explored for gastrointestinal health. Healthy vaginal microbiota typically harbors Lactobacillus spp. providing several health benefits for female reproductive health, but there is more data required in order to compare the relative benefits with probiotic Lactobacillus added through either natural food sources or with standard probiotics supplements. The present article discusses the current status of knowledge about vaginal Lactobacillus as a probiotic and also compares the potential of probiotics from natural sources and through supplements along with recent approaches in this area.

Impact of inflammatory cytokine and adipokine gene variations in the development of HIV-associated lipodystrophy.

Cytokines affect lipid and glucose metabolism and also alter the body's habitus. They play a role in the development of lipodystrophy syndrome. Adipocytes secrete the pro-inflammatory cytokines IL-1, TNF-α and IL-6. The plasma cytokine concentration is associated with the percentage and distribution of fat tissue in the body. The metabolic disturbances are strongly associated with increased levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α). Plasma levels of cytokines such as TNF-α, IL-6 and leptin were found to be increased while plasma resistin levels were found to be variable in patients suffering from obesity and type II diabetes mellitus. Until now, limited information has been available on the polymorphism of cytokine and adipokine genes in patients of HIV-associated lipodystrophy (HIVLD), which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. Hence, we studied the association of cytokine and adipokine gene polymorphisms in various diseases and their impact on HIVLD. We carry out an extensive search using several databases, including PubMed, EMBASE and Google Scholar. The distribution of cytokine and adipokine gene polymorphisms and their expression levels varied among various populations. We examined the variants of cytokine and adipokine genes, which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. In the current review, we present a brief account of the risk factors of HIVLD, the pathogenesis of HIVLD and the polymorphism of cytokine and adipokine genes in various diseases with special reference to their impact on HIVLD.

Effect of genetic variations in drug transporters, metabolizing enzyme and regulatory genes on the development of HIV-associated lipodystrophy.

Adipocytes play a crucial role in the metabolism of lipids and sugars. Their response varies depending on the circumstances or other factors influenced by physiological and metabolic stresses. People living with HIV (PLWH) experience different effects of HIV and highly active antiretroviral therapy (HAART) on their body fat. Some patients respond well to antiretroviral therapy (ART), while others taking similar regimens do not. The genetic makeup of patients has been strongly linked to the variable responses to HAART among PLWH. The cause of HIV-associated lipodystrophy syndrome (HALS) is not well understood, but it may be influenced by genetic variations in the host. The metabolism of lipid effectively modulates plasma triglyceride and high-density lipoprotein cholesterol levels in PLWH. Genes related to drug metabolism and transport play an important role in the transportation and metabolism of ART drugs. Genetic variation in metabolizing enzyme genes of antiretroviral drugs, lipid transport and transcription factor-related genes could interfere with fat storage and metabolism, contributing to the development of HALS. Hence we examined the impact of genes associated with transport, metabolism and various transcription factors in metabolic complications, and their impact on HALS. A study using databases such as PubMed, EMBASE and Google Scholar was conducted to understand the impact of these genes on metabolic complications and HALS. The present article discuss the changes in the expression and regulation of genes and their involvement in the lipid metabolism, lipolysis and lipogenesis pathways. Moreover, alteration of the drug transporter, metabolizing enzyme and various transcription factors can lead to HALS. Single-nucleotide polymorphisms in genes that play an essential role in drug metabolism and drug and lipid transportation may also contribute to individual differences in the emergence of metabolic and morphological alterations during HAART treatment.

Host-microbiota interactions and oncogenesis: Crosstalk and its implications in etiology.

A number of articles have discussed the potential of microbiota in oncogenesis. Several of these have evaluated the modulation of microbiota and its influence on cancer development. Even in recent past, a plethora of studies have gathered in order to understand the difference in microbiota population among different cancer and normal individuals. Although in majority of studies, microbiota mediated oncogenesis has been primarily attributed to the inflammatory mechanisms, there are several other ways through which microbiota can influence oncogenesis. These relatively less discussed aspects including the hormonal modulation through estrobolome and endobolome, production of cyclomodulins, and lateral gene transfer need more attention of scientific community. We prepared this article to discuss the role of microbiota in oncogenesis in order to provide concise information on these relatively less discussed microbiota mediated oncogenesis mechanisms.

Pathogenesis of Human Immunodeficiency Virus and Mycobacterium tuberculosis Infection as Revealed by Transcriptome and Interactome Data.

Tuberculosis (TB) among patients with human immunodeficiency virus (HIV) is a major global health burden and contributes to a high mortality rate due to HIV-mediated immunosuppression and subsequent susceptibility to TB. It is imperative to understand the pathogenesis of the association between HIV and TB for therapeutic innovation and preventive medicine. In the present study, we employed transcriptomic and bioinformatic analyses of differential gene expression data obtained from Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information. The expression data of Mycobacterium tuberculosis-infected macrophages and blood samples from TB patients (GSE54992, GSE52819, and GSE19435) and blood samples from HIV patients (GSE30310) were accessed for identification of differentially expressed genes (DEGs). Data from 20 healthy subjects and 19 patients with TB and 16 healthy subjects and 16 patients with HIV were analyzed. We report here the DEGs shared by HIV and TB infection. Moreover, HIV and TB host-pathogen interaction data were collected from BIOGRID, v 4.4.210, for identifying significantly modulated genes' targets and their interactions with the host. Host targets, including PLSCR1 (phospholipid scramblase 1), STAT1 (signal transducer and activator of transcription-1 alpha/beta), FBXO6 (F-box only protein 6), ITGAL (integrin alpha-L), and APP (amyloid beta precursor protein), are commonly modulated in both diseases. The function of these targets was screened from and reconciled with the literature to understand their role in the pathogenesis of HIV and TB. Overall, the study results suggest that these targets may potentially be important contributors to the pathogenesis of this comorbidity. Further experimental work is needed for evaluating these new observations, with a view to future therapeutic innovation for patients with HIV and TB.

A Systems Biology and LASSO-Based Approach to Decipher the Transcriptome-Interactome Signature for Predicting Non-Small Cell Lung Cancer.

The lack of precise molecular signatures limits the early diagnosis of non-small cell lung cancer (NSCLC). The present study used gene expression data and interaction networks to develop a highly accurate model with the least absolute shrinkage and selection operator (LASSO) for predicting NSCLC. The differentially expressed genes (DEGs) were identified in NSCLC compared with normal tissues using TCGA and GTEx data. A biological network was constructed using DEGs, and the top 20 upregulated and 20 downregulated hub genes were identified. These hub genes were used to identify signature genes with penalized logistic regression using the LASSO to predict NSCLC. Our model's development involved the following steps: (i) the dataset was divided into 80% for training (TR) and 20% for testing (TD1); (ii) a LASSO logistic regression analysis was performed on the TR with 10-fold cross-validation and identified a combination of 17 genes as NSCLC predictors, which were used further for development of the LASSO model. The model's performance was assessed on the TD1 dataset and achieved an accuracy and an area under the curve of the receiver operating characteristics (AUC-ROC) of 0.986 and 0.998, respectively. Furthermore, the performance of the LASSO model was evaluated using three independent NSCLC test datasets (GSE18842, GSE27262, GSE19804) and achieved high accuracy, with an AUC-ROC of >0.99, >0.99, and 0.95, respectively. Based on this study, a web application called NSCLCpred was developed to predict NSCLC.

miR766-3p and miR124-3p Dictate Drug Resistance and Clinical Outcome in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive disease with poor prognosis, which is mainly due to drug resistance. The biology determining the response to chemo-radiotherapy in HNSCC is poorly understood. Using clinical samples, we found that miR124-3p and miR766-3p are overexpressed in chemo-radiotherapy-resistant (non-responder) HNSCC, as compared to responder tumors. Our study shows that inhibition of miR124-3p and miR766-3p enhances the sensitivity of HNSCC cell lines, CAL27 and FaDu, to 5-fluorouracil and cisplatin (FP) chemotherapy and radiotherapy. In contrast, overexpression of miR766-3p and miR124-3p confers a resistance phenotype in HNSCC cells. The upregulation of miR124-3p and miR766-3p is associated with increased HNSCC cell invasion and migration. In a xenograft mouse model, inhibition of miR124-3p and miR766-3p enhanced the efficacy of chemo-radiotherapy with reduced growth of resistant HNSCC. For the first time, we identified that miR124-3p and miR766-3p attenuate expression of CREBRF and NR3C2, respectively, in HNSCC, which promotes aggressive tumor behavior by inducing the signaling axes CREB3/ATG5 and ß-catenin/c-Myc. Since miR124-3p and miR766-3p affect complementary pathways, combined inhibition of these two miRNAs shows an additive effect on sensitizing cancer cells to chemo-radiotherapy. In conclusion, our study demonstrated a novel miR124-3p- and miR766-3p-based biological mechanism governing treatment-resistant HNSCC, which can be targeted to improve clinical outcomes in HNSCC.

Exploring SARS-CoV2 host-pathogen interactions and associated fungal infections cross-talk: Screening of targets and understanding pathogenesis.

The COVID-19 associated opportunistic fungal infections have posed major challenges in recent times. Global scientific efforts have identified several SARS-CoV2 host-pathogen interactions in a very short time span. However, information about the molecular basis of COVID-19 associated opportunistic fungal infections is not readily available. Previous studies have identified a number of host targets involved in these opportunistic fungal infections showing association with COVID-19 patients. We screened host targets involved in COVID-19-associated opportunistic fungal infections, in addition to host-pathogen interaction data of SARS-CoV2 from well-known and widely used biological databases. Venn diagram was prepared to screen common host targets involved in studied COVID-19-associated fungal infections. Moreover, an interaction network of studied disease targets was prepared with STRING to identify important targets on the basis of network biological parameters. The host-pathogen interaction (HPI) map of SARS-CoV2 was also prepared and screened to identify interactions of the virus with targets involved in studied fungal infections. Pathway enrichment analysis of host targets involved in studied opportunistic fungal infections and the subset of those involved in SARS-CoV2 HPI were performed separately. This data-based analysis screened six common targets involved in all studied fungal infections, among which CARD9 and CYP51A1 were involved in host-pathogen interactions with SARS-CoV2. Moreover, several signaling pathways such as integrin signaling were screened, which were associated with disease targets involved in SARS-CoV2 HPI. The results of this study indicate several host targets deserving detailed investigation to develop strategies for the management of SARS-CoV2-associated fungal infections.

Deciphering the involvement of iron targets in colorectal cancer: a network biology approach.

Several studies suggested the role of heme iron, but not non-heme iron in colorectal cancer. A network and system biology-based approach was used to understand the role of heme and non-heme iron on colorectal cancer etiology. Heme and non-heme iron targets were screened in addition to CRC targets. The protein-protein interaction map of both iron targets was prepared with CRC targets. Moreover, functional enrichment analysis was performed in order to understand their role in cancer etiology. The heme iron is predicted to modulate several cancer-associated pathways. Our results indicate several targets and pathways, including IL-4/IL-13, ACE, and HIF-1 signaling, that may have an important role in heme iron-mediated CRC and must be given consideration for understanding their role in colorectal cancer.

Comparative Host-Pathogen Interaction Analyses of SARS-CoV2 and Aspergillus fumigatus, and Pathogenesis of COVID-19-Associated Aspergillosis.

COVID-19 caused a global catastrophe with a large number of cases making it one of the major pandemics of the human history. The clinical presentations of the disease are continuously challenging healthcare workers with the variation of pandemic waves and viral variants. Recently, SARS-CoV2 patients have shown increased occurrence of invasive pulmonary aspergillosis infection even in the absence of traditional risk factors. The mechanism of COVID-19-associated aspergillosis is not completely understood and therefore, we performed this system biological study in order to identify mechanistic implications of aspergillosis susceptibility in COVID-19 patients and the important targets associated with this disease. We performed host-pathogen interaction (HPI) analysis of SARS-CoV2, and most common COVID-19-associated aspergillosis pathogen, Aspergillus fumigatus, using in silico approaches. The known host-pathogen interactions data of SARS-CoV2 was obtained from BIOGRID database. In addition, A. fumigatus host-pathogen interactions were predicted through homology modeling. The human targets interacting with both pathogens were separately analyzed for their involvement in aspergillosis. The aspergillosis human targets were screened from DisGeNet and GeneCards. The aspergillosis targets involved in both HPI were further analyzed for functional overrepresentation analysis using PANTHER. The results indicate that both pathogens interact with a number of aspergillosis targets and altogether they recruit more aspergillosis targets in host-pathogen interaction than alone. Common aspergillosis targets involved in HPI with both SARS-CoV2 and A. fumigatus can indicate strategies for the management of both conditions by modulating these common disease targets.

Microbiota, probiotics and respiratory infections: the three musketeers can tip off potential management of COVID-19.

Rapid infectivity of SARS-CoV2 with recent viral variants is posing a challenge in the development of robust therapeutic strategies. On the other hand, microbiota is debated for its involvement in SARS-CoV2 infection with varied opinions. Although ample data about the role of microbiota and probiotics in respiratory viral infections are available, their role in COVID-19 is limited albeit emerging rapidly. The utilization of probiotics for the management of COVID-19 is still under investigation in many clinical trials. Existing information coupled with recent COVID-19 related studies can suggest various ways to use microbiota modulation and probiotics for managing this pandemic. Present article indicates the role of microbiota modulation and probiotics in respiratory infections. In addition, scattered evidence was gathered to understand the potential of microbiota and probiotics in the management of SARS-CoV2. Gut-airway microbiota connection is already apparent in respiratory tract viral infections, including SARS-CoV2. Though few clinical trials are evaluating microbiota and probiotics for COVID-19 management, the safety evaluation must be given more serious consideration because of the possibility of opportunistic infections among COVID-19 patients. Nevertheless, the information about microbiota modulation using probiotics and prebiotics can be helpful to manage this outbreak and this review presents different aspects of this idea.

Chlamydia Trachomatis Infection: Their potential implication in the Etiology of Cervical Cancer.

Pathogenic bacterial strains can alter the normal function of cells and induce different levels of inflammatory responses that are connected to the development of different diseases, such as tuberculosis, diarrhea, cancer etc. Chlamydia trachomatis (C. trachomatis) is an intracellular obligate gram-negative bacterium which has been connected with the cervical cancer etiology. Nevertheless, establishment of causality and the underlying mechanisms of carcinogenesis of cervical cancer associated with C. trachomatis remain unclear. Studies reveal the existence of C. trachomatis in cervical cancer patients. The DNA repair pathways including mismatch repair, nucleotide excision, and base excision are vital in the abatement of accumulated mutations that can direct to the process of carcinogenesis. C. trachomatis recruits DDR proteins away from sites of DNA damage and, in this way, impedes the DDR. Therefore, by disturbing host cell-cycle control, chromatin and DDR repair, C. trachomatis makes a situation favorable for malignant transformation. Inflammation originated due to infection directs over production of reactive oxygen species (ROS) and consequent oxidative DNA damage. This review may aid our current understanding of the etiology of cervical cancer in C. trachomatis-infected patients.

Immune mediating molecules and pathogenesis of COVID-19-associated neurological disease.

BACKGROUND: Long period of SARS-CoV-2 infection has been associated with psychiatric and cognitive disorders in adolescents and children. SARS-CoV-2 remains dormant in the CNS leading to neurological complications. The wide expression of ACE2 in the brain raises concern for its involvement in SARS-CoV-2 infection. Though, the mechanistic insights about blood-brain barriers (BBB) crossing by SARS-CoV-2 and further brain infection are still not clear. Moreover, the mechanism behind dormant SARS-CoV-2 infections leading to chronic neurological disorders needs to be unveiled. There is an urgent need to find out the risk factor involved in COVID-19-associated neurological disease. Therefore, the role of immune-associated genes in the pathogenesis of COVID-19 associated neurological diseases is presented which could contribute to finding associated genetic risk factors. METHOD: The search utilizing multiple databases, specifically, EMBASE, PubMed (Medline), and Google Scholar was performed. Moreover, the literature survey on the involvement of COVID-19, neuropathogenesis, and its consequences was done. DESCRIPTION: Persistent inflammatory stimuli may promote the progression of neurodegenerative diseases. An increased expression level of cytokine, chemokine, and decreased expression level of immune cells has been associated with the COVID-19 patient. Cytokine storm was observed in severe COVID-19 patients. The nature of SARS-CoV-2 infection can be neuroinflammatory. Genes of immune response could be associated with neurodegenerative diseases. CONCLUSION: The present review will provide a useful framework and help in understanding COVID-19-associated neuropathogenesis. Experimental studies on immune-associated genes in COVID-19 patients with neurological manifestations could be helpful to establish its neuropathogenesis.

Exploring polyps to colon carcinoma voyage: can blocking the crossroad halt the sequence?

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.

Salmonella enterica subsp. enterica host-pathogen interactions and their implications in gallbladder cancer.

BACKGROUND: Several studies have linked chronic typhoid infection with gallbladder carcinoma without completely understood mechanism. This study was performed in order to understand role of Salmonella in gallbladder cancer etiology. METHODS: Known Salmonella host-pathogen interactions were screened from database in addition to known gallbladder carcinoma targets. Host-pathogen interaction map of S. enterica was prepared and screened for interactions with gallbladder carcinoma targets. Further functional overrepresentation analysis was performed to understand the role of human targets involved in Salmonella host-pathogen interactions in gallbladder carcinoma. RESULTS: Salmonella interact with several human proteins involved in gallbladder carcinoma. MAPK and RAC1 are the most important human proteins based on node degree value among all GBC associated interactors identified in current data search. Functional over-representation analysis reveals that Salmonella can induce adenocarcinoma which constitutes 85% of gallbladder cancer. CONCLUSION: Though, the role of MAPK/ERK and PI3K/AKT/mTOR pathway is already suggested for Salmonella mediated gallbladder cancer, but current data based approach indicate several new insight for exploration of the role of Salmonella in gallbladder cancer etiology. The results indicate about several other processes including CREB/SP-1 and BSG(CD147) signaling, that must be given consideration for understanding the role of Salmonella in gallbladder cancer.

Comparative host-pathogen protein-protein interaction analysis of recent coronavirus outbreaks and important host targets identification.

Last two decades have witnessed several global infectious outbreaks. Among these, coronavirus is identified as a prime culprit ranging from its involvement in severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) to COVID-19. These infections involved in huge healthcare and economic cost incurred globally. Every time, coronavirus improved its infection ability and surprised the medical practitioners and researchers. Currently, COVID-19 is also causing numerous infections and stalled global activities. Global efforts are underway to identify potential viral targets for management of these outbreaks, but significant progress in prevention of these outbreaks is not yet achieved. We explored host-pathogen protein-protein interactions of MERS, SARS and COVID-19, and identified host targets common among all recent coronavirus outbreaks. Further, we tried to understand their potential for management of coronavirus. The common proteins involved in coronavirus host-pathogen interactions indicate their indispensable role in the pathogenesis and therefore targeting these proteins can give strategies to prevent current and future coronavirus outbreaks. Viral variability necessitates development of new therapeutic modalities for every outbreak, in contrast targeting necessary human proteins required by all coronaviruses can provide us a clue to prevent current and future coronavirus outbreaks. We found that targeting FURIN and TMPRSS2 can provide good results due to their common involvement in current and previous outbreaks. We also listed some known molecules against these two targets for their potential drug repurposing evaluation. Although, several recent studies undergoing with targeting these proteins for management of coronavirus, but safety evaluation and risk assessment must be given prime importance while targeting human proteins.

ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease.

BACKGROUND: A carboxypeptidase protein called ACE2 is found in many organs. ACE2 protein can play a pivotal role to regulate the pathological changes of several diseases including COVID-19. TMPRSS2 gene is expressed in many human tissues and plays a critical role in spreading the infection of the viruses including coronavirus and progression of prostate cancer, and hence could be used as a potential drug target. There are limited reports on occurrence of genetic polymorphism of ACE2 and TMPRSS2 in general population, expressions in pathological conditions, and its impact on COVID-19 disease. Hence we comprehended the occurrence of ACE2, TMPRSS2 polymorphism in general population, expression in various diseases and its impact on COVID-19 disease. METHOD: We utilized multiple databases, PubMed (Medline), EMBASE and Google Scholar for literature search. DESCRIPTION: ACE2 polymorphisms have significant linkages with various diseases, including severity of SARS-CoV-2 infection. Genetic variations of these genes contribute to individual's genetic susceptibility to viral infection and its subsequent clearance. The diversity and variations in the population distribution of these genes, might greatly influence and in turn reflect into the observed population and gender differences of the severity and clinical outcomes of SARS-CoV-2 infection. CONCLUSION: There are diversities in distribution of ACE2 and TMPRSS2 polymorphisms among different populations. Analyzing the genetic variants and expression of ACE2 and TMPRSS2 genes, in a population may provide the genetic marker for susceptibility or resistance against the coronavirus infection, which might be useful for identifying the susceptible population groups for targeted interventions and for making relevant public health policy decisions.

Bacterial nucleomodulins and cancer: An unresolved enigma.

Recent studies in microbial pathogenesis have identified several bacterial proteins with the potential to influence host cell nuclei. This field of research is in its infancy, however it is rapidly growing. In particular, the role of bacterial nucleomodulins in animal oncogenesis is an area that requires attention. Earlier research has suggested the role of nucleomodulins in plant tumor development and these findings may provide us with a better understanding of the role of these proteins in human cancer development. This proposition is further supported by previous identification of nucleomodulins present in bacteria that have been associated with cancer development, but their role in human cancer is unclear. In this article, we provide an update on the status of these nucleomodulins and their role in cancer etiology. We collected information about known bacterial nucleomodulins and tried to relate their mechanistic implication with already known plant tumor development model. The present research indicates that bacterial nucleomodulins may be an important target in cancer etiology and knowledge of their role in human oncogenesis may help us to create suitable alternative cancer management strategies.