Identification of shared and disease-specific host gene–microbiome associations across human diseases using multi-omic integration

While gut microbiome and host gene regulation independently contribute to gastrointestinal disorders, it is unclear how the two may interact to influence host pathophysiology. Here we developed a machine learning-based framework to jointly analyse paired host transcriptomic (n = 208) and gut microbiome (n = 208) profiles from colonic mucosal samples of patients with colorectal cancer, inflammatory bowel disease and irritable bowel syndrome. We identified associations between gut microbes and host genes that depict shared as well as disease-specific patterns. We found that a common set of host genes and pathways implicated in gastrointestinal inflammation, gut barrier protection and energy metabolism are associated with disease-specific gut microbes. Additionally, we also found that mucosal gut microbes that have been implicated in all three diseases, such as Streptococcus, are associated with different host pathways in each disease, suggesting that similar microbes can affect host pathophysiology in a disease-specific manner through regulation of different host genes. Our framework can be applied to other diseases for the identification of host gene–microbiome associations that may influence disease outcomes

Healthcare Seeking Behaviour of Hospitalised COVID-19 Patients During Second Wave in Tertiary Care Hospital of Northern India

Background: The Coronavirus Disease (COVID-19) pandemic continues its deadly reign all over the world. Devising effective strategies for detecting and controlling the infection has become ever more critical. Effective prevention and control of the pandemic is entirely dependent on human behavior in terms of practicing preventive and curative measures. During the second wave of COVID-19, people’s perceptions of preventive and curative measures changed. Objective: To study healthcare-seeking behavior of hospitalized COVID-19 patients. Methods: Hospitalized patients due to COVID-19 in the month of March, April and May of 2021 were included in the study. Their attendants/close relatives were contacted telephonically to know about the admitted patients’ healthcare-seeking behavior. Verbal consent was taken from attendants before the commencement of the interview, followed by informing them about the purpose of the interview. Results: Amongst the subjects, there were more males than females (67.5 vs 32.4%), age ranged between 18 to 88 with a mean value of 56.61 ± 14.7 years. Self-medication was significantly associated with study subjects’ mortality (p=0.03). Conclusion: Elderly people were having higher mortality rate than their younger counterparts. People were hesitant to visit primary care physicians after having symptoms of COVID-19

Ameliorations in dyslipidemia and atherosclerotic plaque by the inhibition of HMG-CoA reductase and antioxidant potential of phytoconstituents of an aqueous seed extract of Acacia senegal (L.) Willd in rabbits

The assigned work was aimed to examine the capability of phytoconstituents of an aqueous seed extract of Acacia senegal (L.) Willd to inhibit HMG-CoA reductase and regression of the atherosclerotic plaque. The chemical fingerprinting of the test extract was assessed by LC-MS/MS. Consequently, the analyses of in-vitro, in-vivo, and in-silico were executed by using the standard protocols. The in-vitro assessment of the test extract revealed 74.1% inhibition of HMG-CoA reductase. In-vivo assessments of the test extract indicated that treated hypercholesterolemic rabbits exhibited a significant (P≤0.001) amelioration in the biomarker indices of the dyslipidaemia i.e., atherogenic index, Castelli risk index(I&II), atherogenic coefficient along with lipid profile. Subsequently, significant reductions were observed in the atherosclerotic plaque and antioxidant levels. The in-silico study of molecular docking shown interactions capabilities of the leading phytoconstituents of the test extract i.e., eicosanoic acid, linoleic acid, and flavan-3-ol with target protein of HMG-CoA reductase. The values of RSMF and potential energy of top docked complexes were show significant interactions. Accordingly, the free energy of solvation, interaction angle, radius of gyration and SASA were shown significant stabilities of top docked complex. The cumulative data of results indicate phytoconstituents of an aqueous seed extract of Acacia senegal have capabilities to inhibit the HMG-CoA reductase and improve the levels of antioxidants

Therapeutic and diagnostic applications of exosomal circRNAs in breast cancer

Circular RNAs (circRNAs) are regulatory elements that are involved in orchestrating gene expression and protein functions and are implicated in various biological processes including cancer. Notably, breast cancer has a significant mortality rate and is one of the most common malignancies in women. CircRNAs have been demonstrated to contribute to the pathogenesis of breast cancer including its initiation, progression, metastasis, and resistance to drugs. By acting as miRNA sponges, circRNAs can indirectly influence gene expression by disrupting miRNA regulation of their target genes, ultimately altering the course of cancer development and progression. Additionally, circRNAs can interact with proteins and modulate their functions including signaling pathways involved in the initiation and development of cancer. Recently, circRNAs can encode peptides that play a role in the pathophysiology of breast cancer and other diseases and their potential as diagnostic biomarkers and therapeutic targets for various cancers including breast cancer. CircRNAs possess biomarkers that differentiate, such as stability, specificity, and sensitivity, and can be detected in several biological specimens such as blood, saliva, and urine. Moreover, circRNAs play an important role in various cellular processes including cell proliferation, differentiation, and apoptosis, all of which are integral factors in the development and progression of cancer. This review synthesizes the functions of circRNAs in breast cancer, scrutinizing their contributions to the onset and evolution of the disease through their interactions with exosomes and cancer-related intracellular pathways. It also delves into the potential use of circRNA as a biomarker and therapeutic target against breast cancer. It discusses various databases and online tools that offer crucial circRNA information and regulatory networks. Lastly, the challenges and prospects of utilizing circRNAs in clinical settings associated with breast cancer are explored.Open Access funding provided by the Qatar National Library. MKK is the recipient of the extramural grant (Grant # 5/13/55/2020/NCD-III) from the Indian Council of Medical Research (ICMR), Government of India, New Delhi. This work has also been made possible thanks to grants from the University of Sassari (FAR2020-Pintus) and Progetto Fondazione di Sardegna (Bando 2022-2023) to GP.Scopu

Ajmalicine and Reserpine: Indole Alkaloids as Multi-Target Directed Ligands Towards Factors Implicated in Alzheimer’s Disease

Alzheimer’s disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets (amyloid beta, beta-secretase, monoaminoxidase-B, and cholinesterase). The present study explores multi-target directed ligand approach using secondary metabolite reserpine (RES) and ajmalicine (AJM) obtained from Rauwolfia serpentina roots. Novel LCMS and HPLC methods were developed for identification and quantification of reserpine and ajmalicine. In vitro enzyme inhibition assays were performed to evaluate anti-cholinesterase, β-site amyloid cleaving enzyme (BACE-1) inhibition and monoamine oxidase-B (MAO-B) inhibition, further analyzed with in silico analysis. Anti-amyloidogenic potential was studied using anti-aggregation studies along with TEM and circular dichroism (CD) analysis. In vitro neuroprotective potential against Aβ toxicity and anti-oxidative stress was demonstrated using PC12 cell cultures. Reserpine is a more potent dual cholinesterase inhibitor than ajmalicine (IC50 values of 1.7 μM (AChE) and 2.8 μM (BuChE)). The anti-aggregation activity of reserpine (68%) was more than ajmalicine (56%). Both compounds demonstrated neuroprotective activity against Aβ42 (92%) and H2O2 (93%) induced toxicity in PC12 cells against controls. Phytocompounds also inhibited MAO-B and BACE-1 enzymes in concentration dependent manner. Molecular docking studies indicated the strong binding of compounds to the catalytic site of targets. This novel study demonstrated that reserpine and ajmalicine as a multi-target directed ligand that have disease modifying potential for amelioration of AD

Association of vitamin-D with hypothyroidism in adult female patients in north Indian population

Background: Thyroid disorder is found to be most commonly occurring endocrine disorder in females. Thyroid hormones have an imperative position in metabolic methods in human body, and several physiological and pathological stimuli are known to influence thyroid metabolism. The increased incidence of hypovitaminosis D was diagnosed in population with hypothyroidism. Objective: To check the relation of Vitamin D in adult female patients diagnosed with hypothyroidism. Method: We recruited 60 patients and divided these patients into two groups, Group-1- Hypothyroidism patients (n=30) and Group-2- Control patients (n=30). Thyroid-Stimulating Hormone (TSH), total Triiodothyronine (T3), total Thyroxine (T4), and Vitamin D levels were estimated by automated method in Abbott ARCHITECT ci8200 machine. Results: In the present study we found patients with hypothyroidism 73.3% (n=22) has low level of Vitamin D while 26.6% (n=8) of population have normal level of Vitamin D. We could not find significant association between Vitamin D and hypothyroidism (p>0.05). Conclusion: Our study concluded that hypothyroidism has no significant role in lowering the levels of Vitamin D but we also emphasize the fact that Vitamin D should be done as routine investigation in healthy as well as hypothyroidism patients as its value was also less in control subjects

Integrative ontology and pathway-based approach identifies distinct molecular signatures in transcriptomes of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) remains a serious concern globally due to many factors that including late diagnosis, lack of an ideal biomarker for diagnosis and prognosis, and high rate of mortality. In this study, we aimed to identify the essential dysregulated genes and molecular signatures associated with the progression and development of ESCC. The dataset with 15 ESCCs and the 15 adjacent normal tissue samples from the surrounding histopathologically tumor-free mucosa was selected. We applied bioinformatics pipelines including various topological parameters from MCODE, CytoNCA, and cytoHubba to prioritize the most significantly associated DEGs with ESCC. We performed functional enrichment annotation for the identified DEGs using DAVID and MetaCore GeneGo platforms. Furthermore, we validated the essential core genes in TCGA and GTEx datasets between the normal mucosa and ESCC for their expression levels. These DEGs were primarily enriched in positive regulation of transferase activity, negative regulation of organelle organization, cell cycle mitosis/S-phase transition, spindle organization/assembly, development, and regulation of angiogenesis. Subsequently, the DEGs were associated with the pathways such as oocyte meiosis, cell cycle, and DNA replication. Our study identified the eight-core genes (AURKA, AURKB, MCM2, CDC20, TPX2, PLK1, FOXM1, and MCM7) that are highly expressed among the ESCC, and TCGA dataset. The multigene comparison and principal component analysis resulted in elevated signals for the AURKA, MCM2, CDC20, TPX2, PLK1, and FOXM1. Overall, our study reported GO profiles and molecular signatures that might help researchers to grasp the pathological mechanisms underlying ESCC development and eventually provide novel therapeutic and diagnostic strategies. 2022 Elsevier Inc.The authors would like to take this opportunity to thank the management of Vellore Institute of Technology (VIT), Vellore, India, Qatar University, Doha, Qatar, and Amity University, Haryana, Gurugram for providing the necessary facilities and encouragement to carry out this work. SUK, HZ, and CGPD were involved in the design of the study. SUK, AB, and VAP were involved in the data collection and conducted the experiment. SUK, AB, VAP, MKK, and CGPD were involved in the acquisition, analysis, and interpretation of the results. SUK and AB drafted the manuscript. CGPD and HZ supervised the entire study and were involved in study design, the acquisition, analysis, understanding of the data, and critically reviewed the manuscript. All authors edited and approved the submitted version of the article. The authors have declared that no conflicts of interest exist.Scopu

Analysis of signaling cascades from myeloma cells treated with pristimerin

Multiple myeloma (MM) is the 2nd most frequently diagnosed blood cancer after non-Hodgkin's lymphoma. The present study aimed to identify the differentially expressed genes (DEGs) between the control and pristimerin-treated MM cell lines. We examined the GSE14011 microarray dataset and screened DEGs with GEO2R statistical tool using the inbuilt limma package. We used a bioinformatics pipeline to identify the differential networks, signaling cascades, and the survival of the hub genes. We implemented two different enrichment analysis including ClueGO and Metacore, to get accurate annotation for most significant DEGs. We screened the most significant 408 DEGs from the dataset based on p-values and logFC values. Using protein network analysis, we found the genes UBC, HSP90AB1, HSPH1, HSPA1B, HSPA1L, HSPA6, HSPD1, DNAJB1, HSPE1, DNAJC10, BAG3, and DNAJC7 had higher node degree distribution. In contrast, the functional annotation provided that the DEGs were predominantly enriched in B-cell receptor signaling, unfolded protein response, positive regulation of phagocytosis, HSP70, and HSP40-dependent folding, and ubiquitin-proteasomal proteolysis. Using network algorithms, and comparing enrichment analysis, we found the hub genes enriched were INHBE, UBC, HSPA1A, HSP90AB1, IKBKB, and BAG3. These DEGs were further validated with overall survival and gene expression analysis between the tumor and control groups. Finally, pristimerin effects were validated independently in a cell line model consisting of IM9 and U266 MM cells. Pristimerin induced in vitro cytotoxicity in MM cells in a dose-dependent manner. Pristimerin inhibited NF-?B, induced accumulation of ubiquitinated proteins and inhibited HSP60 in the validation of bioinformatics findings, while pristimerin-induced caspase-3 and PARP cleavage confirmed cell death. Taken together, we found that the identified DEGs were strongly associated with the apoptosis induced in MM cell lines due to pristimerin treatment, and combinatorial therapy derived from pristimerin could act as novel anti-myeloma multifunctional agents. 2022The fund of APC was provided with the Qatar University grant: QUST-1-CHS-2021-2. The in vitro experiment is supported by a grant from Medical Research Center, Hamad Corporation to SU (MRC-01-18-120). In addition, the authors would like to thank the Vellore Institute of Technology (VIT), Vellore, India, and Qatar University, Qatar for providing the necessary research facilities and encouragement to carry out this work.Scopu