Types of Cell Death from a Molecular Perspective.

The former conventional belief was that cell death resulted from either apoptosis or necrosis; however, in recent years, different pathways through which a cell can undergo cell death have been discovered. Various types of cell death are distinguished by specific morphological alterations in the cell's structure, coupled with numerous biological activation processes. Various diseases, such as cancers, can occur due to the accumulation of damaged cells in the body caused by the dysregulation and failure of cell death. Thus, comprehending these cell death pathways is crucial for formulating effective therapeutic strategies. We focused on providing a comprehensive overview of the existing literature pertaining to various forms of cell death, encompassing apoptosis, anoikis, pyroptosis, NETosis, ferroptosis, autophagy, entosis, methuosis, paraptosis, mitoptosis, parthanatos, necroptosis, and necrosis.

System biology analysis to develop diagnostic biomarkers, monitoring pathological indexes, and novel therapeutic approaches for immune targeting based on maggot bioactive compounds and polyphenolic cocktails in mice with gastric cancer.

Early diagnosis and prognosis are prerequisites for mitigating mortality in gastric cancer (GaCa). Identifying some causative or sensitive elements (coding RNA (cRNA)-non-cRNAs (ncRNAs)) can be very helpful in the early diagnosis of GaCa. Notably, despite significant development in the GaCa treatment, the outcome of patients does not remain satisfactory due to limitations such as multi-drug resistance and tumor relapse. Therefore, more attention has been drawn to complementary therapies and the use of supplements. In this regard, Polyphenol natural compounds (PNC) and maggot larvae (MaLa) alone or in combination were administered along with chemotherapy (paclitaxel) to N-methyl-N-nitrosourea (MNU)- induced murine tumor model. In addition, in order to identify potential diagnostic or prognostic biomarkers, transcriptomics analysis was performed through a bioinformatics approach. Then transcription profile of ncRNAs with their target hub genes was assessed through qPCR Real-Time, Western blot, and ELISA. According to the bioinformatics results, 17 hub genes (e.g., IL-6, CXCL8, MKI67, IL-2, IL-4, IL-10, IL-1ß, SPP1, LOX, COL1A1, and IFN-γ) were explored that contribute towards inflammation and oxidative stress and ultimately GaCa development. Upstream of the mentioned hub genes, regulatory factors (lncRNA XIST and NEAT1) were also identified and introduced as prognosis and diagnosis biomarkers for GaCa. Our results showed that PNC alone and in combination with MaLa was able to reduce the size and number of tumors, which is related to the reduction of genes expression levels (including IL-6, CXCL8, MKI67, IL-2, IL-4, IL-10, IL-1ß, SPP1, LOX, COL1A1, IFN-γ, NEAT1, and XIST). In conclusion, PNC and MaLa have the potential to be considered as complementary and improving chemotherapy due to their effective compounds. Also, the introduced hub gene and lncRNA in addition to diagnostic and prognostic biomarkers can be used as druggable proteins for novel therapeutic targeting of GaCa.

The molecular perspective on the melanoma and genome engineering of T-cells in targeting therapy.

Melanoma, an aggressive malignant tumor originating from melanocytes in humans, is on the rise globally, with limited non-surgical treatment options available. Recent advances in understanding the molecular and cellular mechanisms underlying immune escape, tumorigenesis, drug resistance, and cancer metastasis have paved the way for innovative therapeutic strategies. Combination therapy targeting multiple pathways simultaneously has been shown to be promising in treating melanoma, eliciting favorable responses in most melanoma patients. CAR T-cells, engineered to overcome the limitations of human leukocyte antigen (HLA)-dependent tumor cell detection associated with T-cell receptors, offer an alternative approach. By genetically modifying apheresis-collected allogeneic or autologous T-cells to express chimeric antigen receptors, CAR T-cells can appreciate antigens on cell surfaces independently of major histocompatibility complex (MHC), providing a significant cancer cell detection advantage. However, identifying the most effective target antigen is the initial step, as it helps mitigate the risk of toxicity due to "on-target, off-tumor" and establishes a targeted therapeutic strategy. Furthermore, evaluating signaling pathways and critical molecules involved in melanoma pathogenesis remains insufficient. This study emphasizes the novel approaches of CAR T-cell immunoediting and presents new insights into the molecular signaling pathways associated with melanoma.

A Cocktail of Polyherbal Bioactive Compounds and Regular Mobility Training as Senolytic Approaches in Age-dependent Alzheimer's: the In Silico Analysis, Lifestyle Intervention in Old Age.

Alzheimer's is a principal concern globally. Machine learning is a valuable tool to determine protective and diagnostic approaches for the elderly. We analyzed microarray datasets of Alzheimer's cases based on artificial intelligence by R statistical software. This study provided a screened pool of ncRNAs and coding RNAs related to Alzheimer's development. We designed hub genes as cut points in networks and predicted potential microRNAs and LncRNA to regulate protein networks in aging and Alzheimer's through in silico algorithms. Notably, we collected effective traditional herbal medicines. A list of bioactive compounds prepared including capsaicin, piperine, crocetin, safranal, saffron oil, coumarin, thujone, rosmarinic acid, sabinene, thymoquinone, ascorbic acid, vitamin E, cyanidin, rhaponticin, isovitexin, coumarin, nobiletin, evodiamine, gingerol, curcumin, quercetin, fisetin, and allicin as an effective fusion that potentially modulates hub proteins and molecular signaling pathways based on pharmacophore model screening and chemoinformatics survey. We identified profiles of 21 mRNAs, 272 microRNAs, and eight LncRNA in Alzheimer's based on prediction algorithms. We suggested a fusion of senolytic herbal ligands as an alternative therapy and preventive formulation in dementia. Also, we provided ncRNAs expression status as novel monitoring strategies in Alzheimer's and new cut-point proteins as novel therapeutic approaches. Synchronizing fusion drugs and lifestyle could reverse Alzheimer's hallmarks to amelioration via an offset of the signaling pathways, leading to increased life quality in the elderly.

Natural remedies medicine derived from flaxseed (secoisolariciresinol diglucoside, lignans, and α-linolenic acid) improve network targeting efficiency of diabetic heart conditions based on computational chemistry techniques and pharmacophore modeling.

Cytokine storms lead to cardiovascular diseases (CVDs). Natural herbal compounds are considered the primary source of active agents with the potential to prevent or treat inflammatory-related pathologies such as CVD and diabetes. Flaxseed contains phytochemicals, including secoisolariciresinol diglucoside (SDG), α-linolenic acid (ALA), and lignans, termed "SAL." Hence, we evaluated the effect of the SAL on the H9c2 cardiac cells in hyperlipidemic and hyperglycemic conditions. Here, candidate hub genes, TNF-α, IL6, SIRT1, NRF1, NPPA, and FGF7, were selected as effective genes in diabetic cardiovascular pathogenesis based on in-silico analysis and chemoinformatic. Myocardial infarction (MI) was induced using H9c2 cardiac cells in hyperlipidemic and hyperglycemic conditions. Real-time qPCR was conducted to assess the expression level of hub genes. This study indicated that SAL compounds bound to the Il-6, SIRT1, and TNF-α active sites as druggable candidate proteins based on the chemoinformatics analysis. This study displayed that the TNF-α, IL6, SIRT1, NRF1, NPPA, and FGF7 network dysfunction in MI models were ameliorated by SAL consumption. Furthermore, SAL compounds improved the function and myogenesis of H9c2 cells in hyperlipidemic and hyperglycemic conditions. Our data suggested that phytochemicals obtained from flaxseed might have proposed potential complementary treatment or preventive strategies for MI. PRACTICAL APPLICATIONS: Phytochemicals obtained from flaxseed (SAL) could reverse diabetic heart dysfunction hallmarks and provide new potential treatment approaches in cardiovascular therapy. SAL could be considered complementary and alternative medicines for treating various disorders/diseases singly or synchronizing with prescription drugs.

Cross Brain-Gut Analysis Highlighted Hub Genes and LncRNA Networks Differentially Modified During Leucine Consumption and Endurance Exercise in Mice with Depression-Like Behaviors.

Depression is a frequent mood disorder that might impair the brain-gut axis. In this study, we divided 30 mice into five groups: untreated mice, mice with depression-like behaviors, mice with depression-like behaviors treated with consumed leucine, mice with depression-like behaviors treated with exercise training, mice with depression-like behaviors treated with exercise training along with consumed leucine. According to artificial intelligence biological analysis, we found some mediators such as lncRNAs profile and Kdr/Vegfα/Pten/Bdnf interactions network in the hippocampus region and ileum tissue which could be decisive molecules in the brain-gut axis. Moreover, KDR as a principal cutpoint protein in the network was identified as the pharmaceutical approach for major depressive ameliorating based on pharmacophore modeling and molecular docking outcomes. Furthermore, we indicated that the mRNA and protein level of the Pten enhanced and Vegfα/Kdr/Bdnf mRNAs, as well as the protein level of KDR, decreased in mice with depression-like behaviors. Moreover, exercise and leucine ameliorated the brain-gut axis in mice with depression-like behaviors. Exercise and leucine regulated the lncRNAs network in the hippocampus and ileum of mice with depression-like behaviors. We suggest that the lncRNAs profiles could be considered as diagnosis and prognosis biomarkers, and exercise + leucine might be a practical approach to improve depression.

The Importance of SNPs at miRNA Binding Sites as Biomarkers of Gastric and Colorectal Cancers: A Systematic Review.

Dysregulated mRNA-miRNA profiles might have the prospective to be used for early diagnosis of gastrointestinal cancers, estimating survival, and predicting response to treatment. Here, a novel biomarker based on miRNAs binding to mRNAs in single nucleotide polymorphism (SNP) sites related to gastrointestinal cancers is introduced that could act as an early diagnosis. The electronic databases used for the recruiting published articles included EMBASE, SCOPUS, Web of Science, and PubMed, based on MESH keywords and PRISMA methodology. Based on the considered criteria, different experimental articles were reviewed, during which 15 studies with the desired criteria were collected. Accordingly, novel biomarkers in prediction, early prognosis, and diagnosis of gastrointestinal cancers were highlighted. Moreover, it was found that 20 SNP sites and 16 miRNAs were involved in gastrointestinal cancers, with altered expression patterns associated with clinicopathological and demographic data. The results of this systematic study revealed that SNPs could affect the binding of miRNAs in the SNP sites that might play a principal role in the progression, invasion, and susceptibility of gastrointestinal cancers. In addition, it was found that the profiles of SNPs and miRNAs could serve as a convenient approach for the prognosis and diagnosis of gastric and colorectal cancers.

Physical activity ameliorates the function of organs via adipose tissue in metabolic diseases.

Adipose tissue is a dynamic organ in the endocrine system that can connect organs by secreting molecules and bioactive. Hence, adipose tissue really plays a pivotal role in regulating metabolism, inflammation, energy homeostasis, and thermogenesis. Disruption of hub bioactive molecules secretion such as adipokines leads to dysregulate metabolic communication between adipose tissue and other organs in non-communicable disorders. Moreover, a sedentary lifestyle may be a risk factor for adipose tissue function. Physical inactivity leads to fat tissue accumulation and promotes obesity, Type 2 diabetes, cardiovascular disease, neurodegenerative disease, fatty liver, osteoporosis, and inflammatory bowel disease. On the other hand, physical activity may ameliorate and protect the body against metabolic disorders, triggering thermogenesis, metabolism, mitochondrial biogenesis, ß-oxidation, and glucose uptake. Furthermore, physical activity provides an inter-organ association and cross-talk between different tissues by improving adipose tissue function, reprogramming gene expression, modulating molecules and bioactive factors. Also, physical activity decreases chronic inflammation, oxidative stress and improves metabolic features in adipose tissue. The current review focuses on the beneficial effect of physical activity on the cardiovascular, locomotor, digestive, and nervous systems. In addition, we visualize protein-protein interactions networks between hub proteins involved in dysregulating metabolic induced by adipose tissue.

MicroRNAs as the actors in the atherosclerosis scenario.

Atherosclerosis is considered as the most common cardiovascular disease and a leading cause of global mortality, which develops through consecutive steps. Various cellular and molecular biomarkers such as microRNAs are identified to be involved in atherosclerosis progression. MicroRNAs are a group of endogenous, short, non-coding RNAs, which are able to bind to specific sequences on target messenger RNAs and thereby modulate gene expression post-transcriptionally. MicroRNAs are key players in wide range of biological processes; thus, their expression level is regulated in pathophysiological conditions. Ample evidences including in vitro and in vivo studies approved a critical role of microRNAs in epigenetic and the sequential processes of atherosclerosis from risk factors to plaque formation, progression, and rupture. Based on these findings, miRNAs seems to be promising candidates for therapeutic approach. This review summarizes the role of miRNAs in atherosclerosis development, epigenetic, and therapy. Moreover, the application of exosomes in miRNA delivery, and/or their prognostic and diagnostic values are also discussed.