Autophagy and apoptosis are two crucial self-destructive processes that maintain cellular homeostasis, which are characterized by their morphology and regulated through signal transduction mechanisms. These pathways determine the fate of cellular organelle and protein involved in human health and disease such as neurodegeneration, cancer, and cardiovascular disease. Cell death pathways share common molecular mechanisms, such as mitochondrial dysfunction, oxidative stress, calcium ion concentration, reactive oxygen species, and endoplasmic reticulum stress. Some key signaling molecules such as p53 and VEGF mediated angiogenic pathway exhibit cellular and molecular responses resulting in the triggering of apoptotic and autophagic pathways. Herein, based on previous studies, we describe the intricate relation between cell death pathways through their common genes and the role of various stress-causing agents. Further, extensive research on autophagy and apoptotic machinery excavates the implementation of selective biomarkers, for instance, mTOR, Bcl-2, BH3 family members, caspases, AMPK, PI3K/Akt/GSK3β, and p38/JNK/MAPK, in the pathogenesis and progression of neurodegenerative diseases. This molecular phenomenon will lead to the discovery of possible therapeutic biomolecules as a pharmacological intervention that are involved in the modulation of apoptosis and autophagy pathways. Moreover, we describe the potential role of micro-RNAs, long non-coding RNAs, and biomolecules as therapeutic agents that regulate cell death machinery to treat neurodegenerative diseases. Mounting evidence demonstrated that under stress conditions, such as calcium efflux, endoplasmic reticulum stress, the ubiquitin-proteasome system, and oxidative stress intermediate molecules, namely p53 and VEGF, activate and cause cell death. Further, activation of p53 and VEGF cause alteration in gene expression and dysregulated signaling pathways through the involvement of signaling molecules, namely mTOR, Bcl-2, BH3, AMPK, MAPK, JNK, and PI3K/Akt, and caspases. Alteration in gene expression and signaling cascades cause neurotoxicity and misfolded protein aggregates, which are characteristics features of neurodegenerative diseases. Excessive neurotoxicity and misfolded protein aggregates lead to neuronal cell death by activating death pathways like autophagy and apoptosis. However, autophagy has a dual role in the apoptosis pathways, i.e., activation and inhibition of the apoptosis signaling. Further, micro-RNAs and LncRNAs act as pharmacological regulators of autophagy and apoptosis cascade, whereas, natural compounds and chemical compounds act as pharmacological inhibitors that rescue neuronal cell death through inhibition of apoptosis and autophagic cell death.

Autophagy and apoptosis cascade: which is more prominent in neuronal death?

Osteoporosis is a common metabolic bone disease that results from the imbalance of homeostasis within the bone. Intra-bone homeostasis is dependent on a precise dynamic balance between bone resorption by osteoclasts and bone formation by mesenchymal lineage osteoblasts, which comprises a series of complex and highly standardized steps. Programmed cell death (PCD) (e.g., apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis) is a cell death process that involves a cascade of gene expression events with tight structures. These events play a certain role in regulating bone metabolism by determining the fate of bone cells. Moreover, existing research has suggested that natural products derived from a wide variety of dietary components and medicinal plants modulate the PCDs based on different mechanisms, which show great potential for the prevention and treatment of osteoporosis, thus revealing the emergence of more acceptable complementary and alternative drugs with lower costs, fewer side effects and more long-term application. Accordingly, this review summarizes the common types of PCDs in the field of osteoporosis. Moreover, from the perspective of targeting PCDs, this review also discussed the roles of currently reported natural products in the treatment of osteoporosis and the involved mechanisms. Based on this, this review provides more insights into new molecular mechanisms of osteoporosis and provides a reference for developing more natural anti-osteoporosis drugs in the future. 

Cell death regulation: A new way for natural products to treat osteoporosis.

The endoplasmic reticulum is responsible for much of a cell's protein synthesis and folding, but it also has an important role in sensing cellular stress. Recently, it has been shown that the endoplasmic reticulum mediates a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins, and these pathways are collectively known as the unfolded-protein response. New observations suggest that the unfolded-protein response can initiate inflammation, and the coupling of these responses in specialized cells and tissues is now thought to be fundamental in the pathogenesis of inflammatory diseases. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation.

From endoplasmic reticulum stress to the inflammatory response.

Long noncoding RNAs (lncRNAs) are considered critical regulators in cancers; however, the clinical significance and mechanisms of MAPKAPK5-AS1 (hereinafter referred to as MK5-AS1) in colorectal cancer (CRC) remain mostly unknown. In this study, quantitative real-time PCR (qPCR) and western blotting were utilized to detect the levels of MK5-AS1, let-7f-1-3p and MK5 (MAPK activated protein kinase 5) in CRC tissues and cell lines. The biological functions of MK5-AS1, let-7f-1-3p and MK5 in CRC cells were explored using Cell Counting Kit-8 (CCK8), colony formation and transwell assays. The potential mechanisms of MK5-AS1 were evaluated by RNA pull-down, RNA immunoprecipitation (RIP), dual luciferase reporter assay, chromatin immunoprecipitation (ChIP) and bioinformatics analysis. The effects of MK5-AS1 and MK5 on CRC were investigated by a xenotransplantation model. We confirmed that MK5-AS1 was significantly increased in CRC tissues. Knockdown of MK5-AS1 suppressed cell migration and invasion in vitro and inhibited lung metastasis in mice. Mechanistically, MK5-AS1 regulated SNAI1 expression by sponging let-7f-1-3p and cis-regulated the adjacent gene MK5. Moreover, MK5-AS1 recruited RBM4 and eIF4A1 to promote the translation of MK5. Our study verified that MK5 promoted the phosphorylation of c-Jun, which activated the transcription of SNAI1 by directly binding to its promoter. MK5-AS1 cis-regulated the nearby gene MK5 and acted as a let-7f-1-3p sponge, playing a vital role in CRC tumorigenesis. This study could provide novel insights into molecular therapeutic targets of CRC.

/pdf/long-noncoding-rna-mapkapk5-as1-promotes-colorectal-cancer-25vlmccaqx.pdf

Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge

Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages are effector cells and accumulate to the damaged and inflamed sites of arteries to internalize native and chemically modified lipoproteins to transform them into cholesterol-loaded foam cells. Foam cell formation is determined by the capacity of phagocytosis, migration, scavenging, and the features of phenotypes. Macrophages are diverse, and the subsets and functions are controlled by their surrounding microenvironment. Generally, macrophages are divided into classically activated (M1) and alternatively activated (M2). Recently, intraplaque macrophage phenotypes are recognized by the stimulation of CXCL4 (M4), oxidized phospholipids (Mox), hemoglobin/haptoglobin complexes [HA-mac/M(Hb)], and heme (Mhem). The pro-atherogenic or anti-atherosclerotic phenotypes of macrophages decide the progression of AS. Besides, apoptosis, necrosis, ferroptosis, autophagy and pyrotopsis determine plaque formation and cardiovascular vulnerability, which may be associated with macrophage polarization phenotypes. In this review, we first summarize the three most popular hypotheses for AS and find the common key factors for further discussion. Secondly, we discuss the factors affecting macrophage polarization and five types of macrophage death in AS progression, especially ferroptosis. A comprehensive understanding of the cellular and molecular mechanisms of plaque formation is conducive to disentangling the candidate targets of macrophage-targeting therapies for clinical intervention at various stages of AS.

Macrophage Subsets and Death Are Responsible for Atherosclerotic Plaque Formation

BAG2 (BCL2 associated athanogene 2) is associated with cell fate determination in response to various pathological conditions. However, the effects of BAG2 on M. tuberculosis-induced endoplasmic re...

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2019.1687214

BAG2 ameliorates endoplasmic reticulum stress-induced cell apoptosis in Mycobacterium tuberculosis-infected macrophages through selective autophagy

Point-of-care testing (POCT) has exhibited broad applications, owing to its rapid on-site detection capability in resource-limited conditions. However, most POCT sensors could only detect single substance in each assay, which...

Simultaneous and Visual Detection for Multiple Dopes by Aptamer/AuNPs Sensor

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BAG2 ameliorates endoplasmic reticulum stress-induced cell apoptosis in Mycobacterium tuberculosis-infected macrophages through selective autophagy

Simultaneous and Visual Detection for Multiple Dopes by Aptamer/AuNPs Sensor