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Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues. Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years. Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases. Cell death mechanisms: implications for disease therapies Cell death is a complex and interconnected process that plays a crucial role in maintaining tissue homeostasis and preventing disease. There are various types of cell death, including necrosis, apoptosis, autophagy, and others, each with distinct morphological features and molecular mechanisms. Understanding the diverse processes underlying cell death is essential for understanding diseases and developing new therapies. Recent research has focused on characterizing and distinguishing various forms of cell death, thereby advancing our understanding of their roles in health and disease. The complex mechanisms underlying cell death are underscored by the intricate interconnections among different types of cell death and the regulation of these mechanisms through diverse signaling pathways and environmental factors. Further research is necessary to fully characterize and differentiate among the various forms of cell death and their roles in pathological conditions.

Pyroptosis, apoptosis, necroptosis, and ferroptosis, which are the most well-studied regulated cell death (RCD) pathways, contribute to the clearance of infected or potentially neoplastic cells, highlighting their importance in homeostasis, host defense against pathogens, cancer, and a wide range of other pathologies. Although these four RCD pathways employ distinct molecular and cellular processes, emerging genetic and biochemical studies have suggested remarkable flexibility and crosstalk among them. The crosstalk among pyroptosis, apoptosis and necroptosis pathways is more evident in cellular responses to infection, which has led to the conceptualization of PANoptosis. In this review, we provide a brief overview of the molecular mechanisms of pyroptosis, apoptosis, necroptosis, and ferroptosis and their importance in maintaining homeostasis. We discuss the intricate crosstalk among these RCD pathways and the current evidence supporting PANoptosis, focusing on infectious diseases and cancer. Understanding the fundamental processes of various cell death pathways is crucial to inform the development of new therapeutics against many diseases, including infection, sterile inflammation, and cancer. Cell death: Interactions between different pathways The different pathways that cause cell death, which are activated under different conditions, have complex relationships and sometimes act together to fight infection or cancer. All the pathways eliminate cells damaged by disease or mutation and are important for development and disease resistance, but can affect immune responses to infection or cause damage if dysregulated. Rajendra Karki at Seoul National University in South Korea and co-workers review recent evidence revealing links, including common molecules, between the pathways. Because cancer cells can become resistant to anti-cancer drugs or to the usual closely regulated cell death pathway, the ability to trigger a different type of cell death or to activate all pathways holds great promise for cancer treatment. Improving our understanding of cell death could help in treating multiple diseases, from infection to cancer.

Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research. Age-related disease: Role of compromised control of mitochondrial quality Therapies directed at the quality control systems of mitochondria have the potential to preserve cellular health in individuals with age-related diseases. Dongryeol Ryu from Gwangju Institute of Science and Technology in South Korea, Riekelt Houtkooper from the Amsterdam University Medical Center in The Netherlands, and colleagues review how dysfunctional mitochondria, which are responsible for producing energy in cells, contribute to cancer and many neurodegenerative, cardiovascular and metabolic conditions. When mitochondria become damaged or stressed, they can trigger cell death mechanisms via impaired quality-control networks and associated signaling pathways, further exacerbating disease processes. By gaining a deeper understanding of how mitochondrial safeguards help to maintain functional integrity, and the different ways in which mitochondria-associated cell death occurs, researchers may identify new targets for drug development.

Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present in various cells throughout the body. Its diverse physiological functions encompass glycolysis, and its abnormal activity is associated with numerous diseases. Targeting LDH has emerged as a vital approach in drug discovery, leading to the identification of LDH inhibitors among natural compounds, such as polyphenols, alkaloids, and terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, and potential toxicity must be addressed. Combining natural compounds with LDH inhibitors has led to promising outcomes in preclinical studies. This review highlights the promise of natural compounds as LDH inhibitors for treating cancer, cardiovascular, and neurodegenerative diseases.

The Warburg effect, wherein cancer cells prefer glycolysis rather than oxidative phosphorylation even under normoxic conditions, is a major characteristic of malignant tumors. Lactate dehydrogenase A (LDHA) is the main enzyme regulating the Warburg effect, and is thus, a major target for novel anti-cancer drug development. Through our ongoing screening of novel inhibitors, we found that several selenobenzene compounds have inhibitory effects on LDHA activity. Among them, 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB) had the most potent inhibitory effect on the enzymatic activity of LDHA. The results from biochemical assays and computational modeling showed that PSTMB inhibited LDHA activity. In addition, PSTMB inhibited the growth of several tumor cell lines, including NCI-H460, MCF-7, Hep3B, A375, HT29, and LLC. In HT29 human colon cancer cells, PSTMB dose-dependently inhibited the viability of the cells and activity of LDHA, without affecting the expression of LDHA. Under both normoxic and hypoxic conditions, PSTMB effectively reduced LDHA activity and lactate production. Furthermore, PSTMB induced mitochondria-mediated apoptosis of HT29 cells via production of reactive oxygen species. These results suggest that PSTMB may be a novel candidate for development of anti-cancer drugs by targeting cancer metabolism.

Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA.

The aim of this study was to investigate the underlying mechanisms responsible for the anticancer effects of lupeol on human non-small cell lung cancer (NSCLC). MTT assay and Trypan blue exclusion assay were used to evaluate the cell viability. DAPI staining and flow cytometric analysis were used to detect apoptosis. Molecular docking and western blot analysis were performed to determine the target of lupeol. We found that lupeol suppressed the proliferation and colony formation of NSCLC cells in a dose-dependent manner. In addition, lupeol increased chromatin condensation, poly(ADP-ribose) polymerase (PARP) cleavage, sub-G1 cell populations, and the proportion of Annexin V-positive cells, indicating that lupeol triggered the apoptosis of NSCLC cells. Notably, lupeol inhibited the phosphorylation of epithelial growth factor receptor (EGFR). A docking experiment revealed that lupeol directly bound to the tyrosine kinase domain of EGFR. We observed that the signal transducer and activator of transcription 3 (STAT3), a downstream molecule of EGFR, was also dephosphorylated by lupeol. Lupeol suppressed the nuclear translocation and transcriptional activity of STAT3 and downregulated the expression of STAT3 target genes. The constitutive activation of STAT3 by STAT3 Y705D overexpression suppressed lupeol-induced apoptosis, demonstrating that the inhibition of STAT3 activity contributed to the induction of apoptosis. The anticancer effects of lupeol were consistently observed in EGFR tyrosine kinase inhibitor (TKI)-resistant H1975 cells (EGFR L858R/T790M). Taken together, the findings of this study suggest that lupeol may be used, not only for EGFR TKI-naïve NSCLC, but also for advanced NSCLC with acquired resistance to EGFR TKIs.

Electroacupuncture (EA) has shown analgesic potential for neuropathic pain, yet its underlying molecular mechanisms remain incompletely understood. This study aimed to investigate whether EA relieves neuropathic pain by modulating CCL2/CCR2 signaling and microglial activation in the spinal cord. Neuropathic pain was induced in rats by L5 spinal nerve ligation. EA was administered at acupoints ST36 and GB34 (1 mA, 2 Hz, 30 min) daily from postoperative days 3 to 7. Rats were assigned to anesthetized control (ANE), non-acupoint stimulation (NAP), and acupoint stimulation (ACU) groups. Pain behavior was evaluated using paw withdrawal threshold and latency. Western blot and immunofluorescence were used to assess CCL2, CCR2, Iba1, IL-1β, and TNF-α expression in the L4–L6 spinal cord. EA significantly attenuated mechanical allodynia and thermal hyperalgesia in the ACU group, accompanied by reductions in CCL2, CCR2, microglial marker Iba1, and pro-inflammatory cytokines. Most importantly, intrathecal administration of recombinant CCL2 completely abolished EA’s analgesic effects, establishing the causal necessity of CCL2/CCR2 signaling in EA-mediated analgesia. These findings suggest that EA exerts its analgesic effects through downregulation of the CCL2/CCR2 pathway and inhibition of microglial activation. The reversal of EA’s effects by exogenous CCL2 supports the critical role of spinal chemokine signaling in EA-mediated analgesia.

Most cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate dehydrogenase (PDH) complex, is commonly overexpressed in tumors and recognized as a therapeutic target in colorectal cancer. Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata Bunge (Compositae). Here, we report that HsA is a PDK1 inhibitor can reduce the growth of colorectal cancer and consequent activation of mitochondrial ROS-dependent apoptotic pathway both in vivo and in vitro. Computational simulation and biochemical assays showed that HsA directly binds to the lipoamide-binding site of PDK1, and subsequently inhibits the interaction of PDK1 with the E2 subunit of PDH complex. As a result of PDK1 inhibition, lactate production was decreased, but oxygen consumption was increased. Mitochondrial ROS levels and mitochondrial damage were also increased. Consistent with these observations, the apoptosis of colorectal cancer cells was promoted by HsA with enhanced activation of caspase-3 and -9. These results suggested that HsA might be a potential candidate for developing a novel anti-cancer drug through suppressing cancer metabolism.

Extraction methods critically influence the phytochemical profile and bioactivity of natural product mixtures, affecting their efficacy as therapeutic agents. This review assesses the impact of various extraction techniques—such as solvent-based extraction, ultrasound-assisted extraction, and enzymatic extraction—on the composition of bioactive compounds in plant extracts. We discuss how extraction parameters modify the bioactivity profiles, influencing their application in pharmaceutics and nutrition. This review critically analyzes these techniques with a special focus on integrated (hybrid) strategies, revealing that while advanced methods like ultrasound-assisted extraction and microwave-assisted extraction offer improved efficiency, the greatest potential lies in the synergistic combination of methods to maximize yield and preserve bioactivity. The insights gathered here aim to guide researchers in developing optimal and sustainable extraction protocols for therapeutic applications.