Local anesthetics promote anticancer immune responses. A machine learning-based algorithm trained with information on the biological effects and molecular descriptors of analgesics, anesthetics, hypnotics and opioids predicted antitumor effects for dexmedetomidine (DEX). DEX is a sedative acting as an alpha2-adrenoceptor (ADRA2) agonist. Based on these premises, we investigated the putative antineoplastic effects of DEX.

In vitro, DEX promoted premortem stresses such as autophagy and partial endoplasmic reticulum stress with the phosphorylation of eukaryotic initiation factor 2 alpha and the inhibition of the splicing of X-box binding protein 1. DEX elicited the biomarkers of immunogenic cell death, including the release of ATP and high-mobility group box 1 protein, and the cell surface exposure of calreticulin, enhancing the engulfment of malignant cells by dendritic cells. In immunocompetent mice, DEX decreased the progression of colorectal cancers, fibrosarcomas, mammary carcinomas and melanomas, as it improved overall survival. These effects were inhibited by the ADRA2 antagonist yohimbine, suggesting that DEX mediates its anticancer effects at least in part on-target. Depending on the specific tumor model, DEX also enhanced the cytotoxic T cell/regulatory T cell ratio in the tumor bed and draining lymph nodes. Programmed cell death protein 1 blockade tended to improve DEX effects. After rechallenge with antigenically identical cells, no tumor appeared, indicating the formation of immunological memory.

These results confirm the machine learning-predicted anticancer activity of DEX. Beyond its utility as a sedative agent in oncological intensive care, DEX may improve anticancer immunosurveillance and sensitize tumors to immune checkpoint blockade.

The silkworm Bombyx mori is an economically important insect for silk production. Its silk glands are responsible for the synthesis and secretion of silk proteins. The naked pupa (Nd), a fibroin heavy chain mutant strain of silkworm, was found to exhibit severe atrophy, degeneration of the posterior silk gland (PSG), and abnormal secretion of fibroin proteins, thereby producing little or no silk. Here, we found that the autophagic marker Atg8-PE was upregulated through the target of rapamycin complex 1 signaling pathway in Nd. However, as autophagy substrates, SQSTM1/p62 and ubiquitinated protein levels increased in Nd. Furthermore, treatment with BafA1 showed no effect on the protein levels of SQSTM1/p62, indicating impaired autophagic flux in Nd. Abnormal acidification of lysosomes was further detected, which resulted in a decreased proportion of matured CtsL1 (cathepsin L1). Thus, the substrate in autolysosomes cannot be degraded within a rapid time frame, resulting in the accumulation of protein aggregates, which cause atrophy and degeneration of the PSG. We also found that acidic nanoparticles rescued lysosomal acidification and relieved the degenerative changes of Nd-PSG. The findings of this study suggest that the Nd mutant silkworm can be used as an animal model for studying protein aggregation diseases.

Acute pancreatitis (AP) is associated with multiple cellular mechanisms that trigger and or are triggered by the inflammatory injury and death of the acinar cells. One of the key mechanisms is the endoplasmic reticulum (ER) stress, which manifests as an accumulation of misfolded proteins within ER, an event that has proinflammatory and proapoptotic consequences. Hence, the degree of cell insult during AP could considerably depend on the signaling pathways that are upregulated during ER stress and its resulting dyshomeostasis such as C/EBP homologous protein (CHOP), cJUN NH2-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and NOD-like receptor protein 3 (NLRP3) inflammasome. Exploring these molecular pathways is an interesting area for translational medicine as it may lead to identifying new therapeutic targets in AP. This review of the literature aims to shed light on the different roles of ER stress in the etiopathogenesis and pathogenesis of AP. Then, it specifically focuses on the therapeutic implications of ER stress in this context.

An overdose of acetaminophen (APAP) is the leading cause of drug-induced hepatotoxicity and acute liver failure in the United States. It is established that the predominant mode of hepatocyte cell death after an APAP overdose is through necrosis, and it is now recognized that this occurs through regulated pathways involving RIP kinases. These kinases, along with the pseudo-kinase MLKL, are central players in classical necroptotic cell death. Despite the skepticism regarding the role of necroptosis in APAP-induced liver injury, recent research demonstrating necroptosis-independent roles for MLKL led us to re-examine the role of this pseudo-kinase in APAP pathophysiology. Treatment of Mlkl-/- mice with a moderate (300 mg/kg) overdose of APAP resulted in an exacerbation of liver injury at 6- and 12-h post-APAP as evidenced by elevated plasma alanine aminotransferase activities, and extensive necrosis accompanied by diminished glutathione levels. Interestingly, these differences between Mlkl-/- and wild-type mice were negated at the 24-h mark, previously scrutinized by others. At 6 and 12 h post-APAP, Mlkl-/- mice exhibited augmented translocation of AIF and Endonuclease G without affecting JNK activation, suggesting enhanced mitochondrial permeability transition in the absence of MLKL. Lack of MLKL also impacted autophagy, the unfolded protein response and endoplasmic reticulum stress, with decreased levels of p62 and LC3B and increased expression of CHOP and GRP78 at 6 h post-APAP. In essence, our findings illuminate a noncanonical role for MLKL in the early phases of APAP-induced liver injury, warranting further exploration of its influence on APAP pathophysiology.

Brain ischemia disrupts endoplasmic reticulum (ER) dynamics, causes ER stress, and triggers the unfolded protein response (UPR). During the UPR, protein kinase RNA-like ER kinase (PERK) phosphorylates eIF2α, shutting down global protein synthesis, inhibits protein synthesis, and provides neuroprotection during acute ischemic stroke. Herein, middle cerebral artery occlusion/reperfusion (MCAO/R) and PERK neuron-specific deletion conditional knockout mice were employed to observe the function and mechanisms of PERK. CCT020312, a novel selective PERK activator, specifically activates PERK and provides neuroprotection both in vivo and in vitro stroke models. Additionally, CCT020312 enhanced neuronal survival and cerebral microvessels and decreased the level of astrogliosis in acute ischemic stroke mice. Furthermore, in vivo experiments demonstrated that CCT020312 not only prevented apoptosis but also enhanced the PERK/p-eIF2α/LC3-II autophagy signaling pathway in MCAO/R mice. In conclusion, our study supports the potential therapeutic value of targeting PERK in acute ischemic stroke, offering a promising strategy for enhancing stroke outcomes through the modulation of protein synthesis and the autophagy pathway.

The endoplasmic reticulum (ER) is a large organelle, found in all eukaryotes, that is essential for normal cellular function. This function encompasses protein folding and quality control, post-translational modifications, lipid regulation, and the storage of intracellular calcium, among others. These diverse processes are essential for maintaining proteome stability. Therefore, a robust surveillance system is established under stress to ensure cell homeostasis. Sources of stress can originate from the cellular environment, including nutrient deprivation, hypoxia, and low pH, as well as from endogenous signals within the cell, such as metabolic challenges and increased demands for protein production. When cellular homeostasis is altered by one of these triggers, ER primary functions are altered which leads to the accumulation of misfolded proteins. These impaired proteins trigger the activation of the Unfolded Protein Response (UPR) pathway. This response aims at reducing ER stress by implementing the induction of complex programs to restore cell homeostasis. However, extended ER stress can modify the UPR response, shifting its signals from promoting survival to triggering pathways that reprogram or eliminate affected cells.

Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.

The endoplasmic reticulum (ER) stress and autophagic pathways offer attractive targets for the development of new cancer drugs. Here, we identified a novel phenyl sulfonyl piperidine, PSP205, that induces prolonged ER-stress-mediated autophagy and apoptosis in colon cancer cells. Transcriptome analysis of cells exposed to PSP205 unveiled transcriptional upregulation of genes associated with the ER stress response or unfolded protein response (UPR), in addition to vesicle transport. Among the top upregulated genes, DNAJB9, XBP1, PDIA4, HSPA5, SEC24D, and SEC11C are implicated in ER stress. Gene set enrichment analysis revealed the enrichment of gene sets involved in the UPR, mTORC1 signaling, hypoxia, the P53 pathway, apoptosis, and the ER-Golgi-vesicle-mediated transport pathway. Mechanistic studies showed that PSP205 acts on the IRE1-TRAF2-JNK pathway to modulate autophagic flux, leading to macroautophagy, ER-phagy, and deformation of Golgi. Our study also demonstrated that PSP205 decreases the expression of the COPI coat complex subunit beta 2 (COPB2) in the presence of COPB2 siRNA. Furthermore, PSP205 synergistically killed colon cancer cells in combination with proteasome and topoisomerase inhibitors. Cumulatively, our findings suggest that PSP205 targets cancer cells via a novel mechanism, specifically by decreasing the level of COPB2, which has not been extensively studied in the context of cancer therapy development and warrants further investigation.

Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME), profoundly influencing cancer progression. These nano-sized vesicles, released by both tumor and stromal cells, carry a diverse cargo of proteins, nucleic acids, and lipids, reflecting the dynamic cellular landscape and mediating intricate interactions between cells. This review provides a comprehensive overview of the biogenesis, composition, and functional roles of EVs in cancer, highlighting their significance in both basic research and clinical applications. We discuss how cancer cells manipulate EV biogenesis pathways to produce vesicles enriched with pro-tumorigenic molecules, explore the specific contributions of EVs to key hallmarks of cancer, such as angiogenesis, metastasis, and immune evasion, emphasizing their role in shaping TME and driving therapeutic resistance. Concurrently, we submit recent knowledge on how the cargo of EVs can serve as a valuable source of biomarkers for minimally invasive liquid biopsies, and its therapeutic potential, particularly as targeted drug delivery vehicles and immunomodulatory agents, showcasing their promise for enhancing the efficacy and safety of cancer treatments. By deciphering the intricate messages carried by EVs, we can gain a deeper understanding of cancer biology and develop more effective strategies for early detection, targeted therapy, and immunotherapy, paving the way for a new era of personalized and precise cancer medicine with the potential to significantly improve patient outcomes.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with potential progression to cirrhosis and impaired regeneration post-resection. A key mechanism underlying lipotoxicity is endoplasmic reticulum (ER) stress, particularly the activation of the unfolded protein response (UPR). This study investigates the interplay between lipid accumulation, endoplasmic reticulum (ER) stress, and cellular outcomes, focusing on the balance between autophagy and apoptosis. We cultured primary human hepatocytes (PHH) in a free fatty acid (FFA)-enriched medium for 120 h, assessing lipid accumulation, metabolism, and the expression of selected UPR markers. Additionally, we investigated the effects of lipid load on cell activity and growth in proliferating HepG2 cells. We observed that FFA uptake consistently induced ER stress, shifting cellular responses toward apoptosis under high lipid loads. Donor-specific differences were evident, particularly in lipid storage, excretion, and sensitivity to lipotoxicity. Some donors exhibited limited triglyceride (TAG) storage and excretion, leading to an excess of FFA whose metabolic fate remains unclear. Proliferation was more sensitive to lipid accumulation than overall cell activity, with even low FFA concentrations impairing growth, highlighting the vulnerability of regenerative processes to steatosis. The study elucidates how ER stress pathways, such as PERK-CHOP and IRE1α-JNK, are differentially activated in response to lipid overload, tipping the balance toward apoptosis in severe cases. The limited activation of repair mechanisms, such as autophagy, further emphasizes the critical role of ER stress in determining hepatocyte fate. The donor-dependent variability highlights the need for personalized strategies to mitigate lipotoxic effects and enhance liver regeneration in steatosis-related conditions.

X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disorder caused by mutations in the VMA21 gene, encoding a chaperone protein present in the endoplasmic reticulum (ER). In yeast and human, VMA21 has been shown to chaperone the assembly of the vacuolar (v)-ATPase proton pump required for the acidification of lysosomes and other organelles. In line with this, VMA21 deficiency in XMEA impairs autophagic degradation steps, which would be key in XMEA pathogenesis. Recent years have witnessed a surge of interest in VMA21, with the identification of novel mutations causing a congenital disorder of glycosylation (CDG) with liver affection, and its potent implication in cancer predisposition. With this, VMA21 deficiency has been further linked to defective glycosylation, lipid metabolism dysregulation and ER stress. Moreover, the identification of two VMA21 isoforms, namely VMA21-101 and VMA21-120, has opened novel avenues regarding the pathomechanisms leading to XMEA and VMA21-CDG. In this review, we discuss recent advances on the clinical spectrum associated with VMA21 deficiency and on the pathophysiological roles of VMA21.

GRP78 (Glucose-related protein 78, BiP/HSPA5) is commonly overexpressed in cancer cells. Acting as an activator of endoplasmic reticulum stress, GRP78 is involved in the resistance of cancer cells to injury. Current evidence suggests that GRP78 plays a significant role in the radiotherapy resistance and chemotherapy resistance of cancers, which is accomplished through a variety of complex pathways. These include the promotion of tumor stemness, inhibition of apoptosis, regulation of autophagy, maintenance of tumor microenvironment homeostasis, protection of dormant cells, evasion of senescence, counteraction of autoantibodies against GRP78, facilitation of DNA damage repair, suppression of ferroptosis, and modulation of metabolic reprogramming in tumor cells. Importantly, chemoradiotherapy resistance in cancers are the main reasons for treatment failure in patients, severely affecting their survival. Investigating the mechanisms of GRP78 in tumor therapeutic resistance is essential. In this article, we review the mechanisms by which GRP78 mediates cell survival and chemoradiotherapy resistance in cancers and provide an overview of clinical trials targeting GRP78 therapy.

Glioblastoma is one of the most aggressive brain cancers, characterized by active infiltrative growth and high resistance to radiotherapy and chemotherapy. Sesquiterpene triterpenoids (STLs) and their semi-synthetic analogs are considered as a promising source of novel anti-tumor agents due to their low systemic toxicity and multi-target pharmacological effects on key processes associated with tumor progression. The current review aims to systematize the knowledge on the anti-glioblastoma potential of STLs accumulated over the last decade and to identify key processes in glioblastoma cells that are most susceptible to the action of STLs. An analysis of published data clearly demonstrated that STLs, which can successfully cross the blood-brain barrier, exert a complex inhibitory effect on glioblastoma cells through the induction of the "mitochondrial dysfunction-oxidative stress-apoptosis" axis, the inhibition of glucose metabolism and cell cycle phase transition, and the suppression of glioblastoma cell motility and invasion through the blockade of proneural-mesenchymal transition. Taken together, this review highlights the promising anti-glioblastoma potential of STLs, which are not only able to induce glioblastoma cell death, but also effectively affect their diffusive spread, and suggests the possible directions for further investigation of STLs in the context of glioblastoma to better understand their mechanism of action.

Fine particulate matter (PM2.5) has become an important risk factor threatening human health. Epidemiological and toxicological investigations have revealed that PM2.5 not only leads to cardiovascular dysfunction, but it also gives rise to various adverse health effects on the human body, such as cardiovascular and cerebrovascular diseases, cancers, neurodevelopmental disorders, depression and autism. PM2.5 is able to penetrate both respiratory and placental barriers, thereby resulting in negative effects on fetal development. A large body of epidemiological evidences has suggested that gestational exposure to PM2.5 increases the incidence of congenital diseases in offspring, including congenital heart defects. In addition, animal model studies have revealed that gestational exposure to PM2.5 can disrupt normal heart development in offspring, although the potential molecular mechanisms have yet to be fully elucidated. The aim of the present review was to provide a brief overview of what is currently known regarding the molecular mechanisms underlying cardiac developmental toxicity in offspring induced by gestational exposure to PM2.5.

Osteoarthritis (OA) is characterized primarily by the degeneration of articular cartilage, with a high prevalence and disability rate. The functional phenotype of chondrocytes, as the sole cell type within cartilage, is vital for OA progression. Due to the avascular nature of cartilage and its limited regenerative capacity, repair following injury poses significant challenges. Various cellular stressors, including hypoxia, nutrient deprivation, oxidative stress, and collagen mutations, can lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress (ERS). In response to restore ER homeostasis as well as cellular vitality and function, a series of adaptive mechanisms are triggered, including the unfolded protein response, ER-associated degradation, and ER-phagy. Prolonged or severe ERS may exceed the adaptive capacity of cells, leading to dysregulation in apoptosis and autophagy-key pathogenic factors contributing to chondrocyte damage and OA progression. This review examines the relationship between ERS in OA chondrocytes and both apoptosis and autophagy in order to identify potential therapeutic targets and strategies for prevention and treatment of OA.

Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling. It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them. Apolipoprotein E polymorphism, combined with environmental stresses and/or age-related alterations, influences the risk of developing late-onset Alzheimer's disease. In this review, we discuss our current knowledge of how apolipoprotein E homeostasis, i.e. its synthesis, secretion, degradation, and lipidation, is affected in Alzheimer's disease.

Calcium ions (Ca2+) regulate cell proliferation and differentiation and participate in various physiological activities of cells. The calcium transfer protein inositol 1,4,5-triphosphate receptor (IP3R), located between the endoplasmic reticulum (ER) and mitochondria, plays an important role in regulating Ca2+ levels. However, the mechanism by which IP3R1 affects porcine meiotic progression and embryonic development remains unclear. We established a model in porcine oocytes using siRNA-mediated knockdown of IP3R1 to investigate the effects of IP3R1 on porcine oocyte meiotic progression and embryonic development. The results indicated that a decrease in IP3R1 expression significantly enhanced the interaction between the ER and mitochondria. Additionally, the interaction between the ER and the mitochondrial Ca2+ ([Ca2+]m) transport network protein IP3R1-GRP75-VDAC1 was disrupted. The results of the Duolink II in situ proximity ligation assay (PLA) revealed a weakened pairwise interaction between IP3R1-GRP75 and VDAC1 and a significantly increased interaction between GRP75 and VDAC1 after IP3R1 interference, resulting in the accumulation of large amounts of [Ca2+]m. These changes led to mitochondrial oxidative stress, increased the levels of reactive oxygen species (ROS) and reduced ATP production, which hindered the maturation and late development of porcine oocytes and induced apoptosis. Nevertheless, after treat with [Ca2+]m chelating agent ruthenium red (RR) or ROS scavenger N-acetylcysteine (NAC), the oocytes developmental abnormalities, oxidative stress and apoptosis caused by Ca2+ overload were improved. In conclusion, our results indicated IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.

Lipotoxicity is defined as a prolonged metabolic imbalance of lipids that results in ectopic fat distribution in peripheral organs such as the liver, heart, and kidney. The harmful consequences of excessive lipid accumulation in cardiomyocytes cause cardiac lipotoxicity, which alters the structure and function of the heart. Obesity and diabetes are linked to lipotoxic cardiomyopathy. These anomalies might be caused by a harmful metabolic shift that accumulates toxic lipids and shifts glucose oxidation to less fatty acid oxidation. Research has linked fatty acids, fatty acyl coenzyme A, diacylglycerol, and ceramide to lipotoxic stress in cells. This stress can be brought on by apoptosis, impaired insulin signaling, endoplasmic reticulum stress, protein kinase C activation, p38 Ras-mitogen-activated protein kinase (MAPK) activation, or modification of peroxisome proliferator-activated receptors (PPARs) family members. Curcuma longa is used to extract curcumin, a hydrophobic polyphenol derivative with a variety of pharmacological characteristics. Throughout the years, curcumin has been utilized as an anti-inflammatory, antioxidant, anticancer, hepatoprotective, cardioprotective, anti-diabetic, and anti-obesity drug. Curcumin reduces cardiac lipotoxicity by inhibiting apoptosis and decreasing the expression of apoptosis-related proteins, reducing the expression of inflammatory cytokines, activating the autophagy signaling pathway, and inhibiting the expression of endoplasmic reticulum stress marker proteins.

Neurodegenerative diseases are complex disorders that significantly challenge human health, with their incidence increasing with age. A key pathological feature of these diseases is the accumulation of misfolded proteins. The underlying mechanisms involve an imbalance in calcium homeostasis and disturbances in autophagy, indicating a likely correlation between them. As the most important second messenger, Ca2+ plays a vital role in regulating various cell activities, including autophagy. Different organelles within cells serve as Ca2+ storage chambers and regulate Ca2+ levels under different conditions. Ca2+ in these compartments can affect autophagy via Ca2+ channels or other related signaling proteins. Researchers propose that Ca2+ regulates autophagy through distinct signal transduction mechanisms, under normal or stressful conditions, and thereby contributing to the occurrence and development of neurodegenerative diseases. This review provides a systematic examination of the regulatory mechanisms of Ca2+ in cell membranes and different organelles, as well as its downstream pathways that influence autophagy and its implications for neurodegenerative diseases. This comprehensive analysis may facilitate the development of new drugs and provide more precise treatments for neurodegenerative diseases.

Pro-survival metabolic adaptations to stress in tumorigenesis remain less well defined. We find that multiple myeloma (MM) is unexpectedly dependent on beta-oxidation of long-chain fatty acids (FAs) for survival under both basal and stress conditions. However, under stress conditions, a second pro-survival signal is required to sustain FA oxidation (FAO). We previously found that CD28 is expressed on MM cells and transduces a significant pro-survival/chemotherapy resistance signal. We now find that CD28 signaling regulates autophagy/lipophagy that involves activation of the Ca2+→AMPK→ULK1 axis and regulates the translation of ATG5 through HuR, resulting in sustained lipophagy, increased FAO, and enhanced MM survival. Conversely, blocking autophagy/lipophagy sensitizes MM to chemotherapy in vivo. Our findings link a pro-survival signal to FA availability needed to sustain the FAO required for cancer cell survival under stress conditions and identify lipophagy as a therapeutic target to overcome treatment resistance in MM.

Autophagy is an evolutionarily conserved process in which intracellular macromolecules are degraded in a lysosomal-dependent manner. It is central to cellular energy homeostasis and to quality control of intracellular components. A decline in autophagic activity is associated with aging, and contributes to the development of various age-associated pathologies, including cancer. There is an ongoing need to develop chemotherapeutic agents to improve morbidity and mortality for those diagnosed with cancer, as well as to decrease the cost of cancer care. Autophagic programs are altered in cancer cells to support survival in genetically and metabolically unstable environments, making autophagy an attractive target for new chemotherapy. Antiretroviral drugs, which have dramatically increased the life- and health spans of people with human immunodeficiency virus (HIV) (PWH), have offered promise in the treatment of cancer. One mechanism underlying the antineoplastic effects of antiretroviral drugs is the alteration of cancer cell autophagy that can potentiate cell death. Antiretroviral drugs could be repurposed into the cancer chemotherapy arsenal. A more complete understanding of the impact of antiretroviral drugs on autophagy is essential for effective repurposing. This review summarizes our knowledge of the effects of antiretroviral drugs on autophagy as potential adjunctive chemotherapeutic agents, and highlights gaps to be addressed to reposition antiretroviral drugs into the antineoplastic arsenal successfully.

The intracellular coral-dinoflagellate symbiosis is the engine that underpins the success of coral reefs, one of the most diverse ecosystems on the planet. However, the breakdown of the symbiosis and the loss of the microalgal symbiont (i.e. coral bleaching) due to environmental changes are resulting in the rapid degradation of coral reefs globally. There is an urgent need to understand the cellular physiology of coral bleaching at the mechanistic level to help develop solutions to mitigate the coral reef crisis. Here, at an unprecedented scope, we present novel models that integrate putative mechanisms of coral bleaching within a common framework according to the triggers (initiators of bleaching, e.g. heat, cold, light stress, hypoxia, hyposalinity), cascades (cellular pathways, e.g. photoinhibition, unfolded protein response, nitric oxide), and endpoints (mechanisms of symbiont loss, e.g. apoptosis, necrosis, exocytosis/vomocytosis). The models are supported by direct evidence from cnidarian systems, and indirectly through comparative evolutionary analyses from non-cnidarian systems. With this approach, new putative mechanisms have been established within and between cascades initiated by different bleaching triggers. In particular, the models provide new insights into the poorly understood connections between bleaching cascades and endpoints and highlight the role of a new mechanism of symbiont loss, i.e. 'symbiolysosomal digestion', which is different from symbiophagy. This review also increases the approachability of bleaching physiology for specialists and non-specialists by mapping the vast landscape of bleaching mechanisms in an atlas of comprehensible and detailed mechanistic models. We then discuss major knowledge gaps and how future research may improve the understanding of the connections between the diverse cascade of cellular pathways and the mechanisms of symbiont loss (endpoints).

Cadmium (Cd) is an important environmental pollutant that poses a threat to human health and represents a critical component of air pollutants, food sources, and cigarette smoke. Cd is a known carcinogen and has toxic effects on the environment and various organs in humans. Heavy metals within an organism are difficult to biodegrade, and those that enter the respiratory tract are difficult to remove. Autophagy is a key mechanism for counteracting extracellular (microorganisms and foreign bodies) or intracellular (damaged organelles and proteins that cannot be degraded by the proteasome) stress and represents a self-protective mechanism for eukaryotes against heavy metal toxicity. Autophagy maintains cellular homeostasis by isolating and gathering information about foreign chemicals associated with other molecular events. However, autophagy may trigger cell death under certain pathological conditions, including cancer. Autophagy dysfunction is one of the main mechanisms underlying Cd-induced cytotoxicity. In this review, the toxic effects of Cd-induced autophagy on different human organ systems were evaluated, with a focus on hepatotoxicity, nephrotoxicity, respiratory toxicity, and neurotoxicity. This review also highlighted the classical molecular pathways of Cd-induced autophagy, including the ROS-dependent signaling pathways, endoplasmic reticulum (ER) stress pathway, Mammalian target of rapamycin (mTOR) pathway, Beclin-1 and Bcl-2 family, and recently identified molecules associated with Cd. Moreover, research directions for Cd toxicity regarding autophagic function were proposed. This review presents the latest theories to comprehensively reveal autophagy behavior in response to Cd toxicity and proposes novel potential autophagy-targeted prevention and treatment strategies for Cd toxicity and Cd-associated diseases in humans.

Chemotherapeutic drugs are indispensable in cancer treatment, but their effectiveness is often lessened because of non-selective toxicity to healthy tissues, which triggers inflammatory pathways that are harmful to vital organs. In addition, tumors' resistance to drugs causes failures in treatment. Chlorogenic acid (5-caffeoylquinic acid, CGA), found in plants and vegetables, is promising in anticancer mechanisms. In vitro and animal studies have indicated that CGA can overcome resistance to conventional chemotherapeutics and alleviate chemotherapy-induced toxicity by scavenging free radicals effectively. This review is a summary of current information about CGA, including its natural sources, biosynthesis, metabolism, toxicology, role in combatting chemoresistance, and protective effects against chemotherapy-induced toxicity. It also emphasizes the potential of CGA as a pharmacological adjuvant in cancer treatment with drugs such as 5-fluorouracil, cisplatin, oxaliplatin, doxorubicin, regorafenib, and radiotherapy. By analyzing more than 140 papers from PubMed, Google Scholar, and SciFinder, we hope to find the therapeutic potential of CGA in improving cancer therapy.

Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance.

Triptolide, a natural bioactive compound derived from herbal medicine Tripterygium wilfordii, has multiple biological activities including anti-cancer effect, which is being tested in clinical trials for treating cancers. However, the exact mechanism by which Triptolide exerts its cytotoxic effects, particularly its specific protein targets, remains unclear. Here, we show that Triptolide effectively induces cytotoxicity in gastric cancer cells by increasing reactive oxygen species (ROS) levels. Further investigations reveal that ROS accumulation contributes to the induction of Endoplasmic Reticulum (ER) stress, and subsequently autophagy induction in response to Triptolide. Meanwhile, this autophagy is cytoprotective. Interestingly, through activity-based protein profiling (ABPP) approach, we identify peroxiredoxins-2 (PRDX2), a component of the key enzyme systems that act in the defense against oxidative stress and protect cells against hydroperoxides, as direct binding target of Triptolide. By covalently binding to PRDX2 to inhibit its antioxidant activity, Triptolide increases ROS levels. Moreover, overexpression of PRDX2 inhibits and knockdown of the expression of PRDX2 increases Triptolide-induced apoptosis. Collectively, these results indicate PRDX2 as a direct target of Triptolides for inducing apoptosis. Our results not only provide novel insight into the underlying mechanisms of Triptolide-induced cytotoxic effects, but also indicate PRDX2 as a promising potential therapeutic target for developing anti-gastric cancer agents.

Chlorocholine chloride (CCC) is a plant growth regulator used worldwide that is detectable in cereals, fruits and animal products. The health effects of CCC exposure have raised public concern. Our previous research showed that CCC exposure decreased testosterone synthesis in pubertal rats. However, little is known about whether and how pubertal CCC exposure impacts spermatogenesis. In this study, we used BALB/c mice and spermatogonia-derived GC-1 cells to examine CCC-induced spermatogenic dysfunction. In vivo, pubertal CCC exposure led to decreased testicular weight, decreased testicular germ cells and poor sperm quality. This effect worsened after cessation of CCC exposure for the next 30 days. RNA-seq and western blot analysis revealed that CCC induced aryl hydrocarbon receptor (AhR) signaling, endoplasmic reticulum stress (ERS) and ferritinophagy. Increased iron content and lipid peroxidation levels were also observed in CCC-treated testes. In vitro, it was identified that iron overload mediated by enhanced ferritinophagy occurred in CCC-treated GC-1 cells, which might be attributed to the PERK pathway in ERS. Further, for the first time, our study elucidated the involvement of AhR in CCC-induced iron overload, which aggravated testicular oxidative damage via lipid peroxidation. Considering the adverse impact of CCC exposure on rodents, supportive evidence from GC-1 cells, and the critical importance of spermatogenesis on male development, the effects of CCC on the male reproduction warrant increased attention.

In eukaryotes, targeting intracellular components for lysosomal degradation by autophagy represents a catabolic process that evolutionarily regulates cellular homeostasis. The successful completion of autophagy initiates the engulfment of cytoplasmic materials within double-membrane autophagosomes and subsequent delivery to autolysosomes for degradation by acidic proteases. The formation of autolysosomes relies on the precise fusion of autophagosomes with lysosomes. In recent decades, numerous studies have provided insights into the molecular regulation of autophagosome-lysosome fusion. In this review, an overview of the molecules that function in the fusion of autophagosomes with lysosomes is provided. Moreover, the molecular mechanism underlying how these functional molecules regulate autophagosome-lysosome fusion is summarized.

Premature birth (PTB) remains a major global health concern due to its association with neonatal morbidity and mortality. The unfolded protein response (UPR) within the endoplasmic reticulum (ER) is tightly regulated by Inositol-requiring enzyme type 1 (IRE-1), a pivotal cellular modulator. This study seeks to elucidate the role of the ER stress (ERS)-related IRE-1 pathway in PTB.

Human placental trophoblast cells HTR8/Svneo were exposed to the ER-stress inducer tunicamycin (TM). The expression of IRE-1 and ERS-associated proteins ATF6, GRP78, and XBP-1 was assessed in placental tissues and TM-treated cells. Cellular viability, migration, invasion, and apoptosis were evaluated through a series of experimental assays. Additionally, various methods were employed to assess and verify the activation of autophagy, using the autophagy marker, microtubule-associated protein 1A/1B-light chain 3 (LC3). Additionally, TUDCA (an ERS inhibitor) was used to assess its potential to counteract the TM-induced cell effects.

Elevated levels of ATF6, GRP78, and XBP-1 were observed in PTB tissues and cells. TM treatment substantially reduced cell viability, migration, and invasion while promoting apoptosis. Treatment with TUDCA (an ERS inhibitor) counteracted the effects of TM on the cells. Furthermore, we identified an overexpression of IRE-1 in PTB tissues and cells and its knockdown enhanced cell viability, migration, and invasion while suppressed apoptosis and autophagy under TM stimulation. Notably, IRE-1 was found to modulate the activity of the IRE-1/XBP1/CHOP signaling pathway in TM-treated cells.

The upregulation of IRE-1 in PTB placental tissues is implicated in the pathogenesis of PTB. Importantly, inhibiting the ERS-associated IRE-1/XBP1/CHOP pathway may be a good strategy in mitigating PTB.

In recent years, the world has seen an alarming increase in obesity and is closely associated with insulin resistance, which is a state of low-grade inflammation, the latter characterized by elevated levels of proinflammatory cytokines in blood and tissues. A shift in energy balance alters systemic metabolic regulation and the important role that chronic inflammation, endoplasmic reticulum (ER) dysfunction, and activation of the unfolded protein response (UPR) plays in this process.Why obesity is so closely associated with insulin resistance and inflammation is not understood well. This suggests that there are probably many causes for obesity-related insulin resistance and inflammation. One of the faulty mechanisms is protein homeostasis, protein quality control system included protein folding, chaperone activity, and ER-associated degradation leading to endoplasmic reticulum (ER) stress.The ER is a vast membranous network responsible for the trafficking of a wide range of proteins and plays a central role in integrating multiple metabolic signals critical in cellular homeostasis. Conditions that may trigger unfolded protein response activation include increased protein synthesis, the presence of mutant or misfolded proteins, inhibition of protein glycosylation, imbalance of ER calcium levels, glucose and energy deprivation, hypoxia, pathogens, or pathogen-associated components and toxins. Thus, characterizing the mechanisms contributing to obesity and identifying potential targets for its prevention and treatment will have a great impact on the control of associated conditions, particularly T2D.

Coronavirus disease 2019 (COVID-19) has affected not only individual lives but also the world and global systems, both natural and human-made. Besides millions of deaths and environmental challenges, the rapid spread of the infection and its very high socioeconomic impact have affected healthcare, economic status and wealth, and mental health across the globe. To better appreciate the pandemic's influence, multidisciplinary and interdisciplinary approaches are needed. In this chapter, world-leading scientists from different backgrounds share collectively their views about the pandemic's footprint and discuss challenges that face the international community.

FAM134B, the initial endoplasmic reticulum (ER)-phagy receptor identified, facilitates ER-phagy during ER stress. The malfunction of FAM134B has been demonstrated to have a crucial role in the pathological mechanisms of diverse human ailments. However, the role of FAM134B-mediated ER-phagy in ototoxicity, particularly in cisplatin-induced ototoxicity, remains unclear. The present study endeavors to investigate whether FAM134B is expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) and C57BL/6 murine cochlear hair cells (HCs), and to explore its potential function in cisplatin-mediated ototoxicity, with the aim of discovering new insights that can mitigate or forestall the irreversible adverse effect of cisplatin.

Immunofluorescence (IF) staining was used to test the expression pattern of FAM134B, levels of C/EBP-homologous protein (CHOP), autophagy, and co-localization ratio of lysosomes and ER. Western blotting was employed to measure changes in expression levels of FAM134B, LC3B, ER stress-related proteins, LAMP1 and apoptotic mediators. Cell apoptosis was examined using transferase dUTP nick end labeling (TUNEL) assay and flow cytometry.

In the present investigation, it was observed that FAM134B exhibited a diffuse expression pattern in the cytoplasm and nuclei of control HEI-OC1 cells. Following cisplatin administration, FAM134B was found to accumulate and form distinct dots around the nuclei, concomitant with increased levels of ER-phagy, ER stress, unfolded protein response (UPR), and cell apoptosis. Additionally, knockdown of FAM134B resulted in reduced ER-phagy, mitigated ER stress and UPR, and decreased apoptotic activity in HEI-OC1 cells following cisplatin exposure.

Collectively, the findings of this study demonstrate that FAM134B-mediated ER-phagy enhances the susceptibility of HCs to ER stress and apoptosis in response to cisplatin-induced stress. This suggests a sequential progression of ER-phagy, ER stress and apoptosis following cisplatin stimulus, and implies the potential therapeutic benefit of inhibiting of FAM134B-mediated ER-phagy in the prevention of cisplatin-related ototoxicity.

The dynamic balance of Ca2+ in oocytes promotes the recovery of the meiotic arrest phase, consequently promoting oocyte maturation. Hence, the analysis of the maintenance and role of calcium homeostasis in oocytes has important guiding significance for obtaining high-quality eggs and maintaining the development of preimplantation embryos. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are calcium channel proteins that regulate the dynamic balance between the endoplasmic reticulum (ER) and mitochondrial Ca2+. Nevertheless, the expression and role of IP3R in normal pig oocytes have not been reported, and other studies have focused on the role of IP3R in damaged cells. The purpose of this study was to investigate the potential role of IP3R in regulating calcium homeostasis in oocyte maturation and early embryonic development. Our results showed that IP3R1 is stably expressed at different stages of porcine oocyte meiosis, IP3R1 gradually converges to the cortex, and cortical clusters are formed in MII stages. The loss of IP3R1 activity contributeds to the failure of porcine oocyte maturation and cumulus cell expansion, as well as the obstruction of polar body excretion. Further analysis showed that IP3R1 plays an important role in affecting calcium balance by regulating the IP3R1-GRP75-VDAC1 channel between mitochondria and the endoplasmic reticulum (ER) during porcine oocyte maturation. Inhibiting IP3R1 expression-induced ER dysfunction, contributeding to ER calcium concentration ([Ca2+]ER) release outwards into mitochondria and causing mitochondrial free calcium concentration ([Ca2+]m) overload and mitochondrial oxidative stress, which was confirmed by the increase in the level of reactive oxygen species (ROS) and apoptosis. Thereby, IP3R1 plays an important role in affecting calcium balance by regulating the IP3R1-GRP75 -VDAC1 channel between mitochondria and the ER during porcine oocyte maturation, inhibiting IP3R1 expression-induced calcium overload and mitochondrial oxidative stress, and increasing ROS levels and apoptosis.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that leads to memory loss and cognitive impairment over time. It is characterized by protein misfolding as well as prolonged cellular stress, such as perturbing calcium homeostasis and redox management. Numerous investigations have proven that endoplasmic reticulum failure may exhibit exacerbation of AD pathogenesis in AD patients, in-vivo and in-vitro models. The endoplasmic reticulum (ER) participates in a variety of biological functions including folding of protein, quality control, cholesterol production, and maintenance of calcium balance. A diverse range of physiological, pathological and pharmacological substances can interfere with ER activity and thus lead to exaggeration of ER stress. The unfolded protein response (UPR), an intracellular signaling network is stimulated due to ER stress. Three stress sensors found in the endoplasmic reticulum, the PERK, ATF6, and IRE1 transducers detect protein misfolding in the ER and trigger UPR, a complex system to maintain homeostasis. ER stress is linked to many of the major pathological processes that are seen in AD, including presenilin1 and 2 (PS1 and PS2) gene mutation, tau phosphorylation and β-amyloid formation. The role of ER stress and UPR in the pathophysiology of AD implies that they can be employed as potent therapeutic target. This study shows the relationship between ER and AD and how the pathogenesis of AD is influenced by the impact of ER stress. An effective method for the prevention or treatment of AD may involve therapeutic strategies that modify ER stress pathways.

Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance. Nevertheless, the specific mechanism through which TAMs regulate drug efflux remains elusive. Here, we discovered that TAMs endow CRC cells with resistance to 5-fluorouracil (5-FU) treatment via a cell-cell interaction-mediated MRP1-dependent drug efflux process. Mechanistically, TAM-secreted C-C motif chemokine ligand 17 (CCL17) and CCL22, via membrane receptor CCR4, activated the PI3K/AKT pathway in CRC tumor cells. Specifically, phosphorylation of AKT inactivated IP3R and induced calcium aggregation in the ER, resulting in the activation of ATF6 and upregulation of GRP78. Accordingly, excessive GRP78 can interact with MRP1 and promote its translocation to the cell membrane, causing TAM-induced 5-FU efflux. Taken together, our results demonstrated that TAMs promote CRC chemotherapy resistance via elevating the expression of GRP78 to promote the membrane translocation of MRP1 and drug efflux, providing direct proof for TAM-induced drug resistance.

Cyclooxygenase-2 plays a role in oncogenesis and its overexpression is associated with triple-negative breast cancer. However, the mechanisms whereby cyclooxygenase-2 contribute to breast cancer are complex and not well understood. Cyclooxygenase-2 overexpression causes hypoxia, oxidative stress, and endoplasmic reticulum stress. The aim of this study is to investigate the correlations among cyclooxygenase-2 expression, endoplasmic reticulum stress-associated molecules, and autophagy-associated molecules in triple-negative breast cancer. Surgical specimens from two cohorts of triple-negative breast cancer patients without neoadjuvant systemic therapy were analyzed: cohorts 1 and 2 consisted of 218 cases from 2004 to 2006 and 221 cases from 2007 to 2009, respectively. Specimens were evaluated by immunohistochemical examination of cyclooxygenase-2, endoplasmic reticulum stress markers, and autophagy markers expression using tissue microarrays. Cyclooxygenase-2 was overexpressed in 29.8% and 23.9% of cases in cohorts 1 and 2, respectively; and it was positively correlated with two out of three endoplasmic reticulum stress-associated molecules (XBP1, p = 0.025 and p = 0.003 in cohort 1 and cohort 2, respectively; PERK, p < 0.001 in both cohorts). Cyclooxygenase-2 was also positively correlated with two out of three autophagy markers (p62, p = 0.002 and p = 0.003 in cohort 1 and cohort 2, respectively; beclin1, p < 0.001 in both cohorts). Although cyclooxygenase-2 was not an independent prognostic factor for distant metastasis free survival and overall survival, its expression was associated with the expression of endoplasmic reticulum stress and autophagy molecules in triple-negative breast cancer.

The endoplasmic reticulum (ER) plays important roles in biosynthetic and metabolic processes, including protein and lipid synthesis, Ca²⁺ homeostasis regulation, and subcellular organelle crosstalk. Dysregulation of ER homeostasis can cause toxic protein accumulation, lipid accumulation, and Ca²⁺ homeostasis disturbance, leading to cell injury and even death. Accumulating evidence indicates that the dysregulation of ER homeostasis promotes the onset and progression of kidney diseases. However, maintaining ER homeostasis through unfolded protein response, ER-associated protein degradation, autophagy or ER-phagy, and crosstalk with other organelles may be potential therapeutic strategies for kidney disorders. In this review, we summarize the recent research progress on the relationship and molecular mechanisms of ER dysfunction in kidney pathologies. In addition, the endogenous protective strategies for ER homeostasis and their potential application for kidney diseases have been discussed.

Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, including cancer. Importantly, both structural and functional changes can alter mitochondrial function. Morphologic and quantifiable changes in mitochondria can affect their function and contribute to disease. Structural mitochondrial changes include alterations in cristae morphology, mitochondrial DNA integrity and quantity, and dynamics, such as fission and fusion. Functional parameters related to mitochondrial biology include the production of reactive oxygen species, bioenergetic capacity, calcium retention, and membrane potential. Although these parameters can occur independently of one another, changes in mitochondrial structure and function are often interrelated. Thus, evaluating changes in both mitochondrial structure and function is crucial to understanding the molecular events involved in disease onset and progression. This review focuses on the relationship between alterations in mitochondrial structure and function and cancer, with a particular emphasis on gynecologic malignancies. Selecting methods with tractable parameters may be critical to identifying and targeting mitochondria-related therapeutic options. Methods to measure changes in mitochondrial structure and function, with the associated benefits and limitations, are summarized.

In this study we aimed to understand the underlying mechanism of Dichlorvos-induced toxicity in cardiac cells. For this end, cells were treated by 170 μM of Dichlorvos (DDVP) (corresponding to the IC50) and molecular events were monitored by flow cytometry and western blotting. We have first demonstrated that cell exposure to DDVP for 24 h induced cell death by necroptosis. In fact, cell treatment with DDVP upregulated RIP1 expression and we have shown that chemical inhibition of RIP1 kinase activity by necrostatin-1 (Nec-1) greatly prevented from the induced cell death. Besides, we have demonstrated that, while there was no observed cell death following short exposure to DDVP (6 h), autophagy was enhanced, as proven by the increase in the level of both Beclin-1 and LC3-II and the accumulation of the CytoID® autophagy detection probe. Besides, when autophagy was inhibited by chloroquine (CQ) the percentage of necroptosis was significantly increased, suggesting that autophagy acts to protect cardiac cells against the toxicity induced by this pesticide. Concurrently, we have shown that the inhibition of the deacetylase sirtuin 1 (SIRT1) by EX527 or its knockdown by siRNA significantly increased DDVP-induced necroptosis, whereas when SIRT1 was activated by resveratrol (RSV) a significant decrease in DDVP-induced cell death was observed. In addition, we revealed that when the autophagy was inhibited by CQ, we can't reveal the protective effect of RSV anymore. Altogether, these results suggest that activation of SIRT1 protects cardiac cells from the toxicity of DDVP through an autophagy-dependent pathway.