Search

BACKGROUND: Buqi Huoxue Compounds have significant clinical efficacy in treating ischemic stroke with Qi deficiency and phlegm stasis; however, the exact mechanism of action is not clear. OBJECTIVE: To observe the effect of Buqi Huoxue Compounds on the expression of vascular endothelial growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor and autophagy related protein Beclin1 and p62 in a rat model of cerebral ischemia/reperfusion. METHODS: Forty male Sprague-Dawley rats were randomly divided into sham operation group, model group, Buqi Huoxue Compounds group and autophagy inhibitor group, with 10 rats in each group. In the latter three groups, a rat model of cerebral ischemia/reperfusion injury was established. The Buqi Huoxue Compounds group was intragastrically given Buqi Huoxue Compounds (6.49 g/kg, administered three times a day) 2 hours after reperfusion; the autophagy inhibitor group was intragastrically given Buqi Huoxue Compounds (6.49 g/kg, administered three times a day) 2 hours after reperfusion and intraperitoneally given 3-methyladenine 2 hours before gavage and at days 1-3 of gavage. The sham operation group and model group were given equal amounts of saline by gavage for 7 consecutive days. Neurological function, cerebral infarct volume, brain tissue morphology and expression of vascular endothelial growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor and autophagy-related proteins Beclin1 and p62 in the ischemic cortical region of rats were detected at 24 hours after the final administration. RESULTS AND CONCLUSION: Zea-Longa scoring results showed that the neurological function of rats was severely damaged after modeling and neurological deficit of rats in the Buqi Huoxue Compounds group was less than that in the model group and the autophagy inhibitor group (P < 0.05). TTC staining showed that cerebral infarct foci were observed in the model group, Buqi Huoxue Compounds group, and autophagy inhibitor group, and the cerebral infarct volume in the Buqi Huoxue Compounds group was lower than that in the model group and the autophagy inhibitor group (P < 0.05). The results of hematoxylineosin staining in ischemic brain tissues showed that there were large gaps between nerve cells in the model group and cell arrangement was not neat, and cytoplasmic agglutination and pyknosis were observed. Immunohistochemical staining results showed that vascular endothelial growth factor was mostly expressed in neuronal cells, glial cells and capillary endothelium; basic fibroblast growth factor and brain-derived neurotrophic factor were mostly expressed in neuronal cells and glial cells; and there was no significant difference in the expression of vascular endothelial growth factor, basic fibroblast growth factor, and brain-derived neurotrophic factor among the four groups (P > 0.05). The results of western blot assay showed that compared with the sham operation group, Beclin1 protein expression was decreased (P < 0.05) and p62 protein expression was elevated (P < 0.05) in the model group; compared with the model group, Beclin1 protein expression was increased (P < 0.05) and p62 protein expression was reduced (P < 0.05) in the Buqi Huoxue Compounds group; compared with the Buqi Huoxue Compounds group, Beclin1 protein expression was decreased (P < 0.05) and p62 protein expression was elevated (P < 0.05) in the autophagy inhibitor group. To conclude, Buqi Huoxue Compounds attenuate cerebral ischemia-reperfusion injury in rats by promoting autophagy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have shown that metformin has anti-inflammatory, anti-tumor, anti-aging and vasoprotective effects, and can inhibit the progression of osteoarthritis, but its specific mechanism of action remains unclear. OBJECTIVE: To investigate the mechanism of metformin on cartilage protection in a rat model of osteoarthritis. METHODS: Forty male Sprague-Dawley rats were randomly divided into four groups (n=10 per group): blank, control, sham-operated, and metformin groups. The blank group did not undergo any surgery. In the sham-operated group, the joint cavity was exposed. In the model group and the metformin group, the modified Hulth method was used to establish the osteoarthritis model. At 1 day after modeling, the rats in the metformin group were given 200 mg/kg/d metformin by gavage, and the model, blank, and sham-operated groups were given normal saline by gavage. Administration in each group was given for 4 weeks consecutively. Hematoxylin-eosin staining, toluidine blue staining, and safranin O-fast green staining were used to observe the morphological structure of rat knee joints. Immunohistochemical staining and western blot were used to detect the protein expression of SOX9, type II collagen, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), Beclin1, P62, phosphatidylinositol 3-kinase (PI3K), p-PI3K, protein kinase B (AKT), p-AKT, mammalian target of rapamycin (mTOR), and p-mTOR in rat cartilage tissue. RESULTS AND CONCLUSION: The results of hematoxylin-eosin, toluidine blue and safranin O-fast green staining showed smooth cartilage surface of the knee joints and normal histomorphology in the blank group and the sham-operated group, while in the model group, there was irregular cartilage surface of the knee joint and cartilage damage, with a decrease in the number of chondrocytes and the content of proteoglycans in the cartilage matrix. In the metformin group, there was a significant improvement in the damage to the structure of the cartilage in the knee joints of the rats, and the cartilage surface tended to be smooth, with an increase in the number of chondrocytes and the content of proteoglycans in the cartilage matrix. Immunohistochemistry staining and western blot results showed that compared with the control and sham-operated groups, the expression of SOX9, type II collagen, and Beclin1 proteins in the cartilage tissue of rats in the model group was significantly decreased (P < 0.05). Conversely, the expression of ADAMTS5, P62, as well as p-PI3K, p-AKT, and p-mTOR proteins was significantly increased (P < 0.05). Furthermore, compared with the model group, the expression of SOX9, type II collagen, and Beclin1 proteins in the cartilage tissue of rats in the metformin group was significantly increased (P < 0.05), while the expression of ADAMTS5, P62, as well as p-PI3K, p-AKT, and p-mTOR proteins was significantly decreased (P < 0.05). To conclude, Metformin can improve the autophagy activity of chondrocytes and reduce the degradation of cartilage matrix in osteoarthritis rats by inhibiting the activation of PI3K/AKT/mTOR signaling pathway, thus exerting a protective effect on articular cartilage. [ABSTRACT FROM AUTHOR]

The mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT) is a biocide widely used as a preservative in various commercial products. This biocide has also been used as an active ingredient in humidifier disinfectants in South Korea, resulting in serious health effects among users. Recent evidence suggests that the underlying mechanism of CMIT/MIT-initiated toxicity might be associated with defects in mitochondrial functions. The aim of this study was to utilize the C2C12 skeletal muscle model to investigate the effects of CMIT/MIT on mitochondrial function and relevant molecular pathways associated with skeletal muscle dysfunction. Data demonstrated that exposure to CMIT/MIT during myogenic differentiation induced significant mitochondrial excess production of reactive oxygen species (ROS) and a decrease in intracellular ATP levels. Notably, CMIT/MIT significantly inhibited mitochondrial oxidative phosphorylation (Oxphos) and reduced mitochondrial mass at a lower concentration than the biocide amount, which diminished the viability of myotubes. CMIT/MIT induced activation of autophagy flux and decreased protein expression levels of myosin heavy chain (MHC). Taken together, CMIT/MIT exposure produced damage in C2C12 myotubes by impairing mitochondrial bioenergetics and activating autophagy. Our findings contribute to an increased understanding of the underlying mechanisms associated with CMIT/MIT-induced adverse skeletal muscle health effects. [ABSTRACT FROM AUTHOR]

Background: Despite the existence of promising outcomes from standard 2D culture systems, these data are not completely akin to in vivo tumor parenchyma. Therefore, the development and fabrication of various 3D culture systems can in part mimic intricate cell-to-cell interaction within the real tumor mass. Here, we aimed to evaluate the tumoricidal impacts of metformin (MTF) on colorectal cancer (CRC) tumoroids in an in vitro system via the modulation of autophagy. Methods: CRC tumoroids were developed using human umbilical vein endothelial cells (HUVECs), adenocarcinoma HT29 cells, and fibroblasts (HFFF2) in a ratio of 1: 2: 1 and 2.5% methylcellulose. Tumoroids were exposed to different concentrations of MTF, ranging from 20 to 1000 mM, for 72 h. The survival rate was detected using an LDH release assay. The expression and protein levels of autophagy-related factors were measured using PCR array and western blotting, respectively. Using H & E, and immunofluorescence staining (Ki-67), the integrity and proliferation rate of CRC tumoroids were examined. Results: The current protocol yielded typical compact tumoroids with a dark central region. Despite slight changes in released LDH contents, no statistically significant differences were achieved in terms of cell toxicity in MTF-exposed groups compared to the control tumoroids, indicating the insufficiency of MTF in the induction of tumor cell death (p > 0.05). Western blotting indicated that the LC3II/I ratio was reduced in tumoroids exposed to 120 mM MTF (p < 0.05). These data coincided with the reduction of intracellular p62 content in MTF 120 mM-treated tumoroids compared to MTF 40 mM and control groups (p < 0.05). PCR array analysis confirmed the up-regulation, and down-regulation of several genes related to various signaling transduction pathways associated with autophagy machinery and shared effectors between autophagy and apoptosis in 40 and 120 mM MTF groups compared to the non-treated control group (p < 0.05). These changes were more prominent in tumoroids incubated with 120 mM MTF. Histological examination confirmed the loosening integrity of tumoroids in MTF-treated groups, especially 120 mM MTF, with the increase in cell death via the induction of apoptosis (chromatin marginalization) and necrotic (pyknotic nuclei) changes. In the 120 mM MTF group, spindle-shaped cells with the remnants of a fibrillar matrix were detected. Data indicated the reduction of proliferating Ki-67+ cells within the tumoroids by increasing the MTF concentration from 40 to 120 mM. Conclusions: Different shared autophagy/apoptosis genes were modulated in CRC tumoroids after MTF treatment coinciding with both typical necrotic and apoptotic cells within the tumoroid structure. MTF can inhibit the integrity and proliferation of CRC tumoroids in dose-dependent manner. [ABSTRACT FROM AUTHOR]

A large body of evidence suggests that mesenchymal stromal cells (MSCs) are able to respond rapidly to the cytokine milieu following systemic infusion. This encounter has the potential to dictate their therapeutic efficacy (also referred to as licensing). MSCs are able to rapidly react to cellular damage by migrating to the inflamed tissue and ultimately modifying the inflammatory microenvironment. However, the limited use of MSCs in clinical practice can be attributed to a lack of understanding of the fate of MSCs in patients after administration and long term MSC-derived therapeutic activity. While the known physiological effectors of viable MSCs make a relative contribution, an innate property of MSCs as a therapeutic agent is their caspase-dependent cell death. These mechanisms may be involving the functional reprogramming of myeloid phagocytes via efferocytosis, the process by which apoptotic bodies (ABs) are identified for engulfment by both specialized and non-specialized phagocytic cells. Recent studies have provided evidence that the uptake of ABs with a distinct genetic component can induce changes in gene expression through the process of epigenetic remodeling. This phenomenon, known as 'trained immunity', has a significant impact on immunometabolism processes. It is hypothesized that the diversity of recipient cells within the inflammatory stroma adjacent to MSCs may potentially serve as a biomarker for predicting the clinical outcome of MSC treatment, while also contributing to the variable outcomes observed with MSC-based therapies. Therefore, the long-term reconstructive process of MSCs may potentially be mediated by MSC apoptosis and subsequent phagocyte-mediated efferocytosis. [ABSTRACT FROM AUTHOR]

DnaJ heat shock protein family member C5 beta (DNAJC5B), also known as cysteine-string protein beta, exhibits a prominent expression in testicular tissue and plays an important role in acrosomal exocytosis in vitro. Nevertheless, the precise role and underlying mechanism of DNAJC5B in spermatogenesis and male fertility remain poorly understood. The meta-analysis of RNA-sequencing datasets from porcine and murine testes reveals that Dnajc5b could be a pivotal factor in spermatogenesis. This study illustrates that male fertility declines with an increased ratio of abnormal spermatozoa in germ-cell knockout Dnajc5b mice. DNAJC5B has been identified as a mitochondrial protein with high expression in spermatids. The absence of DNAJC5B induces a cascade of mitochondrial damages, including oxidative stress, mitochondrial stress in the testes, and lower mitochondrial membrane potential of spermatozoa. In vivo and in vitro evidence demonstrates that DNAJC5B mitigates excessive cellular autophagy and mitophagy via DNAJ domain under environmental stress conditions, such as starvation or exposure to mitochondrial uncouplers FCCP and CCCP. This study highlights the important role of DNAJC5B in safeguarding male fertility by preserving mitochondrial function and regulating autophagy during spermiogenesis. [ABSTRACT FROM AUTHOR]

Hypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T-cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates the expression of MHC class I and its bound peptides (i.e., the immunopeptidome). Hypoxia decreases MHC-I expression in an oxygen-dependent manner, via activation of autophagy through the PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach, we find a significant reduction of presented antigens under hypoxia. Inhibition of autophagy under hypoxia enhances antigen presentation. In experimental tumors, reducing mitochondrial metabolism through a respiratory complex-I inhibitor increases tumor oxygenation, as well as MHC-I levels and the immunopeptidome. These data explain the molecular basis of tumor immune evasion in hypoxic conditions, and have implications for future therapeutic interventions targeting hypoxia-induced alterations in antigen presentation. Synopsis: Hypoxia contributes to cancer resistance to both standard therapies and immunotherapy. This work demonstrates that tumor hypoxia promotes immune evasion by autophagy-mediated downregulation of MHC class I expression leading to reduced antigen presentation. Hypoxia decreases MHC-I expression and the abundance of the immunopeptidome, leading to immune evasion. Activation of autophagy through the PERK arm of the unfolded protein response promotes lysosomal MHC-I degradation. Inhibiting autophagy under hypoxic conditions rescues MHC-I expression and restores immunopeptidome abundance unveiling new antigens. Preventing MHC-I degradation under hypoxia enhances recognition of hypoxic cells by CD8+ T cells. Activation of autophagy and lysosomal MHC-I degradation under low oxygen downregulates the immunopeptidome, explaining therapy resistance of hypoxic tumors. [ABSTRACT FROM AUTHOR]

Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe complication of sepsis and the leading cause of mortality. Although the role of alveolar macrophages (AMs) in stabilizing pulmonary homeostasis is well established, the effects of circulating extracellular vesicles (EVs) on AMs remain largely unknown. In this study, an investigation was conducted to map the miRNA and protein expression profiles of EVs derived from septic plasma. Notably, EV-based panels (miR-122-5p, miR-125b-5p, miR-223-3p, OLFM4, and LCN2) have been found to be associated with the severity or prognosis of sepsis, with promising AUC values. Moreover, the levels of LCN2, miR-122-5p, and miR-223-3p were identified as independent predictors of septic ARDS. The in vitro coculture results revealed that the effects of LPS-EVs from the plasma of sepsis-induced acute lung injury (ALI), which carry pro-inflammatory EVs, were partly mediated by miR-223-3p, as evidenced by the promotion of inflammation, autophagy and ferroptosis in AMs. Mechanistically, the upregulation of miR-223-3p in LPS-EVs triggers autophagy and ferroptosis in AMs by activating Hippo signaling via the targeting of MEF2C. In vivo, the inhibition of miR-223-3p effectively mitigated LPS-EV-induced inflammation and AM death in the lungs, as well as histological lesions. Overall, miR-223-3p in LPS-EVs contributes to sepsis-induced ALI by priming AMs for autophagy and ferroptosis through the MEF2C/Hippo signaling pathway. These findings suggest a novel mechanism of plasma-AM interaction in sepsis-induced ALI, offering a plausible strategy for assessing septic progression and treating lung injury. [ABSTRACT FROM AUTHOR]

The relapse of tongue cancer (TC) after chemotherapy is caused by minimal residual disease (MRD), which is a few remaining cancer cells after chemotherapy. To understand the mechanism of MRD in TC, we created a library of TC organoids (TCOs) from 28 untreated TC patients at diverse ages and cancer stages. These TCOs reproduced the primary TC tissues both in vitro and in a xenograft model, and several TCO lines survived after cisplatin treatment (chemo-resistant TCOs). Of note, the chemo-resistant TCOs showed "heritable" embryonic diapause-like features before treatment and activation of the autophagy and cholesterol biosynthetic pathways. Importantly, inhibiting these pathways with specific inhibitors converted the chemo-resistant TCOs into chemo-sensitive TCOs. Conversely, autophagy activation with mTOR inhibitors conferred chemo-resistance on the chemo-sensitive TCOs. This unique model provides insights into the mechanism of MRD formation in TCs, leading to effective therapeutic approaches to reduce the recurrence of TC. [Display omitted] • A library of tongue cancer organoids (TCOs) is created • Several TCOs survive after cisplatin treatment (chemo-resistance) • Inhibiting autophagy and cholesterol synthesis turns chemo-resistance into susceptibility • Activating autophagy confers chemo-resistance on chemo-sensitive TCOs Sase and Sato et al. demonstrate that chemo-resistant tongue cancer organoids (TCOs), which survive after cisplatin treatment, show activation of autophagy and cholesterol biosynthesis. Declining activity of these pathways converts chemo-resistant TCOs into chemo-sensitive TCOs by eradicating minimal residual disease (MRD). [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. Methods: We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. Results: Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. Conclusion: Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function. [ABSTRACT FROM AUTHOR]

Secretory autophagy is a classical form of unconventional secretion that integrates autophagy with the secretory process, relying on highly conserved autophagy-related molecules and playing a critical role in tumor progression and treatment resistance. Traditional autophagy is responsible for degrading intracellular substances by fusing autophagosomes with lysosomes. However, secretory autophagy uses autophagy signaling to mediate the secretion of specific substances and regulate the tumor microenvironment (TME). Cytoplasmic substances are preferentially secreted rather than directed toward lysosomal degradation, involving various selective mechanisms. Moreover, substances released by secretory autophagy convey biological signals to the TME, inducing immune dysregulation and contributing to drug resistance. Therefore, elucidating the mechanisms underlying secretory autophagy is essential for improving clinical treatments. This review systematically summarizes current knowledge of secretory autophagy, from initiation to secretion, considering inter-tumor heterogeneity, explores its role across different tumor types. Furthermore, it proposes future research directions and highlights unresolved clinical challenges. [ABSTRACT FROM AUTHOR]

Background: In perinatal dairy cows, ketosis is a prevalent metabolic disorder that lowers milk output and performance. Mitochondrial dysfunction and chronic inflammation in mammary tissue are linked to elevated blood ketone levels, particularly β-hydroxybutyrate (BHB). Recent research has linked cytosolic mitochondrial DNA (mtDNA) with chronic aseptic inflammation by activating the cGAS-STING pathway during metabolic disorders, while autophagy activation effectively reverses this process. However, whether it is involved in mammary gland damage during ketosis is poorly understood. Therefore, this study aimed to explore the underlying mechanisms of mtDNA-induced inflammation under BHB stress and evaluate the potential therapeutic strategy of autophagy activation in mitigating this damage. Results: Our study found an increased cytoplasmic mtDNA abundance in mammary gland tissues of dairy cows with ketosis and bovine mammary epithelial cell line (MAC-T) subjected to BHB stress. Further investigations revealed the activation of the cGAS-STING pathway and inflammatory response, indicated by elevated levels of cGAS and STING, along with increased phosphorylation levels of TBK1, P65, and IκB, and higher transcript levels of pro-inflammatory factors (IL-1B, IL-6, and TNF-α) in both in vivo and in vitro experiments. Notably, STING inhibition via si-STING transfection reversed BHB-induced inflammation. Additionally, autophagy activation appeared to protect against BHB stress by facilitating the removal of cytoplasmic mtDNA and preventing cGAS-STING pathway-mediated inflammation. Conclusions: The findings illustrate that elevated BHB levels lead to the release of cytoplasmic mtDNA, which in turn activates the cGAS-STING pathway and triggers an inflammatory response in the mammary glands during hyperketonemia. Conversely, autophagy activation has been shown to alleviate this process by promoting cytoplasmic mtDNA degradation. [ABSTRACT FROM AUTHOR]

Carfilzomib (CFZ), a second-generation proteasome inhibitor, is a key treatment for multiple myeloma (MM), but its use is associated with significant cardiovascular adverse events (CVAEs), including heart failure and hypertension. Endothelial dysfunction is believed to contribute to these CVAEs. Building on our previous findings that CFZ induces endothelial toxicity and that canagliflozin protects against CFZ-induced endothelial apoptosis, this study aimed to evaluate CFZ-induced endoplasmic reticulum (ER) stress and autophagy in endothelial and MM cells, as well as the impact of canagliflozin on these processes and its impact on the anticancer effects of CFZ in MM cells. Endothelial cells (HUVECs and EA.hy926) and multiple myeloma cells (RPMI8226) were treated with 0.5 µM CFZ, either alone or in combination with canagliflozin (5–20 µM), to assess the effects on ER stress and autophagy in both cell types. CFZ induced ER stress in endothelial and MM cells. In endothelial cells, canagliflozin mitigated CFZ-induced markers of ER stress, while unexpectedly upregulating CFZ-induced CHOP. Whereas, in MM cells, canagliflozin did not alter CFZ-induced ER stress, but instead further upregulated CFZ-induced ATF-4. In addition, CFZ induced autophagy in endothelial cells while inhibiting it in MM cells. Canagliflozin abrogated CFZ-induced autophagy in endothelial cells. In striking contrast to its effects in endothelial cells, canagliflozin enhanced the cytotoxic effects of CFZ in MM cells. Intriguingly, in an innovative co-culture system, canagliflozin enhanced CFZ-induced apoptosis in MM cells while protecting endothelial cells. These findings underscore the dual role of canagliflozin in reducing CFZ-induced endothelial toxicity, while enhancing its cytotoxic effect in MM. [ABSTRACT FROM AUTHOR]

Cancer statistics highlight diverse susceptibilities, necessitating tailored global research and interventions. Conventional cancer treatments like chemotherapy and radiotherapy lack specificity, causing severe side effects. Novel targeted therapies exert cytostatic effects by modulating cell cycle regulators, disrupting microtubules, or inducing apoptosis. Tephrosin, a rotenoid isoflavonoid found in the family Fabaceae, exhibits promising anticancer properties against various cancer types. This review aimed to comprehensively summarize tephrosin's anticancer activity, explore its mode of action and safety profile, and address gaps in the literature regarding its pharmacokinetics and pharmacodynamics. Tephrosin exerted anticancer activities against skin, cervical, breast, ovarian, pancreatic, colorectal, lung, and leukemia. Tephrosin acts through various pathways including inhibiting NF-κB signaling, inhibiting autophagy, inducing different types of apoptosis, inhibiting elongation factor-2 kinase, reducing the phosphorylation of growth factors, blocking downstream signaling pathways such as PI3K/Akt and Ras/MAPK, p38/MAPK, and STAT3, arresting the cell cycle at the G2/M phase, inducing DNA damage and oxidative stress in cancer cells, and suppression of enzymes involved in extracellular matrix degradation and metastasis. This review revealed the lack of antioxidant, pharmacodynamics, and pharmacokinetics studies on this promising isoflavonoid. Tephrosin's multifaceted mechanisms make it a compelling candidate for further investigation in cancer therapy. [Display omitted] • Tephrosin is a rotenoid isoflavonoid from the Fabaceae family. • Tephrosin shows promising anticancer activities against various types. • Tephrosin affects apoptosis, autophagy, metastasis, NF-κB, and cell cycle. • There are gaps in antioxidant, pharmacokinetics, and pharmacodynamics studies. • Tephrosin is compelling candidate for further cancer therapy research. [ABSTRACT FROM AUTHOR]

Autophagy is a crucial immune defense mechanism that controls the survival and pathogenesis of M. tb by maintaining cell physiology during stress and pathogen attack. The E3-Ub ligases (PRKN, SMURF1, and NEDD4) and autophagy receptors (SQSTM1, TAX1BP1, CALCOCO2, OPTN, and NBR1) play key roles in this process. Galectins (LGALSs), which bind to sugars and are involved in identifying damaged cell membranes caused by intracellular pathogens such as M. tb, are essential. These include LGALS3, LGALS8, and LGALS9, which respond to endomembrane damage and regulate endomembrane damage caused by toxic chemicals, protein aggregates, and intracellular pathogens, including M. tb. They also activate selective autophagy and de novo endolysosome biogenesis. LGALS3, LGALS9, and LGALS8 interact with various components to activate autophagy and repair damage, while CGAS-STING1 plays a critical role in providing immunity against M. tb by activating selective autophagy and producing type I IFNs with antimycobacterial functions. STING1 activates cGAMP-dependent autophagy which provides immunity against various pathogens. Additionally, cytoplasmic surveillance pathways activated by ds-DNA, such as inflammasomes mediated by NLRP3 and AIM2 complexes, control M. tb. Modulation of E3-Ub ligases with small regulatory molecules of LGALSs and TRIM proteins could be a novel host-based therapeutic approach for controlling TB. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is a disabling tumor with poor response to chemotherapy. Here, we sought to explore a new chemotherapeutic approach based on a combined induction of cytotoxic ROS and targeting of autophagy and aerobic glycolysis as central contributors to OSCC carcinogenesis and chemoresistance. To this end, tongue OSCC was generated in BALB/c mice using 4NQO. Treatment of mouse-derived OSSC explants with NaAsO 2 resulted in a strong inhibition of MTT activity and Bcl-2 and Ki-67 expression. The addition of chloroquine (CQ) and dichloroacetate (DCA) to arsenite, resulted in additive inhibitory effects on Bcl-2 and Ki-67 expression. Whereas NaAsO 2 alone inhibited aerobic glycolysis (LDHA), it also alleviated autophagy (LC3B) and ROS levels (MDA). DCA improved NaAsO 2 -dependent inhibition of aerobic glycolysis. CQ addition to arsenite, suppressed autophagy without affecting the Warburg effect. NaAsO 2 combination with CQ and DCA improved the oxidative status balance by boosting anti-oxidative CAT and SOD and controlling pro-oxidant MDA activity. The administration of the combo to 4NQO-mice resulted in a significant survival advantage over the control group (90 % vs. 35 % survival at week 32, p < 0.02; HR (log-rank) = 0.166, CI 95 % 0.03–0.73). This effect was accompanied by a significant increase in mice's mean body weight (p < 0.009). Contrarily to the control, administration of the combo resulted in the absence of progression towards severe dysplasia and OSCC and an overrepresentation of low/mild dysplasia events (100 %). Interestingly, signs of hepatocellular and renal toxicity following combo administration were limited in comparison to control. Taken together, these results suggest that NaAsO 2 combined with CQ and DCA may constitute an interesting alternative to eliminating chemo-resistant OSSC tumors by inhibiting aerobic glycolysis and autophagy and controlling ROS generation. In vivo, the drugs may provide a survival advantage by inhibiting tumor development. [Display omitted] • Arsenite combined with chloroquine and dichloroacetate exhibit an additive inhibitory effect on Bcl-2 and Ki-67 expression in OSCC tissues. • The triple drug combination inhibits aerobic glycolysis and autophagy in OSCC tissues. • The triple drug combination inhibits ROS production in OSCC explants. • The combo inhibits OSCC development and improves survival of 4NQO BALB/c-treated mice. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease with a serious impact on patients' quality of life. However, single-targeted therapies are not currently effective, and there is a need to find pluripotent drugs with multiple properties. This study aimed to characterize the metabolism of neurotransmitters using a targeted metabolomics approach and to identify the major metabolic pathways mainly affected by 6‴-feruloylspinosin (6-FS). The mechanism of action of 6-FS in the treatment of AD was elucidated based on experimental validation. The metabolomics analysis revealed changes in 13 metabolic profiles by the LC-MS/MS, with significant changes in five amino acid-related neurotransmitters identified primarily. Based on the correlations, we found an effect of mTOR inhibition on the above neurotransmitter metabolism. Furthermore, pretreatment with 6-FS activated the AMPK/mTOR signaling pathway, promoting cellular autophagy, regulating oxidative stress homeostasis and inhibiting mitochondrial dysfunction. In short, these comprehensive analysis methods help clarify the preventive mechanism of 6-FS and potential targets in AD and provide the necessary support for developing natural products to prevent AD. [Display omitted] • Analysis of potential-relevant neurotransmitter modulated by 6-FS using LC-MS/MS. • 6-FS enhances cellular viability and reduces cellular oxidative stress and apoptosis in injured cells. • Activate the AMPK/mTOR signaling pathway to regulate autophagy and improve mitochondrial function. • 6-FS could be a promising therapeutic molecule for AD. [ABSTRACT FROM AUTHOR]

Objective(s): Trans-sodium crocetinate (TSC) is one of the crocetin derivations that is more soluble and stable than crocetin and its cis form. It easily crosses the blood-brain barrier. TSC has neuroprotective effects. Bisphenol A (BPA) is an endocrine-mimicking compound that induces Parkinson-like disease by impacting the dopaminergic system. In this research, the effects of TSCs on BPA-induced Parkinsonlike symptoms via behavioral and molecular assays have been investigated. Materials and Methods: Male Wistar rats received BPA (75 mg/kg, gavage), TSC (10, 20, and 40 mg/kg), and levodopa (L-dopa) (10 mg/kg) via intraperitoneal injection (IP) for 28 days. Parkinsonian-like motor features were evaluated using bar test, rotarod, and open field experiments. Malondialdehyde (MDA) and glutathione (GSH) levels were also measured as the most important indicators of oxidative stress. Western blotting was performed for the molecular assays of alpha-synuclein (a-syn), Bcl-2, Bax, caspase-3, Beclin, and LC3 I/II proteins. Results: Our analyses indicated that treatment with TSC at high dose reduces MDA levels and protects GSH reserves. TSC can also increase anti-apoptotic Bcl-2 and decrease pro-apoptotic Bax and caspase-3 proteins. While it does not affect autophagy markers, TSC decreased a-syn protein expression, reduced the catalepsy time, and improved the time spent staying on the rotating bar and the locomotor activity. Conclusion: Overall, TSC likely ameliorates BPA-mediated Parkinson' s-like symptoms by suppressing oxidative stress inhibition. This leads to reduced a-syn expression, which ultimately results in apoptosis inductions. Therefore, TSC can serve as a promising exploratory target for future research aimed at controlling Parkinson's disease. [ABSTRACT FROM AUTHOR]

Perioperative neurocognitive disorders (PND) is a common complication affecting the central nervous system, commonly induced by anesthesia and surgical procedures. PND has garnered considerable attention in recent years, not only due to its high morbidity but also its negative impact on patient prognosis, such as increased rates of dementia and mortality. Sevoflurane, a common volatile anesthetic in clinical practice, is increasingly linked to being a potential risk factor for PND with prolonged inhalation, yet effective prevention and treatment methods remain elusive. Autophagy, a crucial regulatory process for maintaining organism function, has been shown to play a key role in sevoflurane-induced cognitive dysfunction. In recent years, intermittent fasting (IF), a unique dietary pattern, has gained significant recognition. IF has been shown in multiple studies to offer neuroprotective advantages in different central nervous system conditions. disorders. This study aims to explore the potential neuroprotective effects of intermittent fasting preconditioning through the autophagic pathway in sevoflurane-induced cognitive impairment in rats and its underlying mechanisms. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a severely debilitating neurological condition that often results in significant functional impairment and is associated with poor long-term prognosis. Edema, oxidative stress, inflammatory responses, and cell death are the primary factors contributing to secondary injury following spinal cord damage. Ubiquitination is a crucial intracellular mechanism for protein regulation that has garnered significant attention as a therapeutic target in a variety of diseases. Numerous studies have shown that ubiquitination plays a key role in modulating processes such as inflammatory responses, apoptosis, and nerve regeneration following SCI, thereby influencing injury repair. Accordingly, targeting ubiquitination has the potential for mitigating harmful inflammatory responses, inhibiting dysregulated programmed cell death, and protecting the integrity of the blood–spinal cord barrier, thereby providing a novel therapeutic strategy for SCI. In this review, we discuss the role of ubiquitination and its potential as a therapeutic target in SCI, aiming to offer a foundation for developing ubiquitination-targeted therapies for this condition. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a severely debilitating neurological condition that often results in significant functional impairment and is associated with poor long-term prognosis. Edema, oxidative stress, inflammatory responses, and cell death are the primary factors contributing to secondary injury following spinal cord damage. Ubiquitination is a crucial intracellular mechanism for protein regulation that has garnered significant attention as a therapeutic target in a variety of diseases. Numerous studies have shown that ubiquitination plays a key role in modulating processes such as inflammatory responses, apoptosis, and nerve regeneration following SCI, thereby influencing injury repair. Accordingly, targeting ubiquitination has the potential for mitigating harmful inflammatory responses, inhibiting dysregulated programmed cell death, and protecting the integrity of the blood–spinal cord barrier, thereby providing a novel therapeutic strategy for SCI. In this review, we discuss the role of ubiquitination and its potential as a therapeutic target in SCI, aiming to offer a foundation for developing ubiquitination-targeted therapies for this condition. [ABSTRACT FROM AUTHOR]

A sharp increase in intramedullary pressure after spinal cord injury (SCI) can aggravate secondary injury and lead to severe neurological deficits. Unfortunately, effective treatment options are currently lacking. The mechanosensitive ion channel Piezo1 plays an important role in the pathological process of SCI by transducing mechanical stress. The Piezo1 inhibitor GsMTx4 has been shown to have neuroprotective effects and may hold therapeutic potential for SCI. Given that single drug treatment strategy has limited effect on functional recovery after SCI, we explored the efficacy of combining GsMTx4 with exercise training in treating SCI in rats and investigated the underlying mechanisms. We used the T10 SCI rat model, administered GsMTx4 immediately after injury, and performed 4 weeks of body weight supported treadmill training starting (BWSTT) 2 weeks post injury. Subsequently, HE and LFB staining were used to observe the morphology of spinal cord tissue, WB was used to detect autophagy and apoptosis-related proteins, biochemical detection of calcium ion concentration and CTSD activity, IHC detection of LAMP1 expression, immunofluorescence labeling of NeuN and ChAT-positive motor neurons, as well as MBP and GFAP, and BBB scores were used to evaluate rat motor function. We found that the combined treatment of GsMTx4 drug and exercise training was more effective than single treatment alone. The combined treatment reduced calcium ion concentration, improved lysosomal function, enhanced autophagic flux, reduced cell apoptosis, and significantly improved the motor function of rats. This combined treatment regimen may pave the way for developing more comprehensive treatment strategies for SCI in the future. Mechanism diagram. Piezo1 inhibitors combined with exercise exerts neuroprotective effects by regulating neuronal autophagy. Excessive mechanical stress following spinal cord injury (SCI) over activates the mechanosensitive Piezo1 channel in spinal neurons, leading to increased Ca2+ release and subsequent lysosomal dysfunction. This dysfunction decreases autophagic flux, potentially resulting in neuronal apoptosis, exacerbated glial scar formation, and demyelination. The application of Piezo1 inhibitors improves lysosomal function and enhances autophagic flux, thereby reducing cell apoptosis. Additionally, exercise training further amplifies the neuroprotective effects of Piezo1 inhibitors, contributing to overall neuronal recovery. [ABSTRACT FROM AUTHOR]

Transplantation of bone marrow mesenchymal stem cells (BMSCs) represents an encouraging strategy for the repair of spinal cord injury (SCI), however, its effectiveness on treating SCI remains controversial. Bilobalide isolated from Ginkgo biloba leaves shows significant neuroprotective effects. We examined the role and underlying mechanism of bilobalide in the efficacy of BMSC transplantation on SCI. Primary BMSCs were isolated from neonatal rats, and cell viability was assessed by MTT assay. Neuronal markers (MAP-2, NeuN, NSE and Tuj1), autophagy markers (LC3 and Beclin1), and Fragile X mental retardation protein (FMRP)/With-no-lysine kinase-1 (WNK1) signaling were measured using RT-qPCR and western blotting. The relationship of FMRP and WNK1 was estimated by RNA immunoprecipitation, while WNK1 mRNA stability was assessed with actinomycin D assay. In a SCI rat model, tissue injury was examined using HE and Nissl staining. Bilobalide treatment facilitated neural differentiation of BMSCs, as well as enhanced autophagy and inhibited WNK1 signaling. The promotive effect of bilobalide on BMSC differentiation was antagonized when overexpressing WNK1 or inhibiting autophagy. Bilobalide upregulated FMRP to promote WNK1 mRNA decay, thus reducing WNK1 expression. FMRP knockdown reversed the promoted functions of bilobalide on autophagy and neuronal differentiation in BMSCs. Additionally, compared to either monotherapy, simultaneous treatments with bilobalide and BMSCs further facilitated autophagy and neuronal differentiation, thereby enhancing the repair of SCI in rats. Bilobalide enhances autophagy activity to promote BMSC neuronal differentiation via FMRP/WNK1 axis, thus improving functional recovery following SCI, which indicates a promising therapeutic approach for SCI. [ABSTRACT FROM AUTHOR]

Cerebral ischemia–reperfusion (I/R) injury is a complex pathophysiological process involving multiple mechanisms, including apoptosis and autophagy, which can lead to significant neuronal damage. PIEZO1, a stretch-activated ion channel, has recently emerged as a potential regulator of cellular responses to ischemic conditions. However, its role in neuronal cell survival and death during ischemic events is not well elucidated. This study aimed to ascertain the regulatory function of PIEZO1 in neuronal cell apoptosis and autophagy in an in vitro model of hypoxia-reoxygenation and an in vivo model of brain I/R injury. HT22 hippocampal neuronal cells were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) to simulate ischemic conditions, with subsequent reoxygenation. In vitro, PIEZO1 expression was silenced using small interfering RNA (si-RNA) transfection. The effects on cell viability, apoptosis, and autophagy were assessed using CCK-8 assays, PI-Annexin/V staining combined with flow cytometry, and Western blot analysis. Additionally, intracellular Ca2+ levels in HT22 cells were measured using a Ca2+ probe. The involvement of the AMPK-mTOR pathway was investigated using rapamycin. For in vivo validation, middle cerebral artery occlusion/reperfusion (MCAO/R) in rats was employed. To determine the neuroprotective role of PIEZO1 silencing, sh-PIEZO1 adeno-associated virus was stereotaxically injected into the cerebral ventricle, and neurological and histological outcomes were assessed using neurological scoring, TTC staining, H&E staining, Nissl staining, and immunofluorescence. In HT22 cells, OGD/R injury notably upregulated PIEZO1 expression and intracellular Ca2+ levels. Silencing PIEZO1 significantly diminished OGD/R-induced Ca2+ influx, apoptosis, and autophagy, as indicated by lower levels of pro-apoptotic and autophagy-related proteins and improved cell viability. Additionally, PIEZO1 modulated the AMPK-mTOR signaling pathway, an effect that was counteracted by rapamycin treatment, implying its regulatory role. In vivo, PIEZO1 silencing ameliorated brain I/R injury in MCAO/R rats, demonstrated by improved neurological function scores and reduced neuronal apoptosis and autophagy. However, these neuroprotective effects were reversed through rapamycin treatment. Our findings indicate that PIEZO1 is upregulated following ischemic injury and facilitates Ca2+ influx, apoptosis, and autophagy via the AMPK-mTOR pathway. Silencing PIEZO1 confers neuroprotection against I/R injury both in vitro and in vivo, highlighting its potential as a therapeutic target for stroke management. [ABSTRACT FROM AUTHOR]

Purpose: Autophagy is a degradation process whose activation underlies beneficial effects of caloric restriction. Isothiocyanates (ITCs) induce autophagy in cancer cells, however, their impact on primary cells remains insufficiently explored, particularly in non-epithelial cells. The aim of this study was to investigate whether ITCs induce autophagy in primary (non-immortalized) mesenchymal cells and if so, to determine the molecular mechanism underlying its activation and consequences on cell functioning. Methods: Primary human dermal fibroblasts (HDFa) and prostate cancer cells (PC3) as well as two ITCs, sulforaphane and phenethyl isothiocyanate, were applied. Cell viability was measured by the MTT test, protein synthesis - by 3H-leucine incorporation, and protein level - by immunoblotting. A number of mutant huntingtin (mHtt) aggregates was assessed by fluorescence microscopy. Results: Both ITCs efficiently induced autophagy in fibroblasts which coincided with suppression of mTORC1 – a negative autophagy regulator - and protein synthesis arrest. A dephosphorylation of mTORC1 substrate, S6K1, and ribosomal S6 protein was preceded by activation of AMPK, an inhibitor of mTORC1 and autophagy activator. A similar response was observed in phenethyl isothiocyanate-treated prostate cancer cells. We also showed that ITCs-induced autophagy and/or translation block do not affect cells viability and can protect cells against an accumulation of mHtt aggregates – a main cause of Huntington’s disease. Conclusion: Our study showed that ITCs induce autophagy and inhibit protein synthesis in both primary mesenchymal and cancer cells via modulation of the AMPK-mTORC1-S6K1 pathway. Moreover, it suggests that ITCs might have a potential in developing therapeutics for Huntington’s disease. [ABSTRACT FROM AUTHOR]

The abiotic/abiotic hybrid S@UIL system enhances ICD-associated antitumor effects by inducing excessive autophagy and mild-temperature photothermal therapy. [Display omitted] The tumor microenvironment, characterized by hypoxia, supports the efficacy of anaerobic bacteria like attenuated S. typhimurium in cancer therapies. These bacteria target and penetrate deep tumor regions, significantly reducing tumor size but often lead to tumor regrowth due to limited long-term efficacy. To enhance the therapeutic impact, a novel biohybrid system, S@UIL, has been developed by coating S. typhimurium with a zirconium-based nanoscale metal–organic framework (UiO-66-NH 2) loaded with indocyanine green (ICG) and luteolin (LUT). This system maintains the bacteria's tumor-targeting ability while increasing the penetration and therapeutic effectiveness through excessive autophagy and mild hyperthermia. In a subcutaneous colon cancer model, the integration of LUT and ICG promotes autophagic cell death and photothermal sensitization, leading to the release of damage-associated molecular patterns (DAMPs). These DAMPs activate immune responses through dendritic cells and T -cells, enhancing immunogenic cell death (ICD) and potentially reducing immune evasion by tumors. This single-administration approach also integrates multimodal imaging capabilities, providing a promising strategy for improved tumor ICD induction and cancer progression inhibition. [ABSTRACT FROM AUTHOR]

Beta1‐adrenergic receptor autoantibodies (β1‐AAbs) promote atrial remodelling and ultimately lead to the development of atrial fibrillation (AF). Oroxin B is a natural flavonoid glycoside with a variety of biological activities, including anti‐inflammatory and autophagy‐promoting effects, and has therapeutic benefits for a variety of diseases. The aim of this study was to investigate the potential therapeutic role of Oroxin B in the development of β1‐AAb‐induced atrial fibrillation and to elucidate the underlying mechanisms involved. We established a rat model of β1‐AAb‐induced atrial fibrillation via active immunisation. The first stage was divided into three groups: the control group, the β1‐AAb group and the β1‐AAb + bisoprolol group. The second stage was divided into three groups: the control group, the β1‐AAb group and the β1‐AAb + Oroxin B group. Serum levels of β1‐AAbs, atrial tissue levels of cyclic monophosphate (cAMP), atrial electrophysiological parameters, cardiac structure and function, mitochondrial structure, autophagy levels, cardiomyocyte apoptosis and myocardial fibrosis were examined. The results showed that bisoprolol, a β1‐blocker, improved β1‐AAb‐induced atrial electrical remodelling, reduced atrial collagen deposition, ameliorated the increase in LAD and regulated the balance of autophagy and apoptosis in atrial myocytes through the PTEN/AKT/mTOR signalling pathway. Oroxin B, a PTEN agonist, can improve the impairment of autophagy homeostasis and apoptosis in atrial tissue by activating the PTEN/AKT/mTOR signalling pathway, thereby improving atrial structure and electrical remodelling. Moreover, Oroxin B may play a therapeutic role in β1AAb‐induced atrial fibrillation. In conclusion, our results demonstrate the potential therapeutic role of Oroxin B in β1AAb‐induced atrial fibrillation and the underlying mechanisms, suggesting that Oroxin B may be an effective antiarrhythmic medication. [ABSTRACT FROM AUTHOR]

The Pichia pastoris expression system is a favorable platform for production of pharmaceutical proteins. Treatment of strains with N-acetyl-L-cysteine (NAC) has been shown to enhance the yield of recombinant proteins, thereby contributing to a reduction in production costs. However, the specific mechanism of action of NAC remains unclear. Previous research has indicated that glutathione (GSH) and autophagy are involved in the increased production of human serum albumin and porcine follicle-stimulating hormone β (HSA-pFSHβ) by NAC. This study investigated the potential interaction between GSH and autophagy in the production of HSA-pFSHβ. The findings indicated that sulfhydryl-free antioxidants such as melatonin, vitamin C, or vitamin E did not exhibit similar effects to NAC in enhancing HSA-pFSHβ yield. Moreover, NAC was found to enhance HSA-pFSHβ production by modulating GSH metabolism to reduce GSH consumption, increase total GSH levels, as well as glutathione peroxidase (GSH-Px) and glutathione reductase (GR) activities. Additionally, inhibition of autophagy through disruption of autophagy scaffolding proteins Atg1 or Atg11 led to an increase in recombinant HSA-pFSHβ production. Furthermore, NAC significantly decreased the phosphorylation of Slt2, and the absence of the SLT2 gene influenced the effect of NAC on HSA-pFSHβ secretion by modulating mitophagy and GSH metabolism. In conclusion, these results suggest a complex interplay between GSH metabolism and autophagy in the regulation of NAC-induced HSA-pFSHβ secretion. • N-acetylcysteine supplementation reduce glutathione consumption to improve HSA-pFSHβ production. • Autophagy and glutathione interact in N-acetylcysteine-promoted HSA-pFSHβ secretion. • MAPK signaling pathway play an important role in N-acetylcysteine-promoted HSA-pFSHβ secretion. [ABSTRACT FROM AUTHOR]

Background: Neuregulin (NRG) family is involved in energy metabolism, among which NRG1 is a neuregulin proved to play a protective role in MAFLD cells. But the presice echanism has not been fully illustrated. This study aimed to investigate the role of NRG1 via the ERK/SIRT1 signaling in the pathogenesis of MAFLD. Methods: C57BL/6 mice were fed with high-fat diet for 8 weeks, and then injected with NRG1 (0.3 mg/kg/d) and PD98059 (0.3 mg/kg/d) via tail vein for 5 weeks. HepG2 cells induced by oleic acid and palmitic acid were treated with 20ng/mL NRG1 and 10µmol/L PD98059. The changes of histopathological, biochemical indexes, inflammatory factors, lipid metabolism, apoptosis and autophagy parameters were measured. Results: The expressions of NRG1 in MAFLD cell and animal models were significantly lower than that in the control group. After the intervention of ERK inhibitor PD98059, the expression of NRG1 decreased significantly in vivo, but no significant change was observed in vitro. Moreover, NRG1 ameliorated hepatic steatosis, enhanced cell viability, reduced cell apoptosis, and attenuated liver injury both in vitro and in vivo. After NRG1 intervention, the expressions of ERBB2, ERBB3, p-ERK1/2, SIRT1 and p-FOXO1 as well as the LC3II/I ratio in MAFLD cells and liver tissues of MAFLD mice were significantly increased, while the expression of SREBP1c was decreased. The aforementioned therapeutic effect of NRG1 was lost after the intervention of PD98059. Conclusion: NRG1 might play a protective role in the pathogenesis of MAFLD by activating the downstream ERK1/2 through ErbB2-ErbB3, which promotes the expression of SIRT1 and autophagy markers. This study might indicate a new therapeutic strategy for MAFLD. [ABSTRACT FROM AUTHOR]

Background: Myelin-laden foamy macrophages accumulate extensively in the lesion epicenter, exhibiting characteristics of autophagolysosomal dysfunction, which leads to prolonged inflammatory responses after spinal cord injury (SCI). Trehalose, known for its neuroprotective properties as an autophagy inducer, has yet to be fully explored for its potential to mitigate foamy macrophage formation and exert therapeutic effects in the context of SCI. Results: We observed that trehalose significantly enhances macrophage phagocytosis and clearance of myelin in a dose-dependent manner in vitro. In vivo, trehalose administration markedly reduced myelin debris accumulation, inhibited foamy macrophage formation, suppressed inflammatory responses, decreased fibrotic scarring, and promoted axonal growth and motor function recovery after SCI. These beneficial effects of trehalose may be related to the overexpression of transcription factor EB (TFEB), a key regulator of the autophagy-lysosomal system, which can rescue autophagic dysfunction in foamy macrophages and inhibit inflammatory responses. Additionally, the effects of trehalose on macrophages were abolished by chloroquine, an autophagy inhibitor, suggesting trehalose's potential as a therapeutic candidate for enhancing myelin debris clearance post-SCI. Conclusions: Our findings underscore the pivotal role of trehalose in modulating myelin debris clearance within macrophages, providing new perspectives for the treatment of spinal cord injury. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion injury (MIRI) is an important complication in the treatment of heart failure, and its treatment has not made satisfactory progress. Nitroxyl (HNO) showed protective effects on the heart failure, however, the effect and underlying mechanism of HNO on MIRI remain largely unclear. Methods: MIRI model in this study was established to induce H9C2 cell injury through hypoxia/reoxygenation (H/R) in vitro. The cell viability was assessed by cell counting kit-8 assay. The effect of HNO on the apoptosis was detected by flow cytometry. DCFH-DA fluorescent probe method was applied to detect the level of intracellular reactive oxygen species (ROS). The morphology of mitochondria and autophagosomes were observed by transmission electron microscopy. Apoptosis, autophagy and PI3K/Akt/mTOR pathway-related proteins were detected by western blot. Results: The viability of H9C2 cells was significantly increased in the HNO group. HNO inhibited apoptosis and regulated expressions of key apoptotic protein, including Bax and Bcl-2. HNO reduced ROS levels and alleviated H/R-induced mitochondrial damage. HNO also inhibited autophagy and regulated expressions of key autophagy-related molecules, including LC3II, p62 and Beclin1. Further experiments demonstrated that the effects of HNO were mediated through upregulation of PI3K/Akt/mTOR pathway. Rapamycin reversed the inhibition of HNO on H/R-induced autophagy in H9C2 cells, which abrogated the protective effect of HNO. Conclusion: This study provided the first evidence that HNO protected H/R-induced cardiomyocytes through inhibiting autophagy via the activation PI3K/Akt/mTOR pathway. [ABSTRACT FROM AUTHOR]

Introduction: Bone marrow-derived mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are widely used for therapeutic purposes in preclinical studies. However, their utility in treating diabetes-associated atherosclerosis remains largely unexplored. Here, we aimed to characterize BMSC-EV-mediated regulation of autophagy and macrophage polarization. Methods: EVs were isolated from the supernatant of cultured BMSCs and characterized with transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. A diabetes-related atherosclerotic ApoE−/− mouse model was established through feeding with a high-fat diet (HFD) and streptozotocin (STZ). Histopathological analyses were carried out using Oil Red O, H&E, and Masson staining of the aorta. TEM and immunohistochemistry (IHC) were applied to evaluate autophagy, and immunofluorescence (IF) was used to identify macrophage polarization. RAW264.7 macrophages were induced with oxidized low-density lipoprotein (ox-LDL) and high glucose (HG), co-cultured with BMSC-EVs, and analyzed for macrophage proliferation, migration, and foam cell formation. RAW264.7 cells were transduced with autophagy marker mRFP-GFP-LC3 lentivirus and analyzed with IF and western blotting. Results: Diabetic mice (DA group) had larger aortic plaque areas and lower collagen content than the HFD mice. BMSC-EV treatment significantly reduced blood glucose, LDL levels, and aortic plaque areas while increasing collagen content. BMSC-EV-treated aortas contained a higher number of autophagosomes/autolysosomes, with increased expression of LC3BII correlating with decreased P62 levels and a lower proportion of M1 macrophages. In vitro, BMSC-EVs inhibited proliferation, migration, and foam cell formation in ox-LDL and HG-induced activated RAW264.7 cells. These effects were reversed by the autophagy blocker bafilomycin A1. Consistent with the in vivo findings, BMSC-EVs elevated levels of the autophagy-related protein LC3BII/I and decreased P62 in ox-LDL and HG-induced RAW264.7 cells. These cells also expressed the M1 macrophage markers CD86 and iNOS, but showed reduced expression of the M2 marker Arg-1. Further, BMSC-EVs decreased AMPKα and mTOR phosphorylation levels, which were blocked by the AMPK inhibitor compound C. Conclusions: BMSC-EVs attenuate diabetes-exacerbated atherosclerosis by inhibiting vascular macrophage proliferation, migration, and foam cell formation via AMPK/mTOR signaling-regulated autophagy and macrophage polarization. BMSC-EVs thus hold promise as therapeutic agents for atherosclerosis. Extracellular vesicles derived from bone marrow mesenchymal stem cells may mitigate diabetes-aggravated atherosclerosis by regulating AMPK/mTOR-mediated autophagy-related macrophage polarization and inhibiting macrophage proliferation, migration, foam cell formation, and cholesterol transport. [ABSTRACT FROM AUTHOR]

Background: Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD), and can cause severe cerebral complications and even fatality in children younger than 5 years old. However, there is no specific medication for EV71 infection in clinical practice. Our previous studies had identified the 6-thioguanine (6-TG), an FDA-approved anticancer drug, as a potential antiviral agent, but its anti-EV71 activity is largely unknown, therefore, we aim to explore the antiviral effect of 6-TG on EV71. Results: 6-TG significantly suppressed EV71 mRNA level, VP1 protein expression, and viral progeny production in HT-29 cells. In EV71-infected HT-29 cells, the 50% cytotoxicity concentration of 6-TG (CC50) was > 2000 µM and the 50% inhibitory concentration of 6-TG against EV71 (IC50) was 0.9302 µM. Interestingly, the selectivity index (SI) value of 6-TG against EV71 was > 2150.1, which was higher than the SI value (> 66.7) of ribavirin. Mechanistically, 6-TG treatment reduced the expression of baculoviral IAP repeat containing 3 (BIRC3), and further inhibited EV71 replication by attenuating BIRC3-mediated the complete autophagy. Conclusions: 6-TG exerted a significant inhibitory effect on EV71 infection in vitro and prevented EV71-induced the complete autophagy by decreasing BIRC3 expression. Our work provided a basis for the further development of 6-TG as a therapy for EV71-associated HFMD. [ABSTRACT FROM AUTHOR]

Background: The increased apoptosis of bile duct epithelial cells (BECs) due to some damage factors is considered the initiating factor in the occurrence and progression of biliary atresia (BA). Vitamin D receptor (VDR) is thought to play a crucial role in maintaining the intrinsic immune balance and integrity of bile duct epithelial cells (BECs). To investigate the role of VDRs in the pathogenesis and progression of BA using in vitro and in vivo models. Materials and methods: The VDR expression levels in intrahepatic bile duct epithelial cells (IBDECs) in pediatric patients with BA were examined using immunohistochemical analysis. The correlation of the VDR levels with the incidence of refractory cholangitis after Kasai portoenterostomy (KPE) and the autologous liver survival time was analyzed. The levels of genes and proteins involved in related pathways were examined using quantitative real-time polymerase chain reaction and western blotting, respectively. The secretory levels of inflammatory factors were analyzed using enzyme-linked immunosorbent assay. A BA mouse model was established through the intraperitoneal sequential injection of rhesus rotavirus (RRV). The role of VDR in the pathogenesis and progression of BA was examined using in vitro and in vivo models. Retrospective analysis of patients with BA to examine the therapeutic efficacy of VDR activators on BA. Results: 15 pediatric BA patients exhibiting VDR downregulation in IBDECs showed a higher incidence of refractory cholangitis after Kasai portoenterostomy (p = 0.037) and a lower native liver survival time compare to 23 BA patients without VDR downregulation (p = 0.032). 1,25-VD3 inhibited the degree of autophagy induction in HIBECs by poly(I: C) (p < 0.05), mitigated poly(I: C)-induced BEC damage and apoptosis by inhibiting autophagy (p < 0.05). 1,25-VD3 significantly suppressed the poly(I: C)-induced downregulation of SRC (p < 0.05) and ERK1/2 phosphorylation (p < 0.05). 1,25-VD3 exert a protective effect against RRV-induced BEC damage by inhibiting autophagy in BA mouse model. The incidence of cholangitis and the native liver survival time after surgery in the calcitriol-treated group was significantly lower than that in the control group. (p = 0.033, p = 0.035, respectively). Conclusions: VDR activator mitigated dsRNA-induced BEC damage and apoptosis by inhibiting autophagy in vitro and in vivo. The 1,25-VD3/VDR/Src axis alleviated poly(I: C)-induced HIBEC damage and apoptosis through the PLA2/PKC/ERK pathway. [ABSTRACT FROM AUTHOR]

Ginsenoside Rd (Rd) is a bioactive compound predominantly found in Panax ginseng C.A. Meyer and Panax notoginseng (Burkill) F.H. Chen ex C.H. Chow, both species belonging to genus Panax in the Araliaceae family. However, its hepatic protective effect against acute liver injury and related mechanistic action remain unexplored. To investigate the protective effect of Rd against thioacetamide (TAA)-induced acute liver injury and assess its underlying regulatory mechanisms related to autophagy and inflammation. Forty-eight 8 weeks old C57BL/6 mice were treated with saline (control or model group), Rd (12.5 mg/kg, 25 mg/kg or 50 mg/kg), and diammonium glycyrrhizinate (DG, 30 mg/kg) for three days. Then the mice were stimulated with TAA to establish acute liver injury model, excluding the control group. HSC-T6 cells were treated with Rd at concentrations of 2.5, 5, or 10 µM, for 12 h with or without Lipopolysaccharide (LPS) stimulation at 100 ng/mL. Immunofluorescence staining, qPCR and Western blot were employed to analyze the expressions of genes and proteins associated with inflammation and autophagy. To validate the role of Rd in regulating autophagy and inflammation, the autophagy inducers, rapamycin and GSK621, were utilised in reverse validation experiments in cells. Rd exhibited significant hepatic protective effects in mice by reducing the serum levels of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glutathione S-transferase (GST) and Lactate dehydrogenase (LDH) with acute liver injury. It exhibited strong anti-inflammatory effect by reducing inflammation associated protein, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nod-like receptor protein 3 (NLRP3), associated speck-like protein containing a CARD (ASC), interleukin-18 (IL-18) and interleukin-1β(IL-1β) proteins and the mRNA expression levels of COX-2, Tumor Necrosis Factor α (TNF α), interleukin-6 (IL-6) and iNOS were decreased in liver tissue. And Rd inhibited LPS-induced inflammation by reducing the expression of COX-2 and NLRP3 in HSC-T6 cells. Moreover, not only in vivo but also in vitro, Rd downregulated the expression of LC3II, Beclin1, phosphorylation-AMP-activated protein kinase (p-AMPK), phosphorylation-ULK1 (p-ULK1) and upregulated the expression of p62 and phosphorylation-mechanistic target of rapamycin (p-mTOR) to suppress autophagy via the AMPK/mTOR/ULK1 pathway. Finally, the inhibitory effects of Rd on autophagy and inflammation in HSC-T6 cells were partially blocked by rapamycin and GSK621. Rd is a promising therapeutic agent to protect liver against TAA-induced acute liver injury by regulating the autophagy-NLRP3 inflammasome pathway. [ABSTRACT FROM AUTHOR]

Objective: Lung cancer is one of the main causes of cancer-related mortality globally, and it poses considerable therapeutic challenges. Polo-like kinase 1 (PLK1) exhibits upregulation in lung cancer, and PLK1 silencing promotes autophagy in lung cancer cells, which inhibits tumor progression. The phosphatase and tensin homolog deleted on chromosome ten (PTEN) acts as a tumor suppressor gene. This study aimed to investigate whether PTEN regulates autophagy and inhibits lung cancer-cell proliferation by suppressing PLK1. Material and Methods: In this study, we evaluated cell proliferation by silencing or overexpressing PLK1 and PTEN in A549 cells through 5-ethynyl-2'-deoxyuridine labeling and cloning experiments. The autophagy levels were detected through transmission electron microscopy, real-time quantitative polymerase chain reaction, and Western blot. Finally, the results of in vitro experiment were further verified using an in vivo xenograft tumor animal model. Results: The upregulation of PTEN suppressed PLK1 expression in lung cancer cells and reduced their proliferation rate. In addition, the overexpression of PTEN has been associated with the growth of lung cancer tumors. In parallel, the levels of autophagy of lung cancer cells rose in response to PTEN upregulation in vivo and in vitro. Conclusion: This study revealed that PTEN promotes the autophagy of lung cancer cells and inhibits cell proliferation and tumor growth by suppressing PLK1 expression. This finding provides a new strategy for lung cancer treatment by utilizing the autophagy-regulating effect of PTEN to inhibit lung cancer growth by targeting PLK1. [ABSTRACT FROM AUTHOR]

A silica delivery platform loaded with autophagy-inducing reagents and iron-based Fenton reagents was utilized to explore a novel strategy leveraging autophagy to reduce tumor acidity, thereby enhancing the effectiveness of CDT. [Display omitted] Iron-based chemodynamic therapy (CDT) exhibits commendable biocompatibility and selectivity, but its efficacy is constrained by the intracellular pH of tumors. To overcome this obstacle, we constructed a silica delivery platform loaded with autophagy-inducing reagents (rapamycin, RAPA) and iron-based Fenton reagents (Fe 3 O 4). This platform was utilized to explore a novel strategy that leverages autophagy to decrease tumor acidity, consequently boosting the effectiveness of CDT. Both in vitro and in vivo experiments revealed that RAPA prompted the generation of acidic organelles (e.g., autophagic vacuoles and autophagosomes), effectively changing the intracellular pH in the tumor microenvironment. Furthermore, RAPA-induced tumor acidification significantly amplified the efficacy of Fe 3 O 4 -based Fenton reactions, consequently increasing the effectiveness of Fe 3 O 4 -based CDT. This innovative approach, which leverages the interplay between autophagy induction and iron-based CDT, shows promise in overcoming the limitations posed by tumor pH, thus offering a more efficient approach to tumor treatments. [ABSTRACT FROM AUTHOR]

• PIK3CG is a significantly overexpressed gene in the ischemic stroke datasets. • PIK3CG is highly expressed in the blood of ischemic stroke patients. • Knockdown of PIK3CG can inhibit OGD/R-induced neuronal cell apoptosis. • PIK3CG knockdown can inhibit the AMPK/mTOR autophagy pathway to protect neurons. Ischemic stroke represents an urgent need for more efficacious therapies owing to modest effectiveness of current treatment. Download data from stroke patients and collect blood samples from clinical patients to analyze phosphatidylinositol-3 kinase catalytic subunit γ (PIK3CG) expression. To establish a brain damage model, oxygen glucose deprivation/reperfusion (OGD/R) was applied to SH-SY5Y cells. Impact of PIK3CG on AMPK/mTOR autophagy pathway was verified treating cells with AMPK activator metformin. Proliferation and apoptosis were identified by CCK8 and flow cytometry. Differential expression analysis and clinical testing show that PIK3CG is highly expressed in patients. Prolonged ODG/R exposure increased PIK3CG levels, supressed cell proliferation, and induced apoptosis. KEGG pathway analysis implicated PIK3CG in autophagy pathway. Knockdown of PIK3CG supressed OGD/R-induced reductions in cell proliferation and OGD/R-induced increases in apoptosis and expressions of Beclin 1 and LC3 II. Following OGD/R, AMPK phosphorylation was upregulated while mammalian target of rapamycin (mTOR) phosphorylation was downregulated, indicating AMPK/mTOR autophagy activation. Knockdown of PIK3CG opposed metformin-induced rises in Beclin 1, LC3 II and apoptosis along with decreases in proliferation. PIK3CG knockdown protects neuronal cells by inhibiting AMPK/mTOR autophagy pathway and further inhibiting autophagy. [ABSTRACT FROM AUTHOR]

Objective: Immune response is crucial in the development of gastric cancer (GC), and Jumonji domain-containing protein 6 (JMJD6) plays an important role in mediating GC cell behavior. This study aims to elucidate the mechanisms through which JMJD6 affects autophagy and immune evasion in GC cells. Material and Methods: Immunocytochemistry was employed to assess JMJD6 and programmed death-ligand 1 (PD-L1) levels in gastric cancer cell line (MKN-45) and gastric epithelial cell line cells. MKN-45 cells with JMJD6 knockdown and overexpression were generated. The effect of JMJD6 on MKN-45 cells was evaluated using cell counting kit-8 assay, cellular fluorescence staining, and Transwell assays. Western blot analysis and immunofluorescence techniques were employed to investigate the regulation of autophagy by JMJD6. Reactive oxygen species (ROS) levels were evaluated by applying ROS fluorescence staining. Meanwhile, the protein and gene expression levels of molecules related to antioxidant stress responses were assessed through immunofluorescence assays and quantitative real-time polymerase chain reactions, respectively. Results: The expression levels of JMJD6 and PD-L1 were elevated in GC cells (P < 0.001). JMJD6 overexpression enhanced MKN-45 cell migration, invasion, and colony formation in vitro (P < 0.001). In MKN-45 cells, the epithelial-mesenchymal transition was promoted by JMJD6 upregulation but was notably inhibited by JMJD6 knockdown (P < 0.001). JMJD6 overexpression increased the expression levels of Sequestosome 1, Microtubule-associated protein 1A/1B-light chain 3 (LC3)II/LC3I, and PD-L1 in MKN-45 cells, and autophagy activation further elevated PD-L1 levels (P < 0.001). In addition, JMJD6 overexpression reduced ROS production and increased the expression of molecules related to antioxidant stress response, with the reverse effects observed on JMJD6 knockdown (P < 0.001). Conclusion: JMJD6 notably facilitates GC progression and immune evasion by modulating autophagy and oxidative stress pathways. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a chronic inflammatory condition characterized by plaque formation, often leads to instability, particularly under Type 2 diabetes mellitus (T2DM) conditions, which exacerbate cardiovascular risks. However, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the correlation between acute coronary syndrome (ACS) and serum levels of Nε-carboxyethyl-lysin (CEL), a prominent advanced glycation end product (AGE) elevated in T2DM, in a cohort of 225 patients with coronary artery disease. Using a murine model of atherosclerosis complicated by T2DM, we examined the effects of CEL on plaque stability and macrophage autophagy. Our findings revealed that elevated serum CEL levels are independently associated with increased ACS incidence. Metabolomic profiling identified CEL as a key AGE contributing to plaque instability in diabetic conditions. Mechanistically, CEL disrupted macrophage autophagy and plaque stability by perturbing the Receptor for Advanced Glycation End products (RAGE)/Liver Kinase B1 (LKB1)/AMP-activated Protein Kinase 1 (AMPK1)/Sirtuin 1 (SIRT1) signaling cascade. This pathway further regulated autophagic activity through SIRT1-mediated acetylation of Zinc Finger with KRAB and SCAN Domains 3 (ZKSCAN3). These findings highlight CEL's critical role in promoting plaque instability in T2DM by impairing key molecular pathways that regulate autophagy, offering potential therapeutic targets for managing atherosclerosis in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B virus (HBV) infection is a major risk for development of hepatocellular carcinoma (HCC), a frequent malignancy with a poor survival rate. HBV infection results in significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) signaling, a contributing factor to carcinogenesis. As part of the UPR, the ER-associated degradation (ERAD) pathway is responsible for removing the burden of misfolded secretory proteins, to re-establish cellular homeostasis. Emerging evidence indicates consistent upregulation of ERAD factors, including members of the ER degradation-enhancing alpha-mannosidase-like protein (EDEM) family in infection and various tumor types. However, the significance of this gene expression pattern in HBV-driven pathology is just beginning to be deciphered. Methods: In this study we quantified the expression of the ERAD factor EDEM3, in a cohort of HCC patients with and without HBV infection, and validated our results by analysis of publically available transcriptomic and microarray data sets. We performed mechanistic studies in HepaRG cells with modulated EDEM3 expression to address UPR, ERAD, autophagy and apoptosis signaling, and their consequences on HBV infection. Results: Our work revealed significantly elevated EDEM3 expression in HCC tissues irrespective of HBV infection, while the highest levels were observed in tissues from HBV-infected patients. Investigation of published transcriptomic data sets confirmed EDEM3 upregulation in independent HCC patient cohorts, associated with tumor progression, poor survival prognosis and resistance to therapy. EDEM3-overexpressing hepatic cells exhibited attenuated UPR and activated secretory autophagy, which promoted HBV production. Conversely, cell depletion of EDEM3 resulted in significant ER stress inducing pro-apoptotic mechanisms and cell death. Conclusions: We provide evidence of major implications of the ERAD pathway in HBV infection and HCC development and progression. Our results suggest that ERAD activation in HBV-infected cells is a protective mechanism against prolonged ER stress, potentially contributing to establishment of chronic HBV infection and promoting tumorigenesis. Developing specific inhibitors for ERAD factors may be an attractive approach to improve efficiency of current antiviral and anticancer therapies. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a degenerative joint disease with an immense unmet medical need. FGF18 protein is a potential regenerative factor for cartilage repair. However, traditional protein delivery methods have limited efficacy due to the short lifetime and shallow infiltration. Results: In this work, we discovered that lipid nanoparticle (LNP) can infiltrate and deliver FGF18 mRNA deeper in the cartilage than proteins. After mRNA UTR optimization and chemical modification, the expression of FGF18 can last up to 6 days in the cartilage. Furthermore, delivering FGF18 mRNA activates FOXO3a-autophagy pathway, which protects against chondrocyte degeneration and senescence. Local intra-articular injection of FGF18 mRNA-LNP significantly alleviates OA symptoms in DMM and senile OA models. Sustained expression and accessibility of FGF18-mRNA to deeper chondrocytes makes LNP-mRNA more effective than FGF18 recombinant protein. Conclusions: In summary, this study presents a novel approach superior to recombinant protein alone and holds promise as a new therapeutic strategy for OA. [ABSTRACT FROM AUTHOR]

Nutrient deprivation is a major trigger of autophagy, a conserved quality control and recycling process essential for cellular and tissue homeostasis. In a high-content image-based screen of the human ubiquitome, we here identify the E3 ligase Pellino 3 (PELI3) as a crucial regulator of starvation-induced autophagy. Mechanistically, PELI3 localizes to autophagic membranes, where it interacts with the ATG8 proteins through an LC3-interacting region (LIR). This facilitates PELI3-mediated ubiquitination of ULK1, driving ULK1's subsequent proteasomal degradation. PELI3 depletion leads to an aberrant accumulation and mislocalization of ULK1 and disrupts the early steps of autophagosome formation. Genetic deletion of Peli3 in mice impairs fasting-induced autophagy in the liver and enhances starvation-induced hepatic steatosis by reducing autophagy-mediated clearance of lipid droplets. Notably, PELI3 expression is decreased in the livers of patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting its role in hepatic steatosis development in humans. The findings suggest that PELI3-mediated control of autophagy plays a protective role in liver health. [ABSTRACT FROM AUTHOR]

The nucleus is a highly specialized organelle that houses the cell’s genetic material and regulates key cellular activities, including growth, metabolism, protein synthesis, and cell division. Its structure and function are tightly regulated by multiple mechanisms to ensure cellular integrity and genomic stability. Increasing evidence suggests that nucleophagy, a selective form of autophagy that targets nuclear components, plays a critical role in preserving nuclear integrity by clearing dysfunctional nuclear materials such as nuclear proteins (lamins, SIRT1, and histones), DNA-protein crosslinks, micronuclei, and chromatin fragments. Impaired nucleophagy has been implicated in aging and various pathological conditions, including cancer, neurodegeneration, autoimmune disorders, and neurological injury. In this review, we focus on nucleophagy in mammalian cells, discussing its mechanisms, regulation, and cargo selection, as well as evaluating its therapeutic potential in promoting human health and mitigating disease.Abbreviations: 5-FU: 5-fluorouracil; AMPK, AMP-activated protein kinase; ATG, autophagy related; CMA, chaperone-mediated autophagy; DRPLA: dentatorubral-pallidoluysian atrophy; ER, endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; HOPS, homotypic fusion and vacuole protein sorting; LIR: LC3-interacting region; MEFs: mouse embryonic fibroblasts; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; PCa: prostate cancer; PE: phosphatidylethanolamine; PI3K, phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; rRNA: ribosomal RNA; SCI: spinal cord injury; SCLC: small cell lung cancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SupraT: supraphysiological levels of testosterone; TOP1cc: TOP1 cleavage complexes [ABSTRACT FROM AUTHOR]

Background: Alcoholic pancreatitis is a progressive condition characterized by susceptibility to recurrence, progression to chronic pancreatitis, complications, and high morbidity. Summary: The main causes include long-term alcoholism, excessive drinking, the toxic effects of alcohol metabolites, interactions with biliary diseases, and genetic factors. Alcohol is the second leading cause of acute pancreatitis (AP) in the USA, accounting for one-third of all AP cases. A follow-up study on readmission revealed that the readmission rate of alcoholic acute pancreatitis (AAP) patients within 11 months was 43.1%, of which men dominated the admissions and readmissions of AAP. Among this population, 82.3% have alcohol use disorder, over half have tobacco use disorders, 6.7% have tobacco use disorder, 4.5% have opioid use disorder, and 18.5% of patients exhibit signs of potential alcoholic chronic pancreatitis. Numerous animal and clinical studies suggest that alcohol alone does not cause pancreatitis; rather, additional factors such as smoking, endotoxin lipopolysaccharide (LPS), genetic mutations, or other genetic predispositions – are necessary for the disease’s progression. Key Messages: Given the high rates of admission and readmission for alcoholic pancreatitis, it is essential to further investigate its pathogenesis and pathological processes to develop more effective treatment strategies. Therefore, this paper summarizes the current understanding of the pathogenesis and treatment status of alcoholic pancreatitis, drawing on recently published literature and data to provide insights and references for future research and treatment efforts. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is an irreversible age-related neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Di Huang Yi Zhi (DHYZ) formula, a traditional Chinese herbal compound comprising several prescriptions, demonstrates properties that improve cognitive abilities in clinical. Nonetheless, its molecular mechanisms on treating AD through improving neuron cells mitochondria function have not been deeply investigated. Objective: This study administered DHYZ to APP/PS1 mice to explore its potential therapeutic mechanisms in AD treatment. Methods: APP/PS1 transgenic mice were given DHYZ (L, M, H), donepezil, or distilled water for a consecutive 12-week period. The Morris water maze test was used to assess memory capacity, transmission electron microscopy was used to observe mitochondrial and synaptic structures, immunohistochemistry and western blot detected proteins involved in the mitochondrial autophagy pathway, ELISA measured serum Aβ content, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assessed neuronal cell apoptosis. Results: DHYZ demonstrates a notable therapeutic impact on mice with AD, effectively improving cognitive and memory impairments. DHYZ decreases Aβ accumulation in the hippocampus by reducing BACE1 activity and enhancing Aβ clearance through the blood-brain barrier. Additionally, DHYZ significantly suppresses neuronal apoptosis, enhances synaptic structure, and increases synapse numbers, processes strongly linked to the activation of mitochondrial PINK1-Parkin autophagy. Conclusions: DHYZ enhances cognitive function in APP/PS1 mice by stimulating neuronal mitochondrial autophagy through the PINK1-Parkin pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Telomeres play an integral role in preventing genomic instability by protecting chromosomal ends using telomeric repeats, and their dysfunction may lead to premature aging disorders and age-related diseases. During cellular division, they undergo telomere attrition, resulting in the gradual shortening of those protective caps, leading to genomic instability and cellular aging. Critically short telomeres in normal cells trigger senescence, a major contributor to age-related diseases, and opens the door for genomic instability, which promotes carcinogenesis. This review aims to provide an updated overview of telomere biology and therapeutic strategies around telomere attrition. We emphasize the importance of understanding the complex balance between preserving telomere length in aging while inhibiting telomere maintenance in cancer by proposing Optimal Therapeutic Approaches based on the most updated literature. Background/Objectives: As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer. Methods: We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results. Results: Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson–Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases. Conclusions: The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer continues to pose significant treatment challenges, driving the search for new therapeutic agents with innovative mechanisms of action. Ruthenium-based compounds are emerging as promising anticancer agents due to their unique properties, which differ from those of traditional platinum-based therapies. This study investigates the effects of the ruthenium complex Bis(quinolin-8-olato)bis(triphenylphosphine)ruthenium(II) (Ru(quin)2) in hormone receptor-positive and triple-negative breast cancer cell models. Our results demonstrate that this compound effectively reduces cancer cell viability by inducing programmed cell death, stimulating autophagy, and causing cell cycle arrest. These findings highlight the potential of Ru(quin)2 as a novel therapeutic candidate for breast cancer, warranting further exploration to evaluate its in vivo efficacy and potential for clinical application. Background/Objectives: Breast cancer (BC) remains one of the most prevalent and deadly cancers worldwide, with limited access to advanced treatments in developing regions. There is a critical need for novel therapies with unique mechanisms of action, especially to overcome resistance to conventional platinum-based drugs. This study investigates the anticancer potential of the ruthenium complex Bis(quinolin-8-olato)bis(triphenylphosphine)ruthenium(II) (Ru(quin)2) in ER-positive (T47D) and triple-negative (MDA-MB-231) BC cell lines. Results: Ru(quin)2 demonstrated dose-dependent cytotoxicity, with IC50 values of 48.3 μM in T47D cells and 45.5 μM in MDA-MB-231 cells. Its cytotoxic effects are primarily driven by apoptosis, as shown by increased BAX expression, enhanced caspase-3 activity, reduced Aurora B kinase levels, and elevated histone release. Ru(quin)2 also induced autophagy, evidenced by LC3-I to LC3-II conversion and reduced SQSTM1, partially mediated through MAPK signaling. Furthermore, Ru(quin)2 induced G0/G1 cell cycle arrest by downregulating cyclin D1, CDK4, and CDK6, alongside upregulation of the CDK inhibitor p21. Conclusions: Ru(quin)2 emerges as a potent candidate for BC treatment, with multiple mechanisms of action involving apoptosis, autophagy, and cell cycle arrest. Further studies are warranted to elucidate its detailed molecular mechanisms and evaluate its therapeutic potential in vivo, moving toward clinical applications for both ER-positive and triple-negative BC management. [ABSTRACT FROM AUTHOR]

The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function. [ABSTRACT FROM AUTHOR]

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR. [ABSTRACT FROM AUTHOR]