While NDUFAF6 is implicated in breast cancer, its specific role remains unclear.

The expression levels and prognostic significance of NDUFAF6 in breast cancer were assessed using The Cancer Genome Atlas, Gene Expression Omnibus, Kaplan-Meier plotter and cBio-Portal databases. We knocked down NDUFAF6 in breast cancer cells using small interfering RNA and investigated its effects on cell proliferation and migration ability. We performed gene expression analysis and validated key findings using protein analysis. We also assessed mitochondrial activity and cellular metabolism.

NDUFAF6 was highly expressed in breast cancer, which was associated with a poorer prognosis. Knockdown of NDUFAF6 reduced the proliferation and migration ability of breast cancer cells. Transcriptome analysis revealed 2,101 differentially expressed genes enriched in apoptosis and mitochondrial signaling pathways. Western blot results showed NDUFAF6 knockdown enhanced apoptosis. In addition, differential gene enrichment analysis was related to mitochondrial signaling pathways, and western blot results verified that mitophagy was enhanced in NDUFAF6 knockdown breast cancer cells. JC-1 assay also showed that mitochondrial dysfunction and reactive oxygen species content were increased after knocking down NDUFAF6. In addition, basal and maximal mitochondrial oxygen consumption decreased, and intracellular glycogen content increased.

Knockdown of NDUFAF6 resulted in apoptosis and mitophagy in breast cancer cells and NDUFAF6 may be a potential molecular target for breast cancer therapy.

This study aimed to examine the alterations in apoptosis and autophagy in placental tissues from normal pregnancies compared to those affected by preeclampsia (PE) and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome. We analysed the expression of autophagy-associated proteins, Beclin-1 and BCL-2, in human placental tissues and assessed their variations in placentas from pregnancies complicated by PE and HELLP syndrome by immunohistochemical (IHC) and in silico analyses.

An experimental case-control study was performed, involving 40 pregnant women complicated with preeclampsia, 25 pregnant women with HELLP syndrome, and 40 healthy pregnant women. The placental sections were stained with BCL-2 and Beclin-1 immunostains and subjected to IHC examination. The results of the IHC staining were assessed using semi-quantitative analysis. In silico analyses were performed using STRING and Cytoscape software to construct protein interaction networks for BCL-2 and Beclin-1 in PE and HELLP syndrome, followed by Gene Ontology analysis of common interactors to identify significant biological pathways.

Both BCL-2 expression was significantly decreased (p < 0.001 and p < 0.0001, respectively) and Beclin-1 staining was significantly increased (p < 0.0001 and p < 0.0001, respectively) in the PE group and HELLP group compared to the control group. The changes in BCL-2 and Beclin-1 expression between PE and the HELLP group were also statistically significant. BCL2 expression was notably lower (p < 0.0001), and Beclin-1 staining was significantly higher (p < 0.05) in the HELLP group compared to the PE group. In PE, BCL-2 interactors were enriched in apoptosis, cytokine production, and cell proliferation pathways, while Beclin-1 interactors were linked to autophagy and phosphatidylinositol-mediated signalling. In HELLP, BCL-2 interactors were involved in inflammatory response regulation, whereas Beclin-1 interactors were associated with vascular endothelial growth factor (VEGF) signalling and immune regulation.

The differential expression patterns of BCL-2 and Beclin-1 between the PE and HELLP groups suggest that these proteins play distinct roles in the pathophysiology of these conditions.

Breast cancer, particularly triple-negative breast cancer (TNBC), poses a significant threat to women's health. In tumor cells, autophagy and apoptosis are double-edged swords, playing complex roles in cancer progression and treatment. This study aimed to investigate whether Terrestrosin D (TED) exerts antitumor effects on TNBC by modulating autophagy and apoptosis, and to elucidate the underlying molecular mechanisms.

The antiproliferative and pro-apoptotic effects of TED on TNBC cells were assessed using CCK-8, EdU assay, Live/Dead staining, and flow cytometry. Autophagy was monitored through immunofluorescence and confocal microscopy. RNA sequencing was performed to identify the pathways and molecular targets involved. The anti-TNBC effects of TED were further evaluated in vivo using tumor xenograft models. Western blotting was conducted to validate the relationship between PSMD1, P53, and TED-induced antitumor activity.

TED exhibited significant antitumor effects both in vitro and in vivo. Cellular phenotypic analyses revealed that TED promoted autophagy and apoptosis. Transcriptomic analyses indicated that TED stabilizes P53 expression and activates the P53 signaling pathway by inhibiting the function of PSMD1.

TED exhibits potent antitumor effects on TNBC by promoting autophagy and apoptosis. It achieves this through PSMD1 inhibition, stabilizing P53 expression, and activating the P53 pathway. Notably, this study is the first to demonstrate that TED directly targets PSMD1, a key proteasomal regulator, thereby unveiling a novel mechanism for P53 stabilization in TNBC. These findings provide new insights into the therapeutic modulation of the PSMD1 - P53 axis by natural compounds and support the development of TED as a multi-functional agent for aggressive breast cancers.

Electroacupuncture (EA), a traditional Chinese medicine therapy, exhibits cardioprotective and therapeutic effects against cardiac injury. However, the precise mechanisms underlying these benefits remain unclear.

The aim of this study is to examine the impact of EA on Doxorubicin-Induced heart failure and elucidate the mechanisms involved.

C57BL/6 mice were randomly assigned to six experimental groups, including a control group, a DCM group, a DCM group receiving non-acupoint EA (NEA), and a DCM group receiving acupoint EA (EA). The cardiac function, levels of inflammatory factors, and markers of apoptosis were assessed both in vivo and in vitro. The presence of AMPK/mTOR/ULK1(Ser317) and PI3K/AKT/mTOR/ULK1(Ser757) was confirmed.

EA stimulation significantly improved cardiac function, as evidenced by increased left ventricular ejection fraction (LVEF), E/A ratio, and fractional shortening (FS%) compared to the DCM group (p < 0.05). After EA stimulation, the phosphorylation levels of PI3K/AKT increase, leading to elevated expression of mTOR/ULK1(Ser757), which ultimately inhibited the expression of apoptosis-related proteins and inflammatory factors. Simultaneously, EA stimulation could inhibit the phosphorylation levels of AMPK, reducing the expression of mTOR/ULK1(Ser317), and thereby also inhibiting the expression of apoptosis-related proteins and inflammatory factors.

This study showed that EA stimulation can counteract myocardial damage caused by apoptosis and inflammation, thereby significantly improving cardiac function and prognosis in HF mice. The mechanism may be that EA stimulation activates the PI3K/AKT/mTOR/ULK1(ser757) pathway and inhibits the AMPK/ULK1(ser317) pathway. EA stimulation exerts the same effect by regulating these two pathways in different directions, ultimately reducing myocardial cell apoptosis and cardiac inflammation.

Fucosyltransferase 2 (FUT2) is an enzyme that adds fucose to proteins or lipids via α-1,2-fucosylation in the intestinal mucosa. While FUT2 deficiency is linked to increased susceptibility to inflammatory bowel disease (IBD), its role in colorectal cancer (CRC) is unclear, and the molecular mechanisms involved remain largely unknown. We established an azoxymethane (AOM) and dextran sulfate sodium (DSS) model to induce CRC. FUT2 expression was assessed in human CRC tissues, AOM/DSS-induced mouse models, and CRC cell lines using qRT-PCR, western blotting, and UEA-I staining. FUT2 knockout (FUT2△IEC) mice were treated with AOM/DSS, and FUT2-overexpressing CRC cells were created to evaluate the effects of FUT2 on apoptosis in both in vitro and in vivo settings through Western blot analyses and functional assays. N-glycoproteomics, UEA-I chromatography, and co-immunoprecipitation were utilized to identify regulatory mechanisms and target fucosylated proteins. FUT2 expression and α-1,2-fucosylation were significantly decreased in CRC. FUT2 deficiency worsened AOM/DSS-induced CRC and reduced tumor apoptosis, while FUT2 overexpression induced apoptosis and inhibited proliferation in CRC cells and xenografts. Mechanistically, FUT2 appears to suppress autophagy by impairing lysosomal function and directly targeting and fucosylating LAMP1, contributing to lysosomal dysfunction. Our study reveals a fucosylation-dependent antitumor mechanism of FUT2 in CRC, suggesting potential therapeutic strategies for CRC treatment.

Cadmium (Cd), a well-known toxic heavy metal, adversely affects multiple organs. The SGLT-2 inhibitor empagliflozin (EMPA) exhibits significant antioxidant properties and hypoglycemic potential. This study aimed to investigate the hepatoprotective effect of EMPA against Cd-induced liver injury and elucidate its molecular mechanisms. Thirty-two male rats were allocated into four groups of eight rats each: group I (control group), group II (EMPA group), group III (Cd group), and group IV (Cd + EMPA group). Cd intake disrupted liver enzymes (ALT, AST, and ALP) and impaired hepatic histological architecture. Cd induced hepatic oxidative stress, as evidenced by increased MDA levels and reduced antioxidant enzymes, including SOD, GPx, and CAT. It downregulated the Nrf2/HO-1 pathway and elevated proinflammatory mediators IL-1β, IL-6, and TNF-α. Furthermore, Cd increased ER stress markers GRP78 and CHOP, along with apoptotic markers Bax and caspase-3 while decreasing anti-apoptotic Bcl-2 and reducing the autophagic indicator Beclin-1. Interestingly, EMPA administration in the Cd + EMPA group attenuated Cd-induced hepatic deterioration, improving hepatocyte structure. This beneficial effect was driven by the downregulation of hepatic oxidative stress, inflammation, ER stress, and apoptosis, alongside the upregulation of the autophagy process. In conclusion, this study highlights the hepatoprotective effect of EMPA against Cd-induced liver injury, elucidating its underlying molecular mechanisms.

Tuberculosis is a widely spread disease caused by Mycobacterium tuberculosis (Mtb). The pathogenicity of the pathogen is closely associated with the immune defense mechanisms of the host cells. As key cellular degradation and metabolic centers, lysosomes critically regulate tuberculosis infection. When Mtb invades the host, it is taken up by macrophages and enters phagosomes. Subsequently, the phagosomes fuse with lysosomes and form phagolysosomes, which eliminate the pathogenic bacteria through the acidic environment and hydrolytic enzymes within lysosomes. However, Mtb can interfere with the normal functions of lysosomes through various strategies. It can secrete specific factors (such as ESAT-6, ppk-1, and AcpM) to inhibit the acidification of lysosomes, enzyme activity, and the fusion of phagosomes and lysosomes, thereby enabling Mtb proliferation within host cells. An in-depth exploration of the mechanism of the interaction between Mtb and lysosomes will both uncover bacterial immune evasion strategies and identify novel anti-tuberculosis therapeutic targets.

Does putrescine (PUT) improve oocytes from reproductively old mice by promoting mitochondrial autophagy?

Germinal vesicle stage cumulus-oocyte complexes (COCs) were obtained from 9-month old female C57BL/6N mice and divided into control, PUT and difluoromethylornithine, inhibitor (DFMO) groups. These germinal vesicle COCs underwent mouse in-vitro maturation (IVM) culture to observe the extrusion of the first polar body in each group. Using JC-1, dichloro-dihydro-fluorescein diacetate fluorescent probes and a confocal microscope, the mitochondrial membrane potential integrity and reactive oxygen species levels were measured in metaphase II stage oocytes. The expression and cellular localization of the p53 protein were examined by immunofluorescence. Reverse transcription quantitative polymerase chain reaction was used to detect the activation of mitochondrial autophagy pathways. The potential mechanisms through which PUT improves oocytes from reproductively old mice were explored by single-cell transcriptomic analysis. Autophagosomes, autolysosomes and mitochondria in different groups were directly observed using transmission electron microscopy.

The addition of exogenous PUT can promote IVM of oocytes from reproductively old mice. It reduces oxidative stress by promoting the autophagy of damaged mitochondria, decreasing the levels of reactive oxygen species and increasing mitochondrial membrane potential. It affects the expression and subcellular localization of the p53 protein, and increases the expression of transcription factor EB, which may be the potential mechanism behind its promotion of autophagy.

The target and regulatory pathway of PUT in oocytes was clarified. Putrescine is an effective small molecule compound with significant potential for non-invasively improving the fertility of elderly women.

The combination of photodynamic therapy (PDT) and gene therapy is a viable therapeutic approach for the management of secondary hyperparathyroidism (SHPT). Nevertheless, the effective delivery of photosensitizers or nucleotide drugs remains a crucial limitation in achieving therapeutic efficacy. MiR-146b-3p directly targeted BCL2, and its overexpression enhanced the antiproliferative, proautophagic, and proapoptotic effects during 5-aminolevulinic acid (5-ALA)-mediated PDT in this study. Herein, we investigated the potential of codelivering 5-ALA and miR-146b-3p to SHPT primary cells via polyamidoamine (PAMAM) and achieving enhanced therapeutic efficacy relative to that of monotreatment. The fabrication of the PAMAM-based 5-ALA and miR-146b-3p dual-delivery system (5-ALA@PAMAM/miR) involved the use of covalent condensation reactions and electrostatic self-assembly. The nanoparticles were characterized by various analytical techniques, including transmission electron microscopy (TEM), zeta potential measurements, and size measurements. Fluorescence and confocal laser scanning microscopy demonstrated a greater degree of cellular uptake of nanoparticles. Moreover, the synthesized nanoparticles considerably enhanced the effectiveness of PDT without systemic toxicity both in vitro and in vivo. Overall, the nanocarrier-gene-photosensitizer coloaded system is a promising platform for the efficient simultaneous delivery of miR-146b-3p and 5-ALA and achieves synergistic therapeutic effects.

The heavy metal cadmium (Cd) is an important environmental factor that induces liver injury and contributes to liver disease. Ongoing research aims to refine our understanding of the pathogenesis of cadmium-induced liver injury and the interactions between the various mechanisms. Oxidative stress, described as a pathophysiological basis of liver injury, is a process in which reactive oxygen species are generated, causing the destruction of hepatocyte structure and cellular dysfunction. Additionally, the activation of oxidative stress downstream signals regulates several forms of cell death, such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis, which significantly contributes to liver damage. Furthermore, the interplay between different types of programmed cell death highlights the complexity of liver injury mechanisms. This review summarizes the role of programmed cell death in Cd-induced liver injury and explores the relationships between different programmed cell death pathways, which is expected to provide new insights into the mechanisms of Cd-induced liver injury.

TNF receptor-associated factor 3 interacting protein 3 (TRAF3IP3/T3JAM) exhibits dual roles in cancer progression. While upregulated in most malignancies and critical for immune regulation. However, the specific effects and molecular mechanisms of TRAF3IP3 on the progression of lung adenocarcinoma (LUAD) remains poorly understood. This study reveals TRAF3IP3 is upregulated in several tumor tissues but exclusively decreased in LUAD and Lung squamous cell carcinoma (LUSC) tissues, consequential in a favorable overall survival (OS) in LUAD rather than LUSC. Herein, it is reported that TRAF3IP3 can suppress cell proliferation and promote the apoptosis rate of LUAD cells by inducing excessive ER stress-related apoptosis. Importantly, TRAF3IP3 triggers ER stress via the PERK/ATF4/CHOP pathway, accompanied by stimulated ER stress-induced cytoprotective autophagy in LUAD cells. Through IP-MS analysis, STRN3 is identified as a direct downstream interactor with TRAF3IP3 and corroborated to regulate ER stress positively. Mechanistically, TRAF3IP3 facilitates the recruitment of STRN3 to the ER lumen through its transmembrane domain and fulfills its functional role in ER stress in an STRN3-dependent manner in LUAD cells. Given its dual role in orchestrating ER stress-associated apoptosis and autophagy in LUAD cell fate determination, the importance of TRAF3IP3 is highlighted as novel therapeutic target for LUAD treatment.

Waterborne ammonia is a threat to animal health and its accumulation is typical of aquatic ecosystems. Autophagy serves as a safeguard of intracellular homeostasis, yet its role in maintaining the health of hemocytes, the master regulators of crustacean immunity, remains unclear. Herein, the swimming crab (Portunus trituberculatus) is employed as a case study to illustrate the impact of ammonia on hemocyte health via autophagy. This study showed the occurrence of abnormal cellular structure and significant accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS) (P < 0.05), demonstrating that severe ammonia stress can damage hemocytes. This was accompanied by significant increase of autophagy hemocytes fraction and apoptosis (P < 0.05). Meanwhile, there was a significant increase in the expression of Beclin1 and microtubule-associated protein 1 light chain 3 (LC3-II) (P < 0.05). This suggests an ammonia-induced autophagy initiation. However, ammonia stress significantly decreased lysosomal fluorescence intensity (P < 0.05) and expression of the marker gene lysosomal-associated membrane protein 1 (LAMP1) (P < 0.05). These imply an ammonia-induced repression of lysosome-dependent autophagy degradation, which may underlie the pronounced increase in apoptosis (P < 0.05). After the administration of the autophagy activator rapamycin (Rap), rather than the inhibitor 3-Methyladenine (3-MA), the levels of apoptosis, ROS and the fraction of autophagic cells were significantly decreased (P < 0.05), demonstrating a mitigation of the ammonia-induced cell damage through lysosome-dependent autophagy degradation. This study sheds light on how crustaceans respond to ammonia exposure by demonstrating the significance of lysosome-dependent autophagy in maintaining hemocyte health.

The prevalence of depression has been escalating annually, imposing a substantial burden on both individuals and society. Radix Astragali, a multifaceted herb utilized in traditional Chinese medicine, has been employed in clinical settings for the treatment of depression. Kumatakenin, a principal active constituent of Radix Astragali, has yet to be thoroughly investigated for its potential antidepressant effects. In this study, we elucidated a novel effect of Kumatakenin, which ameliorated depression-like behaviors by modulating excessive autophagy in the hippocampus of mice exhibiting depressive symptoms. Utilizing transmission electron microscopy, we identified a significant increase in autophagosomes within the hippocampal region of depressed mice, which was notably reduced following Kumatakenin administration. Further, molecular docking analyses revealed an interaction between Kumatakenin and autophagy-related gene 5 (ATG5). At the protein level, Kumatakenin administration resulted in a marked decrease in microtubule-associated protein 1 light chain 3 (LC3) and ATG5 levels within hippocampal tissues. At the cellular level, in a corticosterone (CORT)-induced cell model, Kumatakenin significantly diminished the levels of LC3 and ATG5. Upon overexpression of ATG5 through lentiviral transfection, the ability of Kumatakenin to reduce LC3 and ATG5 levels was nullified. These observations suggested that Kumatakenin exerted its antidepressant effects by decreasing LC3 and ATG5 concentrations in hippocampal tissues.

Extracellular vesicles (EVs), defined as cell-secreted nanoscale vesicles that carry bioactive molecules, have emerged as a promising therapeutic strategy in tumor and tissue regeneration. Their potential in repairing intervertebral disc degeneration (IDD) through multidimensional regulatory mechanisms is a rapidly advancing field of research. This paper provided an overview of the mechanisms of EVs in IDD repair, thoroughly reviewed recent literature on EVs for IDD, domestically and internationally, and summarized their therapeutic mechanisms. In IDD repair, EVs could act through different mechanisms at the molecular, cellular, and tissue levels. At the molecular level, EVs could treat IDD by inhibiting inflammatory reactions, suppressing oxidative stress, and regulating the synthesis and decomposition of extracellular matrix. At the cellular level, EVs could treat IDD by inhibiting cellular pyroptosis, ferroptosis, and apoptosis and promoting cell proliferation and differentiation. At the tissue level, EVs could treat IDD by inhibiting neovascularization. EVs have a strong potential for clinical application in the treatment of IDD and deserve more profound study.

Autophagy plays a complex role in cancer progression, serving as both a tumor suppressor and a promoter, depending on the context. In triple-negative breast cancer (TNBC), a particularly aggressive subtype with limited therapeutic options, autophagy inhibition has emerged as a promising strategy to enhance the efficacy of chemotherapy. This study investigates the synergistic effects of autophagy suppression using LC3 siRNA-loaded "smart" nanoparticles (LC3siRNA-NPs) in combination with doxorubicin (DOX) to overcome chemoresistance in TNBC. We engineered a well-defined copolymer, poly[hexyl methacrylate-co-2-(dimethylamino) ethyl methacrylate-co-trimethylaminoethyl methacrylate iodide], and a PEG heteroarm beta-cyclodextrin (βCD) core star copolymer that delivers LC3 siRNA, effectively silencing the autophagy-related gene LC3. In vitro, the coadministration of LC3siRNA-NPs and DOX significantly inhibited TNBC cell proliferation, migration, and colony formation, while inducing apoptosis more effectively than either treatment alone. Mechanistically, this combination downregulated key oncogenic markers such as PARP, cyclin D1, and Src, enhancing the therapeutic outcome. In vivo, treatment with LC3siRNA-NPs and DOX in a TNBC xenograft model resulted in superior tumor growth suppression compared to that with monotherapy alone. Our findings highlight the potential of autophagy-targeting nanocarriers to improve chemotherapy outcomes and provide an effective approach to TNBC treatment by enhancing chemotherapeutic sensitivity and reducing tumor resistance.

Caspase-independent cell death (CICD) has recently become a very important mechanism in lung cancer, in particular, to overcome a critical failure in apoptotic cell death that is common to disease progression and treatment failures. The pathways involved in CICD span from necroptosis, ferroptosis, mitochondrial dysfunction, and autophagy-mediated cell death. Its potential therapeutic applications have been recently highlighted. Glutathione peroxidase 4 (GPX4) inhibition-driven ferroptosis has overcome drug resistance in non-small cell lung cancer (NSCLC). In addition, necroptosis involving RIPK1 and RIPK3 causes tumor cell death and modulation of immune responses in the tumor microenvironment (TME). Mitochondrial pathways are critical for CICD through modulation of metabolic and redox homeostasis. Ferroptosis is amplified by mitochondrial reactive oxygen species (ROS) and lipid peroxidation in lung cancer cells, and mitochondrial depolarization induces oxidative stress and leads to cell death. In addition, mitochondria-mediated autophagy, or mitophagy, results in the clearance of damaged organelles under stress conditions, while this function is also linked to CICD when dysregulated. The role of cell death through autophagy regulated by ATG proteins and PI3K/AKT/mTOR pathway is dual: to suppress tumor and to sensitize cells to therapy. A promising approach to enhancing therapeutic outcomes involves targeting mechanisms of CICD, including inducing ferroptosis by SLC7A11 inhibition, modulating mitochondrial ROS generation, or combining inhibition of autophagy with chemotherapy. Here, we review the molecular underpinnings of CICD, particularly on mitochondrial pathways and their potential to transform lung cancer treatment.

Corticosteroids and immunosuppressants are the mainstay of therapy for idiopathic inflammatory myopathies (IIMs). However, a significant therapeutic challenge extends beyond mitigating inflammation with these agents in achieving meaningful improvements in muscle strength and physical function, a goal that remains largely unmet. IIMs encompass a heterogeneous group of autoimmune disorders, including dermatomyositis, polymyositis, necrotizing autoimmune myopathy, inclusion body myositis, and others, characterized by chronic muscle inflammation, progressive weakness, and fatigue. The etiology of IIMs remains poorly understood, though potential contributors include environmental triggers (e.g., infections, medications, or injury) and genetic predisposition. To advance the development of novel therapeutic strategies, it is critical to elucidate the dysfunctional molecular and cellular pathways underlying IIM pathogenesis. Among these, dysregulated autophagy pathways have emerged as a promising target for therapeutic intervention. Specifically, impairments in lysosomal autophagy and mitophagy have been implicated in IIMs, and modulating these processes through targeted regulatory mechanisms may offer therapeutic benefits. This review provides a comprehensive synthesis of clinical and biological features of IIMs, the current diagnostic approaches and emerging biomarkers, evaluates the utility of existing biomarkers, and examines the relevance of animal models in IIM research. Furthermore, we explore the role of autophagic dysregulation in disease pathogenesis and provide a critical appraisal of current treatment modalities. Finally, we highlight emerging therapeutic targets and regulatory molecules under investigation, with a particular focus on autophagy modulation. Notably, autophagy inhibitors represent a novel and potentially transformative therapeutic avenue for patients with IIMs, offering hope for improved clinical outcomes.

To investigate the effects of comparable dietary excess of fat or fructose and the combination of these two insults (mimicking ultra-processed foods) on interscapular brown adipose tissue (iBAT) whitening and markers of mitochondrial dynamics in adult male mice.

Male C57BL/6 mice were randomly assigned into four groups according to the diet: control diet (C, following AIN-93M), high-fat diet (HF, 32% energy as lard), high-fructose diet (HFRU, 32% energy as fructose) or for high-fat/high-fructose diet (HF-HFRU, 32% as lard and 32% as fructose) for 12 weeks. Data were tested with one-way ANOVA and Dunnet T3 post-test (n=5 per analysis, significance level P < 0.05).

All diets caused insulin resistance and iBAT whitening, albeit with overweight only in the HF and HF-HFRU groups. Principal component analysis indicated that the HFRU scores loaded next to inflammation (Nlrp3) and adipogenesis markers (Pparg), and the HF diet influenced more a mitochondrial gene (Tomm20). However, iBAT whitening in all groups was associated with deficits in mitochondrial dynamics (Ppargc1a, Dnml1, and Pink1), vascularization (Vegfa), and thermogenic markers (Bmp8b, and Ucp1).

Similar increases in dietary saturated fat or fructose (32% as energy) and the combination of these two insults (32% / 32%) caused insulin resistance and brown adipocyte dysfunction (whitening) in adult mice after 12 weeks independent of being overweight. In comparison, the PC scores of the HFRU groups were closer to the HF-HFRU group than the HF group, implying a worse outcome and highlighting the importance of limiting saturated fat and fructose intake from ultra-processed foods.

Liver cancer is one of the most lethal cancers, and apoptosis resistance is a major obstacle contributing to chemotherapy failure in liver cancer treatment. Inducing cancer cell death by bypassing the apoptotic pathway is considered a promising approach to overcome this problem. Necroptosis is a non-caspase-dependent regulated mode of cell death mainly mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) protein, and the utilization of necroptosis for treating hepatocellular carcinoma (HCC) also offers a new hope for addressing liver cancer in the clinic. In this paper, the role of necroptosis in HCC as well as the effect on differentiation of liver cancer are reviewed. We also comparatively analyze the relationship among necroptosis, apoptosis, and necrosis, as well as summarize the characteristics and functions of key proteins involved in this pathway. The bidirectional regulation of necroptosis and the mitochondrial machinery within this pathway deserve attention.

The tumor microenvironment (TME) of gliomas comprises glioma cells and surrounding cells, such as astrocytes, macrophages, T cells, and neurons. In the TME, glioma cells can activate normal human astrocytes (NHAs) through the secretion of exosomes and the activation of astrocytes can further improve the progression of glioma, leading to a poor prognosis for patients. However, the molecular mechanisms underlying NHAs activation by gliomas remain largely unknown. It this study, glioma-derived exosomes (GDEs) play an important role in the modulation of autophagy and activation of NHAs. Compared with normoxic GDEs, hypoxic glioma-derived exosomes (H-GDEs) further improved autophagy and activation of astrocytes, which strongly promoted the progression of glioma cells. In an miRNA array between two types of exosomes from gliomas, miR-423-3p was highly expressed in H-GDEs and played an important role in autophagy, resulting in the activation of NHAs. The mechanism by which hypoxic glioma cells react with NHAs to create an immunosuppressive microenvironment was identified and 15d-PGJ2 was established as an effective inhibitor of miR-423-3p to suppress NHAs activation. These findings provide new insights into the diagnosis and treatment of gliomas by targeting autophagy and miR-423-3p expression.

This study aims to explore how exercise enhances mitochondrial regulation and mitigates pathological cardiac hypertrophy. Rat groups were assigned as the control group (CN, n = 8), sham group (sham, n = 8), model group (SC, n = 16) and exercise group (SE, n = 20). A bioinformatics analysis was conducted to uncover the underlying mechanisms.H9C2 cells were divided into: the Ang II 0 h group (CON), Ang II 48 h group (Ang II), Ang II 48 h + sh-control group (sh-GFP + Ang II), Ang II 48 h + sh-ndufb10 group (sh-ndufb10 + Ang II), Ang II 48 h + overexpressedndufb10 control group (Ad-GFP + Ang II) and Ang II 48 h + over-expressedndufb10group (Ad-ndufb10 + Ang II). Mitochondrial function was measured. mRNA and protein expression were assessed by qPCR or western blot analysis respectively. In the SC group, a significant increase was observed in cardiomyocyte diameter, cardiac function, autophagy, and apoptosis. After 8 weeks of swimming exercise, there was a substantial reduction in cardiomyocyte diameter, an improvement in cardiac function, a mitigation of mitochondrial fission and autophagy. Ndufb10 was markedly enriched in oxidative phosphorylation and downregulated in the SC group, while it was upregulated in the SE group. In the sh-ndufb10 group, mitochondrial fusion was suppressed; fission and autophagy were further facilitated; mitochondrial membrane potential, mPTP, and ROS levels increased; and TUNEL positive nuclei and apoptosis-related proteins showed significant upregulation. Overexpression of ndufb10 reversed pathological hypertrophy, mitochondrial autophagy, mitochondrial dysfunction, and cardiomyocyte apoptosis in vitro. Swimming exercise improves mitochondrial abnormalities and reduces cardiomyocyte hypertrophy through regulation of the ndufb10 in left ventricular hypertrophy.

SNS-032 is a synthetic compound that specifically inhibits cyclin-dependent kinases 2, 7 and 9. Its primary anticancer activity involves cell cycle arrest, which prevents tumor cell growth. However, there are limited reports on whether SNS-032 induces pyroptosis, a novel inflammation-mediated programmed cell death pathway in breast cancer (BC). The present study demonstrated that SNS-032 treatment decreased cell viability by inducing pyroptosis in BC cells. Typical morphological indications of pyroptosis were observed, including cell swelling and destruction of cell membrane integrity, leading the release of adenosine 5'-triphosphate and lactate dehydrogenase. Furthermore, the expression of caspase-3, the N terminus of gasdermin E (GSDME) and B-cell lymphoma-2 (BCL-2)-associated X protein increased, whereas expression of BCL-2 decreased. In addition, Z-DEVD-FMK, a specific caspase-3 inhibitor, markedly alleviated pyroptosis triggered by SNS-032. These findings suggested that SNS-032 induced caspase-3/GSDME-dependent pyroptosis. Furthermore, the present study demonstrated that decitabine (DAC), a DNA methyltransferase inhibitor, upregulated the expression of GSDME protein and enhanced SNS-032-induced caspase-3/GSDME-dependent pyroptosis in BC cells. In conclusion, these results suggest that caspase-3/GSDME-induced pyroptosis can be facilitated by SNS-032 treatment in BC cells, and DAC has the potential to enhance SNS-032-induced pyroptosis by increasing GSDME expression. This mechanistic insight indicates that SNS-032 is a promising therapeutic agent for BC treatment.

MicroRNA-126 (miR-126) has emerged as one of the most extensively studied microRNAs in the context of human diseases, particularly in vascular disorders and cancer. Its high degree of conservation across vertebrates underscores its evolutionary significance and essential functional roles. Extensive research has been devoted to elucidating the molecular mechanisms through which miR-126 modulates key physiological and pathological processes, including angiogenesis, immune response, inflammation, tumor growth, and metastasis. Furthermore, miR-126 plays a causal role in the pathogenesis of various diseases, serving as potential biomarkers for disease prediction, diagnosis, prognosis and drug response, as well as a promising therapeutic target. In this review, we synthesize findings from 283 articles, focusing on the roles of miR-126 in critical biological processes such as cell development, survival, cycle regulation, proliferation, migration, invasion, communication, and metabolism. Additionally, miR-126 represents a promising candidate for miRNA-based therapeutic strategies. A comprehensive understanding and evaluation of miR-126 are crucial for advancing its clinical applications and therapeutic potential.

Delayed tooth extraction socket (TES) healing can cause failure of subsequent oral implantation and increase socioeconomic burden on patients. Excessive amounts of M1 macrophages, apoptotic neutrophils (ANs), and neutrophil extracellular traps (NETs) impair alveolar bone regeneration during TES healing. In the present study, we first discovered that conditioned medium (CM) collected from berberine-treated human bone marrow mesenchymal stem cells (BBR-HB-CM) accelerated TES healing. BBR-HB-CM contained bioactive materials that promoted the polarization of macrophages from M1 to M2, impeded the formation of ANs and NETs, and modulated M2 macrophage efferocytosis in vivo and in vitro. Mechanistically, BBR-HB-CM promoted bone formation by inhibiting macrophage-myofibroblast transition and reprogrammed macrophage polarization through p85/AKT/mTOR pathway-dependent autophagy. The 3-methyladenine abolished the therapeutic effects of BBR-HB-CM. Further studies revealed that BBR-HB-CM accelerated TES healing in rats with type 2 diabetes mellitus. Overall, our results demonstrated that BBR-HB-CM had high potential to promote rapid TES healing.

Cadmium is a widely distributed heavy metal found in the environment that poses serious hazards to human health. Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, exhibited antioxidant, antiapoptotic, and anti-inflammatory properties. Our data assessed the effect of DAPA against Cd-triggered renal and testicular impairment in rats, as well as the underlying mechanisms. Cd (30 mg/kg) and DAPA (5 and 10 mg/kg) were administrated by oral gavage to rats and continued for 21 days. DAPA attenuated Cd-triggered renal and testicular injury as shown by diminishing serum creatinine, BUN, and urinary total protein concentration in addition to increasing creatinine clearance, urinary creatinine, and serum testosterone. Moreover, it diminished renal and testicular histopathological alterations induced by Cd. DAPA stimulated the impaired autophagy flux as seen by significantly elevating the p-AMPK/total AMPK, decreasing p-mTOR/total mTOR ratios, and diminishing p62 & LC3 protein levels. Additionally, DAPA significantly lowered MDA content, increased GSH level and SOD activity. Moreover, it augmented the cytoprotective Nrf2/HO-1 signaling pathway. Furthermore, it attenuated renal and testicular apoptotic cell death via decreasing caspase-3 expression. Conclusion: Boosting autophagic events and combating oxidative stress and apoptosis by DAPA were engaged in alleviating Cd-induced renal and testicular impairment. This was accomplished by modulating the AMPK/mTOR and enhancing the Nrf2/HO-1 pathways.

Blueberries are a rich source of anthocyanins, which have been established to have multiple beneficial properties. However, the structure of anthocyanin monomers is unstable and their bioavailability is low. To date, whereas functional studies on anthocyanins have focused mainly on the effects of their monomers on liver and kidney, few have examined the interventional effects on pulmonary fibrosis.

In this study, we combined malvidin-3-O-galactoside (M3G)1 derived from blueberries with pectin (PEC)2 to form an anthocyanin-pectin complex (M3G-PEC),3 the anti-fibrotic effects of which were examined by administering to mice with modeled pulmonary fibrosis induced by silica particles (SP).4 METHODS: To evaluate the therapeutic effects and mechanisms of action of M3G-PEC with respect to the progression of pulmonary fibrosis, we measured autophagy- and apoptosis-related indices in C57BL/6 mice and mouse alveolar macrophage cell line (MH-S).5 RESULTS: The results of in vivo and in vitro studies revealed that M3G-PEC can alleviate the degree of pulmonary fibrosis, enhances the expression of Microtubule-associated protein light chain 3 (LC3),6 PTEN-inducible putative kinase 1 (PINK1),7 Parkin and B-cell lymphoma-2 (BCL-2),8 and causes the down-regulation of Caspase-3, P62, p-mammalian target of rapamyein (p-mTOR),9 phosphorylated protein kinase B (p-Akt)10 and Bax. And then, M3G-PEC contributes to maintaining a steady mitochondrial membrane potential and reduces the release of cytochrome c (Cyt-C)11 in cells.

Collectively, these findings indicate that M3G-PEC can preserve the bioactivity of anthocyanins and effectively enhance their bioavailability. Moreover, by regulating the BECN-1/Akt/mTOR pathway, M3G-PEC can influence the progression of silica-induced pulmonary fibrosis.

Begomoviruses are a group of single stranded DNA plant viruses exclusively transmitted by the sweet potato whitefly Bemisia tabaci in a persistent, circulative manner. After acquisition from plant phloem, this group of viruses circulate and are retained within the whitefly, interacting with tissues, cells and molecular pathways for maintaining the safety of the infective intact virions, by exploiting cellular mechanisms and avoiding degradation by the insect immune responses. During retention, the virions are internalized in the midgut cells, exit and spend hours-days in the hemolymph and cross into salivary gland cells, before transmission. Destroying this group of viruses by the insect immune system seems inefficient for the most part, by examining their very efficient transmission. Thus, within the various sites along the transmission pathway especially in the midgut, it is thought that the immune system with its various layers is activated for avoiding the damage caused by the viruses on one hand, and for ensuring their safe circulation and transmission on the other hand. Begomoviruses have evolved mechanisms for counteracting and exploiting the activated immune system for their safe translocation within the whitefly. In this review, we discuss the various levels of immunity activated against begomoviruses in B. tabaci, taking other pathogen-vector systems as examples and reflecting relevant components on the interactions between B. tabaci and Begomoviruses.

Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. The mechanisms orchestrating such an infection course remain to be elucidated. AMP-activated protein kinase (AMPK) is a pivotal cellular sensor for maintaining metabolic homeostasis. Here, we show that AMPK is activated in response to HEV infection and is associated with mitochondrial damage and ATP deficiency. AMPK activation, in turn, inhibits HEV replication. Mechanistic studies reveal that AMPK activation triggers the expression of interferon (IFN)-stimulated genes that possess antiviral properties. In parallel, AMPK inhibits autophagosome accumulation to exert antiviral effects. Interestingly, AMPK activation also suppresses the inflammatory response triggered by HEV infection. Consistently, AMPK activation simultaneously exerts anti-inflammatory and antiviral effects in a coculture system of HEV-infected liver cells with macrophages. These findings pave the way for the development of AMPK-targeted therapeutics to treat hepatitis E.

Triclosan (TCS) is a highly effective broad-spectrum antibacterial agent; however, the specific roles of TCS in oocyte maturation remain poorly understood. This research investigated the influence of TCS on biologically active processes during the in vitro maturation of porcine oocytes. Our results demonstrated that TCS significantly decreased the maturation rate of porcine oocytes in a concentration-dependent manner and impaired cumulus expansion. These detrimental effects were mediated by the disruption of mitochondrial function and distribution, leading to oxidative stress characterized by an accumulation of reactive oxygen species (ROS), a decrease in the expression of the antioxidant enzymes SOD2 and GSH, reduced ATP production, and a loss of mitochondrial membrane potential (ΔΨm). We also observed interference with endoplasmic reticulum (ER) distribution, disturbances in Ca2+ homeostasis, and fluctuations in ER stress, as evidenced by reduced expression of ER stress-related proteins. Furthermore, TCS exposure induced autophagy, as indicated by the levels of SQSTM1 (P62) and LC3-II. Additionally, TCS increased apoptosis rates, corresponding with a downregulation of Bcl-2 expression. Collectively, our findings suggest that exposure to TCS can impair cytoplasmic function, thereby affecting oocyte quality.

Myocardial ischemia-reperfusion (I/R) injury is a multifaceted process observed in patients with coronary artery disease when blood flow is restored to the heart tissue following ischemia-induced damage. Cardiomyocyte cell death, particularly through apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, is pivotal in myocardial I/R injury. Preventing cell death during the process of I/R is vital for improving ischemic cardiomyopathy. These multiple forms of cell death can occur simultaneously, interact with each other, and contribute to the complexity of myocardial I/R injury. In this review, we aim to provide a comprehensive summary of the key molecular mechanisms and regulatory patterns involved in these five types of cell death in myocardial I/R injury. We will also discuss the crosstalk and intricate interactions among these mechanisms, highlighting the interplay between different types of cell death. Furthermore, we will explore specific molecules or targets that participate in different cell death pathways and elucidate their mechanisms of action. It is important to note that manipulating the molecules or targets involved in distinct cell death processes may have a significant impact on reducing myocardial I/R injury. By enhancing researchers' understanding of the mechanisms and interactions among different types of cell death in myocardial I/R injury, this review aims to pave the way for the development of novel interventions for cardio-protection in patients affected by myocardial I/R injury.

The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.

In most types of erectile dysfunction, particularly in advanced stages, typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis. However, the current treatment methods have shown limited success in reversing these pathologic changes. Recent research has revealed that changes in autophagy levels, along with alterations in apoptosis and fibrosis-related proteins, are linked to the progression of erectile dysfunction, suggesting a significant association. Autophagy, known to significantly affect cell fate and tissue fibrosis, is currently being explored as a potential treatment modality for erectile dysfunction. However, these present studies are still in their nascent stage, and there are limited experimental data available. This review analyzes erectile dysfunction from a pathological perspective. It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum. This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction, thus encouraging further investigation among researchers in this area.

Colorectal cancer (CRC) is one of the most common types of cancer with high incidence and mortality. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is overexpressed in CRC. This study aims to explore the role of ERO1L in CRC progression and evaluate the anti-tumor efficacy of the combination treatment of ERO1L inhibition with endoplasmic reticulum (ER) stress-inducing therapies. Herein, we found that ERO1L was elevated in CRC cell lines and patients. ER stress upregulated the expression of ERO1L, and ERO1L deficiency induced ER stress in CRC. ERO1L knockdown increased the susceptibility of CRC cells to ER stress. ERO1L contributed to the malignant phenotypes of CRC cells. Inhibition of ERO1L induced autophagy and caspase-dependent apoptosis by the induction of ER stress in CRC cells. Mechanically, the ERK1/2 pathway was involved in ERO1L knockdown-mediated apoptosis and autophagy. Combination treatment of ERO1L inhibition with ER stress-inducing agents, such as unfolded protein response (UPR)-targeting inhibitors and proteasome inhibitors, demonstrated enhanced anti-tumor capacity. In conclusion, ERO1L is overexpressed in CRC, and ERO1L deficiency induces apoptosis and autophagy via ER stress. ERO1L inhibition combined with ER stress-inducing therapies exhibits more effective anti-tumor activity against CRC. ERO1L may serve as a biomarker and therapeutic target for CRC treatment.

Despite multiple diagnostic and therapeutic advances, including surgery, radiation therapy, and chemotherapy, cancer preserved its spot as a global health concern. Prompt cancer diagnosis, treatment, and prognosis depend on the discovery of new biomarkers and therapeutic strategies. Circular RNAs (circRNAs) are considered as a stable, conserved, abundant, and varied group of RNA molecules that perform multiple roles such as gene regulation. There is evidence that circRNAs interact with RNA-binding proteins, especially capturing miRNAs. An extensive amount of research has presented the substantial contribution of circRNAs in various types of cancer. To fully understand the linkage between circRNAs and cancer growth as a consequence of various cell death processes, including autophagy, ferroptosis, and apoptosis, more research is necessary. The expression of circRNAs could be controlled to limit the occurrence and growth of cancer, providing a more encouraging method of cancer treatment. Consequently, it is critical to understand how circRNAs affect various forms of cancer cell death and evaluate whether circRNAs could be used as targets to induce tumor death and increase the efficacy of chemotherapy. The current study aims to review and comprehend the effects that circular RNAs exert on cell apoptosis, autophagy, and ferroptosis in cancer to investigate potential cancer treatment targets.

Autophagosome cancer vaccines can promote cross-presentation of multiple tumour antigens and induce cross-reactive T cell responses. However, so far, there is no effective method for obtaining a highly immunogenic autophagosomal cancer vaccine because autophagosomes, once formed, quickly fuse with lysosomes and cannot easily escape from cells. Here we report a functional Ti2NX nanodot that caps the autophagosome membrane lipid phosphatidylinositol-4-phosphate, blocking the fusion of autophagosomes with lysosomes and producing stable nanodot-coated autophagosomes in tumours. The formed nanodot-coated autophagosomes can escape from cancer cells to lymph nodes, where they activate tumour-specific T cells. We show that our approach reduces tumour burden and provide long-term immune surveillance protection for cured mice. This work provides a method for the direct formation of personalized autophagosome-based cancer vaccines in vivo, offering a promising strategy for tumour treatment.

Monosodium glutamate (MSG) is one of the most commonly used food additives, known for its adverse health effects. Alogliptin (ALO) is a highly selective dipeptidyl peptidase-4 inhibitor, but its role in male reproductive function remains debated. The study was designed to evaluate and compare the potential of ALO in mitigating MSG-induced testicular toxicity in juvenile and adult male rats. Juvenile and adult male rats were treated with either MSG or pretreated with ALO before MSG administration. The rats then received ALO and MSG concurrently for 28 days. Testicular tissues were isolated and subjected to histo-biochemical and molecular assessments. Our results demonstrated that ALO reversed MSG-induced testicular injury, as evidenced by the restoration of reproductive hormone balance (increased serum luteinizing hormone and testosterone concentrations), suppression of oxidative stress injury (decreased testicular malondialdehyde, increased superoxide dismutase activity, and minimal 8-hydroxy-2'-deoxyguanosine immunoreactivity), inflammation (reduced testicular tumor necrosis factor-alpha levels), and fibrosis (decreased testicular collagen fiber deposition). Additionally, ALO impeded apoptosis and activated autophagy by decreasing caspase-3 activity, stimulating the AMPK/mTOR pathway, downregulating Bax and SQSTM-1/p62 expression, upregulating Bcl2 and Beclin 1, promoting testicular proliferation (increased number of proliferating cell nuclear antigen-positive cells in the testis), restoring glycogen content in the testis (mild to moderate periodic acid-Schiff reaction), and preserving testicular architecture. MSG induced more severe adverse testicular effects in juvenile rats, while ALO pretreatment was more protective in adult rats. ALO's anti-inflammatory, antioxidant, antiapoptotic, pro-autophagic, antifibrotic, and proliferative actions in the testis suggest its promising potential for combating male reproductive dysfunction.