Lung cancer exhibits the highest incidence and mortality rates among cancers globally, with a five-year overall survival rate alarmingly below 20%. Targeting autophagy, though a controversial therapeutic strategy, is extensively employed in clinical practice. Current research is actively pursuing various therapeutic strategies using small molecules to exploit the dual function of autophagy. Nevertheless, the pivotal question of enhancing or inhibiting autophagy in cancer therapy merits further attention. This review aims to provide a comprehensive overview of the mechanisms of autophagy in lung cancer. It also explores recent advances in targeting cytotoxic autophagy and inhibiting protective autophagy with small molecules to induce cell death in lung cancer cells. Notably, most autophagy-targeting drugs, primarily natural small molecules, have demonstrated that activating cytotoxic autophagy effectively induces cell death in lung cancer, as opposed to inhibiting protective autophagy. These insights contribute to identifying druggable targets and drug candidates for potential autophagy-related lung cancer therapies, offering promising approaches to combat this disease.

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Objective To investigate the effects and related mechanisms of mitochondrial-derived peptide MOTS-c on glycochenodeoxycholic acid (GCDCA)-induced injury in human hepatocytes (THLE-3 cells). Methods THLE-3 cells were cultured in vitro and treated with different concentrations of GCDCA and MOTS-c. The optimal concentrations of GCDCA and MOTS-c were determined by cell counting kit (CCK)-8 method. Subsequently, THLE-3 cells were treated or pre-treated with GCDCA (200 µmol/L), MOTS-c (15, 30, 60 µmol/L), the multidrug resistance protein 2 (MRP2) inhibitor Probenecid (500 µmol/L), and the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385 (10 µmol/L). Cell proliferation was assessed by CCK-8 method. Lactate dehydrogenase (LDH) levels in the culture medium were measured by biochemical method. Cell apoptosis rates were determined by flow cytometry. MRP2 messenger RNA (mRNA) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). MRP2 and Nrf2 protein expression levels were analyzed by Western blotting. Results As the concentration of GCDCA increased, the proliferation activity of THLE-3 cells gradually decreased, while LDH activity in the culture medium and apoptosis levels increased, and the expression levels of MRP2 in the cells decreased (all P<0.05). Treatment with 30 and 60 µmol/L MOTS-c significantly enhanced the proliferation activity of THLE-3 cells exposed to GCDCA, upregulated the expression of MRP2 and Nrf2, and reduced LDH activity and apoptosis levels (all P<0.05). Co-treatment with Probenecid partially reversed the protective effects of MOTS-c on GCDCA-induced THLE-3 cells injury, while co-treatment with ML385 partially inhibited the induction of MRP2 expression by MOTS-c in THLE-3 cells exposed to GCDCA. Conclusions MOTS-c may alleviate GCDCA-induced injury in human hepatocytes (THLE-3 cells), and its mechanism may be related to the upregulation of MRP2 expression mediated by Nrf2.

Iron overload is strongly associated with heart disease. Ferroptosis is a new form of regulated cell death indicated in cardiac ischemia-reperfusion (I/R) injury. However, the specific molecular mechanism of myocardial injury caused by iron overload in the heart is still unclear, and the involvement of ferroptosis in iron overload-induced myocardial injury is not fully understood. In this study, we observed that ferroptosis participated in developing of iron overload and I/R-induced cardiomyopathy. Mechanistically, we discovered that Parkin inhibited iron overload-induced ferroptosis in cardiomyocytes by promoting the ubiquitination of long-chain acyl-CoA synthetase 4 (ACSL4), a crucial protein involved in ferroptosis-related lipid metabolism pathways. Additionally, we identified p53 as a transcription factor that transcriptionally suppressed Parkin expression in iron-overloaded cardiomyocytes, thereby regulating iron overload-induced ferroptosis. In animal studies, cardiac-specific Parkin knockout mice (Myh6-CreER ^T2 /Parkin ^fl/fl ) fed a high-iron diet presented more severe myocardial damage, and the high iron levels exacerbated myocardial I/R injury. However, the ferroptosis inhibitor Fer-1 significantly suppressed iron overload-induced ferroptosis and myocardial I/R injury. Moreover, Parkin effectively protected against impaired mitochondrial function and prevented iron overload-induced mitochondrial lipid peroxidation. These findings unveil a novel regulatory pathway involving p53-Parkin-ACSL4 in heart disease by inhibiting of ferroptosis.

Local anesthetics (LAs), such as articaine (AT), exhibit limited efficacy in inflammatory environments, which constitutes a significant limitation in their clinical application within oral medicine. In our prior research, we developed AT-17, which demonstrated effective properties in chronic inflammatory conditions and appears to function as a novel oral LA that could address this challenge. In the present study, we further elucidated the beneficial effects of AT-17 in acute inflammation, particularly in oral acute inflammation, where mitochondrial-related apoptosis played a crucial role. Our findings indicated that AT-17 effectively inhibited lipopolysaccharide (LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro. This process involved the inhibition of mitochondrial reactive oxygen species (mtROS) production and the subsequent activation of the NRF2 pathway. Most notably, improvements in mitochondria-related apoptosis were key contributors to AT-17's inhibition of voltage-gated sodium channels. Additionally, AT-17 was shown to reduce mtROS production in nerve cells through the Na⁺/NCLX/ETC signaling axis. In conclusion, we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis. This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.

Objective: To investigate the role and mechanism of PGC-1 α-mediated mitochondrial biosynthesis in AMP-activated protein kinase (AMPK) agonist anti-hepatic ischemia-reperfusion injury (HIRI) ． Methods : SD rats were randomly divided into Control group，HIRI group，HIRI + AICAR group，HIRI + SR-18292 group and HIRI + AICAR + SR-18292 group，with 8 rats in each group．The rats were intraperitoneally injected with AICAR (500 mg / kg) or SR-18292 (32 mg / kg) before operation，and then the HIRI model was established by non-invasive vascular clamp clamping method．The samples were taken 24 hours after reperfusion．The contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and the levels of malondialdehyde (MDA) ，superoxide dis- mutase (SOD) and adenosine triphosphate (ATP) in liver tissue were detected．HE staining was used to observe the pathological changes of liver tissue．The level of reactive oxygen species (ROS) and the changes of mitochondri- al membrane potential in liver tissue were detected by fluorescence probe．The copy number of mitochondrial DNA (mtDNA) and the mitochondrial biosynthesis-related genes PGC-1 α, NRF1，TFAM，UQCRC2 and other mRNA ex- pression levels were detected by qRT-PCR. Western blot was used to detect the protein expression levels of AMPKα, p-AMPKα , mTOR , p-mTOR , PGC-1α and TFAM in liver tissue． Results : Compared with the control group，the levels of ALT and AST in serum and MDA and ROS in liver tissue of rats in HIRI group increased，while the levels of SOD and ATP decreased ( all P ＜0. 05) ．At the same time，the mtDNA copy number，mitochondrial membrane potential and the mRNA expression levels of PGC-1α , NRF1，TFAM，and UQCRC2 in liver tissues de- creased，and the protein ratio of p-AMPKα/AMPKα and the protein expression levels of PGC-1α and TFAM de- creased．The ratio of p-mTOR/ mTOR protein increased (both P＜0. 05) ．Compared with HIRI group，the levels of ALT and AST in serum and MDA and ROS in liver tissue of rats in HIRI + AICAR group decreased，while the levels of SOD and ATP increased ( all P ＜0. 05) ．At the same time，the mtDNA copy number，mitochondrial membrane potential and the mRNA expression levels of PGC-1α , NRF1，TFAM，and UQCRC2 in liver tissue increased，and the protein ratio of p-AMPKα/AMPKα and the protein expression levels of PGC-1α and TFAM increased．The ratio of p-mTOR/ mTOR protein decreased (both P＜0. 05) ．However，combined with SR-18292 intervention，the protective effect of AICAR on liver tissue of HIRI rats was significantly reversed． Conclusion PGC-1α mediated mitochondri- al biosynthesis is involved in the regulation of AMPK agonist-mediated protective effect of HIRI，and its mechanism may be related to the activation of AMPK/ mTOR signaling pathway．

Objective:To investigate the improvement of the inhibition ability and brain activity characteristics in female methamphetamine addicts by rehabilitation exercise training. Method:Fifty-two females were methamphetamine addicts in abstinence were randomly divided into the inter-vention group and control group.All groups were completed the stop signal task and the desire for speed ques-tionnaire both before and after the intervention.Reaction times,the scores of the desire for speed question-naire and the amplitude of P3 were recorded and analyzed. Result:Compared with the control group,the stop signal response time was significantly decreased(P=0.003),the induced P3 amplitude was significantly increased(P=0.031),and the score of craving was signifi-cantly decreased in the intervention group(P=0.012)after rehabilitation exercise training. Conclusion:Rehabilitation exercise training for female methamphetamine addicts in the period of educational correction can effectively improve their inhibition ability and promote the reduction of amphetamine craving.

Frailty is a geriatric syndrome associated with aging, which is characterized by a decrease in the ability to stress and maintain homeostasis after the loss of physiological reserve function, resulting in an increased risk of falls, disability, and even death.Cognitive impairment is a disorder of cognitive function due to a variety of causes, between normal aging and dementia.In the early stages, frailty is a certain reversibility.As the core of physical frailty, sarcopenia has been a research hotspot in recent years.With the deep research on sarcopenia, researchers have found that is closely related to cognitive disorder.Muscle-brain axis may play a role in sarcopenia and cognitive impairment.This article illustrates its possible mechanisms at the crossroad of sarcopenia and cognitive disorder, and to provide reference for exploring new targets for intervention of sarcopenia and cognitive impairment.

Objectives:To explore the antitumor effects of redox-responsive nanoparticles containing platinum(Ⅳ)—NP@Pt(Ⅳ) in ovarian cancer.Methods:Redox-responsive polymer carriers were synthesized. Polymer carriers and platinum(Ⅳ)—Pt(Ⅳ) can self-assemble into NP@Pt(Ⅳ). Inductively coupled plasma mass spectrometry was performed to detect the platinum release from NP@Pt(Ⅳ) in reducing environment and the platinum content in ovarian cancer cells ES2 treated with cisplatin, Pt(Ⅳ) and NP@Pt(Ⅳ). The proliferation ability of the ovarian cancer cells were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was assessed by flow cytometry. Collection of primary ovarian cancer tissues from patients with primary high-grade serous ovarian cancer who were surgically treated at the Cancer Hospital of the Chinese Academy of Medical Sciences from October to December 2022. The high-grade serous ovarian cancer patient-derived xenograft (PDX) mice were intravenously injected with Cy7.5 labeled NP@Pt(Ⅳ) followed by in vivo imaging system. Mice were treated with PBS, cisplatin and NP@Pt(Ⅳ). Tumor volume and weight were measured in each group. Necrosis, apoptosis and cell proliferation of tumor tissues were detected by hematoxylin-eosin (HE) staining, TUNEL fluorescence staining and Ki-67 immunohistochemistry staining. Body weight and HE staining of heart, liver, spleen, lung and kidney of mice in each group were measured.Results:The platinum release of NP@Pt(Ⅳ) after 48 hours in reducing environment was 76.29%, which was significantly higher than that of 26.82% in non-reducing environment ( P<0.001). The platinum content in ES2 cells after 4 hours and 7 hours of treatment with NP@Pt(Ⅳ) (308.59, 553.15 ng/million cells) were significantly higher than those of Pt(Ⅳ) (100.21, 180.31 ng/million cells) and cisplatin (43.36, 50.36 ng/million cells, P＜0.05). The half inhibitory concentrations of NP@Pt(Ⅳ) in ovarian cancer cells ES2, A2780, A2780DDP were 1.39, 1.42 and 4.62 μmol/L, respectively, which were lower than those of Pt(IV) (2.89, 7.27, and 16.74 μmol/L) and cisplatin (5.21, 11.85, and 71.98 μmol/L). The apoptosis rate of ES2 cells treated with NP@Pt(Ⅳ) was (33.91±3.80)%, which was significantly higher than that of Pt(Ⅳ) [(16.28±2.41)%] and cisplatin [(15.01±1.17)%, P＜0.05]. In high-grade serous ovarian cancer PDX model, targeted accumulation of Cy7.5 labeled NP@Pt(Ⅳ) at tumor tissue could be observed. After the treatment, the tumor volume of mice in NP@Pt(IV) group was (130±98) mm 3, which was significantly lower than those in control group [(1 349±161) mm 3, P<0.001] and cisplatin group [(715±293) mm 3, P=0.026]. The tumor weight of mice in NP@Pt(IV) group was (0.17±0.09)g, which was significantly lower than those in control group [(1.55±0.11)g, P<0.001] and cisplatin group [(0.82±0.38)g, P=0.029]. The areas of tumor necrosis and apoptosis in mice treated with NP@Pt(Ⅳ) were higher than those in mice treated with cisplatin. Immunohistochemical staining revealed that there were low expressions of Ki-67 at tumor tissues of mice treated with NP@Pt(Ⅳ) compared with cisplatin. The change in body weight of mice in NP@Pt(Ⅳ) group was not significantly different from that of the control group [(18.56±2.04)g vs.(20.87±0.79)g, P=0.063]. Moreover, the major organs of the heart, liver, spleen, lung, and kidney were also normal by HE staining. Conclusion:Redox-responsive NP@Pt(Ⅳ), produced in this study can enhance the accumulation of cisplatin in ovarian cancer cells and improve the efficacy of ovarian cancer chemotherapy.