Cuproptosis in cancer: biological implications and therapeutic opportunities.

Cuproptosis, a newly identified copper (Cu)-dependent form of cell death, stands out due to its distinct mechanism that sets it apart from other known cell death pathways. The molecular underpinnings of cuproptosis involve the binding of Cu to lipoylated enzymes in the tricarboxylic acid cycle. This interaction triggers enzyme aggregation and proteotoxic stress, culminating in cell death. The specific mechanism of cuproptosis has yet to be fully elucidated. This newly recognized form of cell death has sparked numerous investigations into its role in tumorigenesis and cancer therapy. In this review, we summarized the current knowledge on Cu metabolism and its link to cancer. Furthermore, we delineated the molecular mechanisms of cuproptosis and summarized the roles of cuproptosis-related genes in cancer. Finally, we offered a comprehensive discussion of the most recent advancements in Cu ionophores and nanoparticle delivery systems that utilize cuproptosis as a cutting-edge strategy for cancer treatment.

Montelukast prevents mice against carbon tetrachloride- and methionine-choline deficient diet-induced liver fibrosis: Reducing hepatic stellate cell activation and inflammation.

AIMS: Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1) that protects against inflammation and oxidative stress. However, the function of montelukast in liver fibrosis remains unknown. In this study, we examined whether the pharmacological inhibition of CysLTR1 could protect mice against hepatic fibrosis. MATERIALS AND METHODS: Carbon tetrachloride (CCl4) and methionine-choline deficient (MCD) diet models were used in this study. The expression of CysLTR1 in liver were detected by RT-qPCR and Western blot analysis. Liver hydroxyproline levels, fibrotic genes expression, serum biochemical indexes and inflammatory factors were used to evaluate the effect of montelukast on liver fibrosis, injury, and inflammation. In vitro, we used the RT-qPCR and Western blot analysis to assess CysLTR1 in mouse primary hepatic stellate cell (HSC) and human LX-2 cell line. The role of montelukast on HSC activation and the underlying mechaisms were determined using RT-qPCR analysis, Western blot and immunostaining assays. KEY FINDINGS: Chronic stimulation from CCl4 and MCD diet upregulated the mRNA and protein levels of CysLTR1 in the liver. Pharmacological inhibition of CysLTR1 by montelukast ameliorated liver inflammation and fibrosis in both models. Mechanistically, montelukast suppressed HSC activation by targeting the TGFß/Smad pathway in vitro. The hepatoprotective effect of montelukast was also associated with reduced liver injury and inflammation. SIGNIFICANCE: Montelukast suppressed CCl4- and MCD-induced chronic hepatic inflammation and liver fibrosis. CysLTR1 might be a therapeutic target for treating liver fibrosis.

Associations between ambient fine particulate (PM2.5) exposure and cardiovascular disease: findings from the China Health and Retirement Longitudinal Study (CHARLS).

The evidence regarding the association between long-term fine particulate (PM2.5) exposure and cardiovascular disease (CVD) in developing countries is limited. This study investigated the association between long-term exposure to PM2.5 and the prevalence of CVD among middle-aged and older adults. A total of 13,484 adults ≥ 45 years of age were surveyed in China, and logistic regression models were used to examine the association between PM2.5 and the prevalence of CVD. Furthermore, stratified analyses were conducted to explore potential effect modifiers. In addition, the burden of CVD attributable to PM2.5 was estimated. The analyses revealed that PM2.5 was associated with CVD, with an adjusted odds ratio (OR) of 1.18 (95% confidence interval [CI]: 1.12, 1.26) for each 10 µg/m3 increment in ambient PM2.5. Stratified analyses found that the elderly may be a vulnerable population. It was further estimated that approximately 20.27% (95% CI: 11.86%, 29.96%) of CVD cases could be attributable to PM2.5. This nationwide study confirmed that long-term exposure to PM2.5 was associated with an increased prevalence of CVD in China.

Klotho as Potential Autophagy Regulator and Therapeutic Target.

The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer's disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer's disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.

Roles of nuclear receptors in hepatic stellate cells.

Introduction: Hepatic stellate cells (HSCs) are essential for physiological homeostasis of the liver extracellular matrix (ECM). Excessive transdifferentiation of HSC from a quiescent to an activated phenotype contributes to disrupt this balance and can lead to liver fibrosis. Accumulating evidence has suggested that nuclear receptors (NRs) are involved in the regulation of HSC activation, proliferation, and function. Therefore, these NRs may be therapeutic targets to balance ECM homeostasis and inhibit HSC activation in liver fibrosis.Areas covered: In this review, the authors summarized the recent progress in the understanding of the regulatory role of NRs in HSCs and their potential as drug targets in liver fibrosis.Expert opinion: NRs are still potential therapy targets for inhibiting HSCs activation and liver fibrosis. However, the development of NRs agonists or antagonists to inhibit HSCs requires fully consideration of systemic effects.

Fingolimod suppressed the chronic unpredictable mild stress-induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation.

Depression is a common aspect of the modern lifestyle, and most patients are recalcitrant to the current antidepressants. Fingolimod (FTY720), a sphingosine analogue approved for the treatment of multiple sclerosis, has a significant neuroprotective effect on the central nervous system. The aim of this study was to determine the potential therapeutic effect of FTY720 on the behavior and cognitive function of rats exposed daily to chronic unpredictable mild stress (CUMS), and elucidate the underlying mechanisms. The 42-day CUMS modeling induced depression-like behavior as indicated by the scores of sugar water preference, forced swimming, open field and Morris water maze tests. Mechanistically, CUMS caused significant damage to the hippocampal neurons, increased inflammation and oxidative stress, activated the NF-κB/NLRP3 axis, and skewed microglial polarization to the M1 phenotype. FTY720 not only alleviated neuronal damage and oxidative stress, but also improved the depression-like behavior and cognitive function of the rats. It also inhibited NF-κB activation and blocked NLRP3 inflammasome assembly by down-regulating NLRP3, ACS and caspase-1. Furthermore, FTY720 inhibited the microglial M1 polarization markers iNOS and CD16, and promoted the M2 markers Arg-1 and CD206. This in turn reduced the levels of TNF-α, IL-6 and IL-1ß, and increased that of IL-10 in the hippocampus. In conclusion, FTY720 protects hippocampal neurons from stress-induced damage and alleviates depressive symptoms by inhibiting neuroinflammation. Our study provides a theoretical basis for S1P receptor modulation in treating depression.

Alpha-lipoic acid attenuates cardiac hypertrophy via inhibition of C/EBPß activation.

Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in numerous cardiovascular disease models. However, the pharmacological property of ALA on cardiac hypertrophy has not been well investigated. The present study was carried out to determine whether ALA exerts a direct anti-hypertrophic effect in cultured cardiomyocytes and whether it modifies the hypertrophic process in vivo. Furthermore, we determined the potential underlying mechanisms for these actions. Treatment of cardiomyocytes with phenylephrine (PE) for 24 h produced a marked hypertrophic effect as evidenced by significantly increased in ANF and BNP mRNA levels, as well as cell surface area. These effects were attenuated by ALA in a concentration-dependent manner with a complete inhibition of hypertrophy at a concentration of 100 µg/mL. PE-induced cardiomyocyte hypertrophy was associated with increased mRNA and protein levels of C/EBPß, which were inhibited by pretreatment with ALA. However, when cardiomyocytes were co-transfected with C/EBPß, ALA failed to inhibit hypertrophic responses. Upregulation of C/EBPß expression was also evident in rats subjected to 4 weeks of coronary artery ligation (CAL). However, rats treated with ALA demonstrated markedly reduced hemodynamic and hypertrophic responses, which were accompanied by attenuation of upregulation of C/EBPß. Taken together, our results revealed a robust anti-hypertrophic and anti-remodeling effect of ALA, which is mediated by inhibition of C/EBPß activation.

C/EBPß knockdown protects cardiomyocytes from hypertrophy via inhibition of p65-NFκB.

C/EBPß, a member of the bHLH gene family of DNA-binding transcription factors, has been indicated as a central signal in physiologic hypertrophy. However, the role of C/EBPß in pathological cardiac hypertrophy remains to be elucidated. In this study, we revealed that C/EBPß is involved in cardiac hypertrophy, the expression of C/EBPß were significantly increased in response to hypertrophic stimulation in vitro and in vivo. C/EBPß knockdown inhibited PE-induced cardiac hypertrophy, and diminished the nuclear translocation and DNA binding activity of p65-NFκB. These results suggested that C/EBPß knockdown protected cardiomyocytes from hypertrophy, which may be attributed to inhibition of NFκB-dependent transcriptional activity. These findings shed new light on the understanding of C/EBPß-related cardiomyopathy, and suggest the potential application of C/EBPß inhibitors in cardiac hypertrophy.