Boosting synergism of chemo- and immuno-therapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

Resveratrol promotes the survival and neuronal differentiation of hypoxia-conditioned neuronal progenitor cells in rats with cerebral ischemia / 医学前沿

Hypoxia conditioning could increase the survival of transplanted neuronal progenitor cells (NPCs) in rats with cerebral ischemia but could also hinder neuronal differentiation partly by suppressing mitochondrial metabolism. In this work, the mitochondrial metabolism of hypoxia-conditioned NPCs (hcNPCs) was upregulated via the additional administration of resveratrol, an herbal compound, to resolve the limitation of hypoxia conditioning on neuronal differentiation. Resveratrol was first applied during the in vitro neuronal differentiation of hcNPCs and concurrently promoted the differentiation, synaptogenesis, and functional development of neurons derived from hcNPCs and restored the mitochondrial metabolism. Furthermore, this herbal compound was used as an adjuvant during hcNPC transplantation in a photothrombotic stroke rat model. Resveratrol promoted neuronal differentiation and increased the long-term survival of transplanted hcNPCs. 18-fluorine fluorodeoxyglucose positron emission tomography and rotarod test showed that resveratrol and hcNPC transplantation synergistically improved the neurological and metabolic recovery of stroke rats. In conclusion, resveratrol promoted the neuronal differentiation and therapeutic efficiency of hcNPCs in stroke rats via restoring mitochondrial metabolism. This work suggested a novel approach to promote the clinical translation of NPC transplantation therapy.

Association between height-related polymorphism rs17081935 and reduced handgrip strength in relation to status of atherosclerosis: a cross-sectional study

BACKGROUND@#Aging is a process that increases oxidative stress. Increased oxidative stress leads to the development of atherosclerosis and mitochondrial dysfunction. Mitochondria contribute to energy production that might have a beneficial influence on maintaining muscle strength. Therefore, the height-related single nucleotide polymorphism (SNP) rs17081935, which is also reported to be associated with mitochondrial metabolism, might be associated with reduced muscle strength and this association might be affected by atherosclerosis status. To clarify those associations, a cross-sectional study of 1374 elderly Japanese individuals aged 60-89 years was conducted.@*METHODS@#Logistic regression was used to clarify the association between rs17081935 and reduced handgrip strength. Since atherosclerosis might affect handgrip strength, participants were stratified by atherosclerosis status. Reduced handgrip strength was defined as being in the lowest quintile of handgrip strength (< 25.6 kg for men and < 16.1 kg for women).@*RESULTS@#No significant associations were found between a minor allele of rs17081935 and reduced handgrip strength among elderly participants without atherosclerosis. A significant inverse association was observed among elderly participants with atherosclerosis. After adjusting for known cardiovascular risk factors and height, the adjusted odd ratio (OR) and 95% confidence interval (CI) for reduced handgrip strength and a minor allele of rs17081935 were 1.13 (0.86, 1.43) for elderly participants without atherosclerosis and 0.55 (0.36, 0.86) for those with atherosclerosis, respectively.@*CONCLUSION@#A minor allele of the height-related SNP rs17081935 was significantly inversely associated with reduced handgrip strength among older individuals with atherosclerosis, but not among those without atherosclerosis.

Roles of SIRT2 in the tumorigenesis and development of hepatocellular carcinoma / 上海交通大学学报（医学版）

Silence information regulators (sirtuins) are highly conserved nicotinamide adenine dinucleotide (NAD+) dependent histone deacetylases, which play important roles in the process of aging, metabolism, apoptosis, gene transcription, and inflammation. There are seven kinds of sirtuins in mammals, SIRT1-SIRT7. These proteins have different subcellular localization and play diverse roles in metabolism. SIRT2, one of the members of sirtuins family, is mainly located in the cytoplasm and participates in the cell cycle control, oxidative stress and glycolipid metabolism. In addition, the expression level of SIRT2 has been widely associated with the development of cancers, including hepatocellular carcinoma. SIRT2 possesses a dual role in tumorigenesis, with both tumor-promoting and tumor-suppressing function. However, the mechanisms in which SIRT2 plays the roles in cancer are still controversial. In this review, the conflicting roles of SIRT2 in the tumorigenesis and development of hepatocellular carcinoma were mainly discussed.

Repression of SIRT5 is Involved in RIP140-mediated Metabolic Dysregulation in Cardiomyocytes / 中山大学学报(医学科学版)

[Objective]To investigate the effect of desuccinylase Sirtuin5 (SIRT5) on receptor-interacting protein 140 (RIP140)- mediated metabolic dysfunction in cardiomyocytes.[Methods]RIP140 was overexpressed by Adenovirus infection and SIRT5 was overexpressed by plasmid transfection. RIP140 and SIRT5 were knocked down by siRNA interference. The expression of RIP140 and SIRT5 were measured by qRT-PCR and western blot. The transcription levels of mitochondrial DNA-encoded genes were detected by qRT-PCR. Mitochondrial membrane potential was detected by tetramethylrhodamine ethyl ester(TMRE)fluorescence anl?ysis. Cellular oxygen consumption and ATP production were investigated by assay kits. All data are from at least three independent ex?periments.[Results]RIP140 overexpression significantly attenuated SIRT5 expression(P<0.05),whereas knockdown of endogenous RIP140 elevated SIRT5 expression(P<0.05)in cardiomyocytes. Superabundant RIP140 also induced hypersuccinylation of mitochon?drial proteins,suggesting RIP140 could repress the desuccinylase activity of SIRT5. Moreover,SIRT5 overexpression reversed RIP140-mediated mitochondrial dysfunction and energy metabolic impairment ,such as repression of mitochondrial DNA-encoded genes(P<0.05),decrease of mitochondrial membrane potential(P<0.05),as well as reduction of cellular oxygen consumption(P<0.05)and ATP production(P<0.05). Furthermore,the regulation of RIP140 on SIRT5 was dependent on the peroxisome proliferator-activated receptorα(PPARα)in cardiomyocytes.[Conclusion]RIP140 induces mitochondrial dysfunction and metabolic impairment through repression of SIRT5 in cardiomyocytes.

Regulação do metabolismo de glicose e ácido graxo no músculo esquelético durante exercício físico / Regulation of glucose and fatty acid metabolism in skeletal muscle during contraction

O ciclo glicose-ácido graxo explica a preferência do tecido muscular pelos ácidos graxos durante atividade moderada de longa duração. Em contraste, durante o exercício de alta intensidade, há aumento na disponibilidade e na taxa de oxidação de glicose. A produção de espécies reativas de oxigênio (EROs) durante a atividade muscular sugere que o balanço redox intracelular é importante na regulação do metabolismo de lipídios/carboidratos. As EROs diminuem a atividade do ciclo de Krebs e aumentam a atividade da proteína desacopladora mitocondrial. O efeito oposto é esperado durante a atividade moderada. Assim, as questões levantadas nesta revisão são: Por que o músculo esquelético utiliza preferencialmente os lipídios no estado basal e de atividade moderada? Por que o ciclo glicose-ácido graxo falha em exercer seus efeitos durante o exercício intenso? Como o músculo esquelético regula o metabolismo de lipídios e carboidratos em regime envolvendo o ciclo contração-relaxamento.

The glucose-fatty acid cycle explains the preference for fatty acid during moderate and long duration physical exercise. In contrast, there is a high glucose availability and oxidation rate in response to intense physical exercise. The reactive oxygen species (ROS) production during physical exercise suggests that the redox balance is important to regulate of lipids/carbohydrate metabolism. ROS reduces the activity of the Krebs cycle, and increases the activity of mitochondrial uncoupling proteins. The opposite effects happen during moderate physical activity. Thus, some issues is highlighted in the present review: Why does skeletal muscle prefer lipids in the basal and during moderate physical activity? Why does glucose-fatty acid fail to carry out their effects during intense physical exercise? How skeletal muscles regulate the lipids and carbohydrate metabolism during the contraction-relaxation cycle?.

Fuel-Stimulated Insulin Secretion Depends upon Mitochondria Activation and the Integration of Mitochondrial and Cytosolic Substrate Cycles

The pancreatic islet beta-cell is uniquely specialized to couple its metabolism and rates of insulin secretion with the levels of circulating nutrient fuels, with the mitochondrial playing a central regulatory role in this process. In the beta-cell, mitochondrial activation generates an integrated signal reflecting rates of oxidativephosphorylation, Kreb's cycle flux, and anaplerosis that ultimately determines the rate of insulin exocytosis. Mitochondrial activation can be regulated by proton leak and mediated by UCP2, and by alkalinization to utilize the pH gradient to drive substrate and ion transport. Converging lines of evidence support the hypothesis that substrate cycles driven by rates of Kreb's cycle flux and by anaplerosis play an integral role in coupling responsive changes in mitochondrial metabolism with insulin secretion. The components and mechanisms that account for the integrated signal of ATP production, substrate cycling, the regulation of cellular redox state, and the production of other secondary signaling intermediates are operative in both rodent and human islet beta-cells.