The pandemic tendency of obesity and its strong association with serious co-morbidities have elicited interest in the underlying mechanisms of these pathologies. Lipid homeostasis, closely involved in obesity, has been reported to be regulated by multiple pathways. mTORC1 is emerging as a critical regulator of lipid metabolism. Here, we describe that the consumption of soy isoflavones, with a structural similarity to that of estradiol, could mitigate obesity through an AKT/mTORC1 pathway. Fed with soy isoflavones, the diet-induced obesity (DIO) male rats exhibited decreased body weight, accompanied with suppressed lipogenesis and adipogenesis, as well as enhanced lipolysis and β‑oxidation. The phosphorylation of AKT and S6 were decreased after soy isoflavone treatment in vivo and in vitro, suggesting an inhibition effect of soy isoflavones on mTORC1 activity. Our study reveals a potential mechanism of soy isoflavones regulating lipid homeostasis, which will be important for obesity treatment.

We conducted a systematic review and meta-analysis of observational case-control studies to evaluate markers of oxidative stress in seminal plasma of patients with male infertility.

The high recurrence frequency of gliomas but deficiency of effective treatment and prevalent chemoresistance have elicited interests in exploring and developing new agents. Paris polyphyllins are monomers extracted from rhizome of Paris polyphylla var. yunnanensis. Here, we first reported that polyphyllin VII (PP7) exhibited cytotoxic effect on glioma cells. PP7 significantly suppressed the viability and induced cell death of U87-MG and U251 cells after 24 h, with the IC50 values 4.24 ± 0.87 μM and 2.17 ± 0.14 μM, respectively. Both apoptotic and autophagic processes were involved in the cytotoxic effect of PP7, as PP7 activated the Bcl2/Bax pathway and the inhibition of autophagy partly rescued the toxicity of PP7 in glioma cells. In addition, an inhibition of AKT/mTORC1 activity was found after PP7 administration, and it seemed that the overproduction of reactive oxygen species (ROS) was responsible for this effect. Namely, the removal of ROS by NAC treatment mitigated PP7-induced cell death, autophagy, and its effect on the AKT/mTORC1 signaling. Additionally, a combination assay of PP7 with temozolomide (TMZ), the most used chemotherapy for glioma patients, was performed resulting in synergism, while PP7 reduced TMZ resistance through inhibition of MGMT expression. Thus, our study reports PP7 as a potential agent for glioma treatment and reveals its underlying mechanisms of action.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

Obesity is a common metabolic disorder that increases the risk of many diseases, such as type II diabetes, hypertension, cardiovascular disease. Hypothalamus plays a very important role in the progression of obesity, and many studies reveal that hypothalamic injures are implicated in obesity processes. Here, we describe that the consumption of soy isoflavones, with a structural similarity to that of estradiol, could mitigate obesity through improving the hypothalamic inflammation and apoptosis, which are induced by oxidative stress. Also, our in vitro studies demonstrate that daidzein and genistein, common ingredients of soy isoflavones, could protect hypothalamic N42 cells against palmitic acid induced oxidative stress and apoptosis. Moreover, the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1-alpha), which plays a role in oxidative defense, is increased after soy isoflavone treatment in vivo and in vitro, suggesting an improved effect of soy isoflavones on hypothalamic antioxidant defense is mediated by PGC-1α. Our study reveals a potential mechanism of soy isoflavones regulating oxidative stress induced hypothalamic inflammation and cellular apoptosis, which will be important for obesity treatment.

Neuronal activity increases energy consumption and requires balanced production to maintain neuronal function. How activity is coupled to energy production remains incompletely understood. Here, we report that Rheb regulates mitochondrial tricarboxylic acid cycle flux of acetyl-CoA by activating pyruvate dehydrogenase (PDH) to increase ATP production. Rheb is induced by synaptic activity and lactate and dynamically trafficked to the mitochondrial matrix through its interaction with Tom20. Mitochondria-localized Rheb protein is required for activity-induced PDH activation and ATP production. Cell-type-specific gain- and loss-of-function genetic models for Rheb reveal reciprocal changes in PDH phosphorylation/activity, acetyl-CoA, and ATP that are not evident with genetic or pharmacological manipulations of mTORC1. Mechanistically, Rheb physically associates with PDH phosphatase (PDP), enhancing its activity and association with the catalytic E1α-subunit of PDH to reduce PDH phosphorylation and increase its activity. Findings identify Rheb as a nodal point that balances neuronal activity and neuroenergetics via Rheb-PDH axis.

Epidemiological and clinical studies have suggested comorbidity between frontotemporal dementia (FTD) and psychiatric disorders. FTD patients carrying specific mutations were at higher risk for some psychiatric disorders, and vice versa, implying potential shared genetic etiology, which is still less explored.

Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral metabolism need to be better understood for developing pharmacological interventions to manage eating behavior and obesity. Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a master regulator of cellular metabolism in different cell types. Pharmacological manipulations of mTOR complex 1 (mTORC1) activity in hypothalamic neurons alter food intake and body weight. Our previous study identified Rheb1 (Ras homolog enriched in brain 1) as an essential activator of mTORC1 activity in the brain. Here we examine whether central Rheb1 regulates food intake and peripheral metabolism through mTORC1 signaling. We find that genetic deletion of Rheb1 in the brain causes a reduction in mTORC1 activity and impairs normal food intake. As a result, Rheb1 knockout mice exhibit hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver. Our work highlights the importance of central Rheb1 signaling in euglycemia and energy homeostasis in animals.

Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.

A variant of the phospholipase A2 group VI gene (PLA2G6, PARK14) has been found to cause early-onset Parkinson's disease (EOPD). In this study, we reprogrammed peripheral blood mononuclear cells from a 39-year-old patient with EOPD carrying a homozygous PLA2G6 mutation c.1898C > T (p. A633V) to generate the human induced pluripotent stem cell line LNDWCHi001-A. This cell line was identified based on pluripotent markers and displayed differentiation capacity, providing an essential model for studying the pathogenesis of EOPD and drug screening.

Neuroglobin (NGB), distributed mainly in central and peripheral nervous systems, is a nerve globin with neuroprotective effects against oxidative stress resulting from hypoxia and ischemia. Recent studies have indicated that the expression of NGB is related to neurodegenerative disorders and cancers, but the molecular mechanisms for its transcriptional regulation and protection are not well defined. Here, we report that the expression of NGB in glioma is grade related and is negatively regulated by PPARγ. Specific PPARγ agonist reduces the expression of NGB, while its inhibitor enhances the expression. Moreover, NGB participates in regulating the phosphorylation of AKT in glioma cells, which may contribute to the glioma progression where accumulating oxidative pressure presents. Overexpression of NGB could protect glioma cells against 4-HNE induced cell death, and partially reverse PPARγ's pro-apoptotic and anti-proliferative abilities. These results display an important role of NGB in glioma progression and a mechanism for its transcriptional regulation, and suggest that the treatment on glioma through PPARγ agonist appears to be triggered by the modulation of NGB.

The morbidity and mortality of primary liver cancer is one of the highest amongst all cancers. Deficiency of effective treatment and characteristics of cancer metastasis are believed to be responsible for this situation, thus a great demand is required for new agent development. Polyphyllin II (PP2), an important steroidal saponin extracted from Rhizoma Paris, has emerged as a potential anti-cancer agent, but the effects of PP2 in liver cancers and its underlying mechanisms remain unexplored. In our study, we found that PP2 could remarkably suppress the proliferation of two liver cancer cell lines, HepG2 and BEL7402, resulting in significant cell death. Besides, low doses of PP2 have displayed properties that inhibit cellular motility and invasion of liver cancer cells. In addition, we have found that PP2-mediated cofilin activity suppression was implicated in the inhibition of liver cancer cell motility. Decreased expression of two major hydrolytic enzymes (MMP2/MMP9), through the AKT/NF-κB signaling pathway may also be also responsible for this process. Rescue experiments done with either non-phosphorylatable mutant cofilin-1 (S3A) transfection or an activator of the AKT pathway significantly reversed the inhibition effects of PP2 on liver cancer cells. Taken together, we report a potential agent for liver cancer treatment and reveal its underlying mechanisms.

Oligodendrocytes ensheath axons to form compact insulating multilamellar structures known as myelin. Tmem10 is a novel type I transmembrane glycoprotein that is highly expressed in oligodendrocytes and whose biological function remains largely unknown. Furthermore, the expression pattern of Tmem10 remains a matter of some controversy. Given the inconsistency of its expression pattern and the lack of validated specific antibodies, Tmem10 is not widely accepted as a marker for mature oligodendrocytes. As a means to solve these problems and to aid future studies of oligodendrocyte-associated diseases, we have generated a highly specific Tmem10 antibody. Using this Tmem10 antibody, we clarify that Tmem10 protein is firstly expressed at 2 weeks in the postnatal mouse brain with age-related increase, only in the central nervous system (CNS). We also reveal that Tmem10 is expressed specifically in late stage oligodendrocytes and later than MAG, a late-stage myelin marker. Finally, we show that Tmem10 co-expresses with MOG- and MBP-positive myelin fibers and is dramatically reduced in a hypomyelination mouse model. In conclusion, our study demonstrates that Tmem10 can be used as a specific marker for myelinating oligodendrocytes and perhaps for the evaluation of myelination diseases, such as multiple sclerosis.