Blocking salt-inducible kinases with YKL-06-061 prevents PTZ-induced seizures in mice.

INTRODUCTION: Epilepsy is one of the most common neurological diseases, while over one third of adults with epilepsy still have inadequate seizure control. Although mutations in salt-inducible kinases (SIKs) have been identified in epileptic encephalopathy, it is not known whether blocking SIKs can prevent pentylenetetrazole (PTZ)-induced seizures. METHODS: We first determined the time course of SIKs (including SIK 1, 2, and 3) in the hippocampus of PTZ treated mice. And then, we evaluated the effects of anti-epilepsy drug valproate acid (VPA) on the expression of SIK 1, 2, and 3 in the hippocampus of PTZ treated mice. Next, we investigated the effect of different dose of SIKs inhibitor YKL-06-061 on the epileptic seizures and neuronal activation by determining the expression of immediate early genes (IEGs) in the PTZ treated mice. RESULTS: We found that PTZ selectively induced enhanced expression of SIK1 in the hippocampus, which was blocked by VPA treatment. Notably, YKL-06-061 decreased seizure activity and prevented neuronal overactivity, as indicated by the reduced expression of IEGs in the hippocampus and prefrontal cortex. CONCLUSION: Our findings provide the first evidence that SIK1 affects gene regulation in neuronal hyperactivity, which is involved in seizure behavior. Targeting SIK1 through the development of selective inhibitors may lead to disease-modifying therapies that reduce epilepsy progression.

Ferroptosis and Cancer Immunotherapy.

Traditional treatment strategies for cancer are unsatisfactory. As a nonapoptotic cell death process and owning to the characteristics of iron-dependent lipid peroxide accumulation, ferroptosis has become a new target of tumor treatment. Numerous studies have proved that ferroptosis could enhance the immunogenicity of cancer and interact with immune cells. Cancer antigens, exposed to cancer cells that underwent ferroptosis, effectively improve the immunogenicity of the tumor microenvironment and promote the activation and maturation of immune cells. Meantime, immune cells release immunostimulatory cytokines including TNF-α and IFN-γ to downregulate the expression of SLC7A11 and SLC3A2, and reduce the absorption of cysteine, leading to lipid peroxidation and iron deposition in cancer cells. Consequently, induction of ferroptosis via iron deposition-based combination strategies could stimulate and activate natural and adaptive immune responses which release immune-stimulating factors to induce iron deposition in cancer cells. In this review, we provided a critical analysis of the correlation between ferroptosis and the immune responses, providing a novel way to effectively induce ferroptosis in cancer, which may be one of the focuses in future to improve the development of new therapeutic strategies of cancer.

FOXO3 is a potential biomarker and therapeutic target for premature ovarian insufficiency (Review).

Premature ovarian insufficiency (POI) is a common clinical disease of the reproductive system in which patients lose normal gonadal function prior to the age of 40. Common pathogenic factors include iatrogenic injury, genetics, inflammation, autoimmune, environmental and psychological factors. Patients with POI experience decreased estrogen secretion levels, ovulation disorder and infertility. POI appears frequently in clinical practice and the burden of the disease is heavy; however, the detailed pathological mechanism requires further experimental evaluation. Furthermore, there is a lack of effective treatment options. Certain causes of the pathogenesis of POI can be explained by epigenetic changes. Front fork transcription factor 3 (FOXO3) is a member of the forkhead box family of transcription factors. FOXO3 was initially considered to affect insulin/insulin growth factor signal transduction. However, the target gene range of FOXO3 includes numerous genes that affect metabolism and protein stability and are associated with aging. There is an association between decreased FOXO3 expression levels and POI. In the present review article, the role of FOXO3 in POI was evaluated, which emphasized the importance of this protein in the investigation of this disease. Moreover, the present review evaluated the evidence for the potential targets and biomarkers of FOXO3 that may be used in the treatment and diagnosis of POI.

Betaine attenuate chronic restraint stress-induced changes in testicular damage and oxidative stress in male mice.

SCOPE: Male fertility and sperm quality are negatively affected by psychological stress. Chronic restraint stress (CRS) is a common psychological stress that has a negative effect on sperm. Betaine (BET), an active ingredient isolated from Lycium barbarum, has anti-oxidant, anti-inflammatory and other pharmacological activities. This study aims to explore whether betaine has a therapeutic effect on sperm deformity and vitality under CRS and its mechanism. METHODS AND RESULTS: Chronic restraint stress was induced in 8-week-old male C57BL/6 J mice by fixation for 6 h a day for 35 days. Mice were intraperitoneally injected with betaine (BET) or normal saline (NS) for 14 days. Thirty-five days later, the animals were sacrificed. The results showed that the detrimental effects of CRS on testes as evident by disrupted histoarchitecture, increased oxidative stress, inflammation and apoptosis that compromised male fertility. BET injections can reverse these symptoms. CONCLUSIONS: BET can improve spermatogenesis dysfunction caused by CRS, which may provide potential dietary guidance.

Potential clinical applications of alpha­ketoglutaric acid in diseases (Review).

As an intermediate of the tricarboxylic acid cycle, also known as 2­oxoglutarate, α­ketoglutaric acid (AKG) plays an important role in maintaining physiological functions and cell metabolism. AKG is involved in both energy metabolism, and carbon and nitrogen metabolism; thus, exhibiting a variety of functions. Moreover, AKG plays an important role in various systems of the body. Results of previous research indicated that AKG may act as a regulator in the progression of a variety of diseases; thus, it exhibits potential as a novel drug for the clinical treatment of age­related diseases. The present review aimed to summarize the latest research progress and potential clinical applications of AKG and provided novel directions and scope for future research.