Transcription factor Sp1 transcriptionally enhances GSDME expression for pyroptosis.

Gasdermin-E (GSDME), the executioner of pyroptosis when cleaved by caspase 3, plays a crucial role in tumor defense and the response to chemotherapy drugs in cells. So far, there are poorly known mechanisms for the expression regulation of GSDME during cell death. Here, we identify the transcription factor Sp1 (Specificity protein 1) as a positive regulator of GSDME-mediated pyroptosis. Sp1 directly interacts with the GSDME promoter at -36 ~ -28 site and promotes GSDME gene transcription. Further, Sp1 knockdown or inhibition suppresses GSDME expression, thus reducing chemotherapy drugs (topotecan, etoposide, doxorubicin, sorafinib and cisplatin) induced cell pyroptosis. The regulation process synergizes with STAT3 (Signal transducer and activator of transcription 3) activity and antagonizes with DNA methylation but barely affects GSDMD-mediated pyroptosis or TNF-induced necroptosis. Our current finding reveals a new regulating mechanism of GSDME expression, which may be a viable target for the intervention of GSDME-dependent inflammatory diseases and cancer therapy.

Cardiac injury activates STING signaling via upregulating SIRT6 in macrophages after myocardial infarction.

AIMS: This work sought to investigate the mechanism underlying the STING signaling pathway during myocardial infarction (MI), and explore the involvement and the role of SIRT6 in the process. MAIN METHODS: Mice underwent the surgery of permanent left anterior descending (LAD) artery constriction. Primary cardiomyocytes (CMs) and fibroblasts were subjected to hypoxia to mimic MI in vitro. STING expression was assessed in the infarct heart, and the effect of STING inhibition on cardiac fibrosis was explored. This study also evaluated the regulatory effect of STING by SIRT6 in macrophages. KEY FINDINGS: STING protein was increased in the infarct heart tissue, highlighting its involvement in the post-MI inflammatory response. Hypoxia-induced death of CMs and fibroblasts contributed to the upregulation of STING in macrophages, establishing the involvement of STING in the intercellular signaling during MI. Inhibition of STING resulted in a significant reduction of cardiac fibrosis at day 14 after MI. Additionally, this study identified SIRT6 as a key regulator of STING via influencing its acetylation and ubiquitination in macrophages, providing novel insights into the posttranscriptional modification and expression of STING at the acute phase after myocardial infarction. SIGNIFICANCE: This work shows the key role of SIRT6/STING signaling in the pathogenesis of cardiac injury after MI, suggesting that targeting this regulatory pathway could be a promising strategy to attenuate cardiac fibrosis after MI.

AKT2 deficiency alleviates doxorubicin-induced cardiac injury via alleviating oxidative stress in cardiomyocytes.

Doxorubicin (DOX), a widely used chemotherapy agent in cancer treatment, encounters limitations in clinical efficacy due to associated cardiotoxicity. This study aims to explore the role of AKT serine/threonine kinase 2 (AKT2) in mitigating DOX-induced oxidative stress within the heart through both intracellular and extracellular signaling pathways. Utilizing Akt2 knockout (KO) and Nrf2 KO murine models, alongside neonatal rat cardiomyocytes (NRCMs), we systematically investigate the impact of AKT2 deficiency on DOX-induced cardiac injury. Our findings reveal that DOX administration induces significant oxidative stress, a primary contributor to cardiac injury. Importantly, Akt2 deficiency exhibits a protective effect by alleviating DOX-induced oxidative stress. Mechanistically, Akt2 deficiency facilitates nuclear translocation of NRF2, thereby suppressing intracellular oxidative stress by promoting the expression of antioxidant genes. Furthermore, We also observed that AKT2 inhibition facilitates superoxide dismutase 2 (SOD2) expression both inside macrophages and SOD2 secretion to the extracellular matrix, which is involved in lowering oxidative stress in cardiomyocytes upon DOX stimulation. The present study underscores the important role of AKT2 in mitigating DOX-induced oxidative stress through both intracellular and extracellular signaling pathways. Additionally, our findings propose promising therapeutic strategies for addressing DOX-induced cardiomyopathy in clinic.

The role of Keap1-Nrf2 signaling pathway during the progress and therapy of diabetic retinopathy.

Diabetic retinopathy is a complex and progressive ocular complication of diabetes mellitus and is a leading cause of blindness in people of working age worldwide. The pathophysiology of diabetic retinopathy involves multifactorial processes, including oxidative stress, inflammation and vascular abnormalities. Understanding the underlying molecular mechanisms involved in its pathogenesis is essential for the development of effective therapeutic interventions. One of the pathways receiving increasing attention is the Keap1-Nrf2 signaling pathway, which regulates the cellular response to oxidative stress by activating Nrf2. In this review, we analyze the current evidence linking Keap1-Nrf2 signaling pathway dysregulation to diabetic retinopathy. In addition, we explore the potential therapeutic implications and the challenges of targeting this pathway for disease management. A comprehensive understanding of the molecular mechanisms of diabetic retinopathy and the therapeutic potential of the Keap1-Nrf2 pathway may pave the way for innovative and effective interventions to combat this vision-threatening disease.

The role of sirtuins in the regulatin of oxidative stress during the progress and therapy of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defense systems, plays a significant role in the development and progression of T2DM. The sirtuin family, particularly Sirt1, Sirt3, and Sirt6, have emerged as key regulators of oxidative stress in various cellular processes. This review aims to explore the role of the sirtuin family in oxidative stress during the progression of T2DM and their potential as therapeutic targets. We discussed the mechanisms through which sirtuins modulate oxidative stress, their impact on insulin sensitivity, and beta-cell function involved in T2DM. Furthermore, we highlight drugs targeting sirtuin activation and related complications in T2DM. This review summarizes the role as well as mechanism of sirtuins in the regulation of oxidative stress in T2DM and available drugs targeting sirtuins in clinic, which may provide novel insights into the mechanism and therapy of T2DM.

Akt2 deficiency alleviates oxidative stress in the heart and liver via up-regulating SIRT6 during high-fat diet-induced obesity.

The present study aims to investigate the role of AKT2 in the pathogenesis of hepatic and cardiac lipotoxicity induced by lipid overload-induced obesity and identify its downstream targets. WT and Akt2 KO mice were fed either normal diet, or high-fat diet (HFD) to induce obesity model in vivo. Human hepatic cell line (L02 cells) and neonatal rat cardiomyocytes (NRCMs) were used as in vitro models. We observed that during HFD-induced obesity, Akt2 loss-of-function mitigated lipid accumulation and oxidative stress in the liver and heart tissue. Mechanistically, down-regulation of Akt2 promotes SIRT6 expression in L02 cells and NRCMs, the latter deacetylates SOD2, which promotes SOD2 activity and therefore alleviates oxidative stress-induced injury of hepatocytes and cardiomyocytes. Furthermore, we also proved that AKT2 inhibitor protects hepatocytes and cardiomyocytes from HFD-induced oxidative stress. Therefore, our work prove that AKT2 plays an important role in the regulation of obesity-induced lipid metabolic disorder in the liver and heart. Our study also indicates AKT2 inhibitor as a potential therapy for obesity-induced hepatic and cardiac injury.

Metformin alleviates HFD-induced oxidative stress in hepatocyte via activating SIRT6/PGC-1α/ENDOG signaling.

Metformin is accepted as a first-line drug for the therapy of Type 2 diabetes (T2D), while its mechanism is still controversial. In the present study, by taking advantage of mouse model of high-fat-diet (HFD)-induced obesity and primary mouse hepatocytes (PMHCs) as well as human hepatocyte L02 cell line, we aimed to investigate the involvement of SIRTs during the application of metformin for the therapy of T2D. Our data evidenced that during HFD-induced obesity, there was elevation of nucleus protein acetylation. Analysis of liver tissue showed that among all SIRT members, SIRT6 expression was significantly down-regulated during HFD feeding, which was sustained to regular level with metformin administration. Our result also showed that SIRT6 suppressed intracellular oxidative stress upon FAs stimulation in PMHCs and L02 cells. Mechanistically, SIRT6, but not SIRT1 promoted PGC-1α expression. We further prove that ENDOG is downstream of PGC-1α. In addition, we evidenced that ENDOG protects hepatocytes from lipid-induced oxidative stress, and down-regulation of Endog blunted the protective role of metformin in defending against FAs-induced oxidative stress. Our study established a novel mechanism of metformin in counteracting lipid-induced hepatic injury via activating SIRT6/PGC-1α/ENDOG signaling, thus providing novel targets of metformin in the therapy of T2D.

Changes in intracranial pressure gradients between the cerebral hemispheres in patients with intracerebral hematomas in one cerebral hemisphere.

BACKGROUND: Intracranial-pressure (ICP) monitoring is useful for patients with increased ICP following hemorrhagic stroke. In this study, the changes in pressure gradients between the two cerebral hemispheres were investigated after hemorrhagic stroke of one side, and after a craniotomy. METHODS: Twenty-four patients with acute cerebral hemorrhages and intracerebral hematomas who exhibited mass effect and midline shift to the contralateral side on computed tomography were selected for this study. After admission, both sides of the cranium were drilled, and optical fiber sensors were implanted to monitor the brain parenchyma pressure (BPP) in both cerebral hemispheres. All patients underwent surgical hematoma evacuations. The preoperative and postoperative BPP data from both cerebral hemispheres were collected at various time points and compared pairwise. RESULTS: There were statistically significant differences (P < 0.01) in the preoperative BPP values between the two hemispheres at three different time points. Differences in the BPP values between the two hemispheres at the time of surgery, and 24 and 48 h after surgery, were not statistically significant (P > 0.05). The posteroperative BPPs of both hemispheres were statistically significantly lower than preoperative recordings. CONCLUSIONS: BPP sensors should be applied to the injured cerebral hemisphere, because this becomes the source of increased ICP. Hematoma evacuation surgery effectively decreases ICP and eliminates pressure gradients between the two cerebral hemispheres, consequently enabling brain shift correction.

Protective effect of C-phycocyanin against carbon tetrachloride-induced hepatocyte damage in vitro and in vivo.

This study focused on the hepatoprotective activity of C-phycocyanin (C-PC) against carbon tetrachloride-induced hepatocyte damage in vitro and in vivo. In in vitro study, human hepatocyte cell line L02 was used. C-PC showed its capability to reverse CCl(4)-induced L02 cells viability loss, alanine transaminase (ALT) leakage and morphological changes. C-PC also showed the following positive effects: prevent the CCl(4)-induced overproduction of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA); prevent changes in superoxide dismutase (SOD) activity; and reduce glutathione (GSH) level. In vivo, C-PC showed its capability to decrease serum ALT and aspartate transaminase (AST) levels in CCl(4)-induced liver damage in mice. The histological observations supported the results obtained from serum enzymes assays. C-PC also showed the following effects in mice liver: prevent the CCl(4)-induced MDA formation and GSH depletion; prevent SOD and glutathione peroxidase (GSH-Px) activity; and prevent the elevation of transforming growth factor-beta1 (TGF-beta1) and hepatocyte growth factor (HGF) mRNAs. Both the in vitro and in vivo results suggested that C-PC was useful in protecting against CCl(4)-induced hepatocyte damage. One of the mechanisms is believed to be through C-PCs scavenging ability to protect the hepatocytes from free radicals damage induced by CCl(4). In addition, C-PC may be able to block inflammatory infiltration through its anti-inflammatory activities by inhibiting TGF-beta1 and HGF expression.

Effects of unilateral decompressive craniectomy on patients with unilateral acute post-traumatic brain swelling after severe traumatic brain injury.

INTRODUCTION: Acute post-traumatic brain swelling (BS) is one of the pathological forms that need emergent treatment following traumatic brain injury. There is controversy about the effects of craniotomy on acute post-traumatic BS. The aim of the present clinical study was to assess the efficacy of unilateral decompressive craniectomy (DC) or unilateral routine temporoparietal craniectomy on patients with unilateral acute post-traumatic BS. METHODS: Seventy-four patients of unilateral acute post-traumatic BS with midline shifting more than 5 mm were divided randomly into two groups: unilateral DC group (n = 37) and unilateral routine temporoparietal craniectomy group (control group, n = 37). The vital signs, the intracranial pressure (ICP), the Glasgow outcome scale (GOS), the mortality rate and the complications were prospectively analysed. RESULTS: The mean ICP values of patients in the unilateral DC group at hour 24, hour 48, hour 72 and hour 96 after injury were much lower than those of the control group (15.19 +/- 2.18 mmHg, 16.53 +/- 1.53 mmHg, 15.98 +/- 2.24 mmHg and 13.518 +/- 2.33 mmHg versus 19.95 +/- 2.24 mmHg, 18.32 +/- 1.77 mmHg, 21.05 +/- 2.23 mmHg and 17.68 +/- 1.40 mmHg, respectively). The mortality rates at 1 month after treatment were 27% in the unilateral DC group and 57% in the control group (p = 0.010). Good neurological outcome (GOS Score of 4 to 5) rates 1 year after injury for the groups were 56.8% and 32.4%, respectively (p = 0.035). The incidences of delayed intracranial hematoma and subdural effusion were 21.6% and 10.8% versus 5.4% and 0, respectively (p = 0.041 and 0.040). CONCLUSIONS: Our data suggest that unilateral DC has superiority in lowering ICP, reducing the mortality rate and improving neurological outcomes over unilateral routine temporoparietal craniectomy. However, it increases the incidence of delayed intracranial hematomas and subdural effusion, some of which need secondary surgical intervention. These results provide information important for further large and multicenter clinical trials on the effects of DC in patients with acute post-traumatic BS. TRIAL REGISTRATION: ISRCTN14110527.

[Clinical study on the therapeutic effects and mechanism of progesterone in the treatment for acute severe head injury].

OBJECTIVE: To evaluate the therapeutic effects of Progesterone (PG) on the patients with acute severe traumatic brain injury, and investigate it's neuroprotective mechanisms. METHODS: Fifth-six patients with acute severe traumatic head injury were divided randomly into two groups: 26 cases were treated with PG and 30 cases were control. Neurological outcome of the patients were assessed using Glasgow Coma Scale (GCS), Glasgow Outcome Scale (GOS), verbal and motor functions scale and Karnofsky Performance Scale (KPS). The serum concentrations of PG, TNF-alpha and 15-F(2t)-isoprostane were measured at day 1, 5 and 10 after trauma. RESULTS: In the two groups, There were no significant difference in the mortality, GCS of acute healing phase, GOS and verbal and motor functions at 10th days after treatment (P>0.05); After follow-up for 3 months, GOS, verbal functions and KPSin the PG treatment group were better than those in the control group (P<0.05); In addition, there was no difference of motor functions in the two groups (P>0.05). At 5th day after trauma, serum 15-F(2t)-isoprostane and TNF-alpha levels increased in the control group, but decreased at 10th day after trauma. Compared with the control group serum PG levels increased, serum 15-F(2t)-isoprostane and TNF-alpha levels reduced significantly in the PG treatment group at 5th and 10th day after injury (P<0.05). CONCLUSION: It indicated that successive early application of PG will benefit the patients with acute severe head injury by improving the recovery and reducing the disability, which may be related to its alleviating inflammatory and lipid peroxidation response.

Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury.

Therapeutic hypothermia is a promising treatment for patients with severe traumatic brain injury (TBI). We present here the results of a study in which noninvasive selective brain cooling (SBC) was achieved using a head cap and neckband. Ninety patients with severe TBI were divided into a normothermia control group (n=45) and a SBC group (n=45), whose brain temperature was maintained at 33-35 degrees C for 3 days using a combination of head and neck cooling. At 24, 48 and 72h after injury, the mean intracranial pressure (ICP) values of the patients who underwent SBC were lower than those of the normothermia controls (19.14+/-2.33, 19.72+/-1.73 and 17.29+/-2.07 mmHg, versus 23.41+/-2.51, 20.97+/-1.86, and 20.13+/-1.87 mmHg, respectively, P<0.01). There was a significant difference in the neurological recovery of the two groups at the 6-month follow-up after TBI. Good neurological outcome (Glasgow Outcome Scale score of 4 to 5) rates 6 months after injury were 68.9% for the SBC group, and 46.7% for the control group (P<0.05). There were no complications resulting in severe sequelae. In conclusion, the noninvasive SBC described here is a safe method of administering therapeutic hypothermia, which can reduce ICP and improve prognosis without severe complications in patients with severe TBI.