The activation of spliced X-box binding protein 1 by isorhynchophylline therapy improves diabetic encephalopathy.

The primary symptom of diabetic encephalopathy (DE), a kind of central diabetic neuropathy caused by diabetes mellitus (DM), is cognitive impairment. In addition, the tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of X-box binding protein 1 (sXBP1) translocation into the nucleus under high glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of phosphatidylinositol 3-kinase (PI3K) p85α or p85ß with XBP1 to restore high glucose impairment. Also, IRN treatment improves high glucose-mediated impairment of insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates cognitive impairment, ameliorating peripheral insulin resistance, activating insulin signaling, inactivating activating transcription factor 6 (ATF6) and C/EBP homology protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.

Autocrine S100B in astrocytes promotes VEGF-dependent inflammation and oxidative stress and causes impaired neuroprotection.

Minimal hepatic encephalopathy (MHE) is strongly associated with neuroinflammation. Nevertheless, the underlying mechanism of the induction of inflammatory response in MHE astrocytes remains not fully understood. In the present study, we investigated the effect and mechanism of S100B, a predominant isoform expressed and released from mature astrocytes, on MHE-like neuropathology in the MHE rat model. We discovered that S100B expressions and autocrine were significantly increased in MHE rat brains and MHE rat brain-derived astrocytes. Furthermore, S100B stimulates VEGF expression via the interaction between TLR2 and RAGE in an autocrine manner. S100B-facilitated VEGF autocrine expression further led to a VEGFR2 and COX-2 interaction, which in turn induced the activation of NFƙB, eventually resulting in inflammation and oxidative stress in MHE astrocytes. MHE astrocytes supported impairment of neuronal survival and growth in a co-culture system. To sum up, a comprehensive understanding of the role of S100B-overexpressed MHE astrocyte in MHE pathogenesis may provide insights into the etiology of MHE.

Hydrogen sulphide ameliorates dopamine-induced astrocytic inflammation and neurodegeneration in minimal hepatic encephalopathy.

It has been demonstrated that the action of dopamine (DA) could enhance the production of tumour necrosis factor-α (TNF-α) by astrocytes and potentiate neuronal apoptosis in minimal hepatic encephalopathy (MHE). Recently, sodium hydrosulfide (NaHS) has been found to have neuroprotective properties. Our study addressed whether NaHS could rescue DA-challenged inflammation and apoptosis in neurons to ameliorate memory impairment in MHE rats and in the neuron and astrocyte coculture system. We found that NaHS suppressed DA-induced p65 acetylation, resulting in reduced TNF-α production in astrocytes both in vitro and in vivo. Furthermore, decreased apoptosis was observed in neurons exposed to conditioned medium from DA + NaHS-challenged astrocytes, which was similar to the results obtained in the neurons exposed to TNF-α + NaHS, suggesting a therapeutic effect of NaHS on the suppression of neuronal apoptosis via the reduction of TNF-α level. DA triggered the inactivation of p70 S6 ribosomal kinase (S6K1) and dephosphorylation of Bad, resulting in the disaggregation of Bclxl and Bak and the release of cytochrome c (Cyt. c), and this process could be reversed by NaHS administration. Our work demonstrated that NaHS attenuated DA-induced astrocytic TNF-α release and ameliorated inflammation-induced neuronal apoptosis in MHE. Further research into this approach may uncover future potential therapeutic strategies for MHE.

New Measures for the Coronavirus Disease 2019 Response: A Lesson From the Wenzhou Experience.

As the outbreak of coronavirus disease 2019 (COVID-19) has spread globally, determining how to prevent the spread is of paramount importance. We reported the effectiveness of different responses of 4 affected cities in preventing the COVID-19 spread. We expect the Wenzhou anti-COVID-19 measures may provide information for cities around the world that are experiencing this epidemic.

Oridonin prevents insulin resistance-mediated cognitive disorder through PTEN/Akt pathway and autophagy in minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) was characterized for cognitive dysfunction. Insulin resistance (IR) has been identified to be correlated with the pathogenesis of MHE. Oridonin (Ori) is an active terpenoid, which has been reported to rescue synaptic loss and restore insulin sensitivity. In this study, we found that intraperitoneal injection of Ori rescued IR, reduced the autophagosome formation and synaptic loss and improved cognitive dysfunction in MHE rats. Moreover, in insulin-resistant PC12 cells and N2a cells, we found that Ori blocked IR-induced synaptic deficits via the down-regulation of PTEN, the phosphorylation of Akt and the inhibition of autophagy. Taken together, these results suggested that Ori displays therapeutic efficacy towards memory deficits via improvement of IR in MHE and represents a novel bioactive therapeutic agent for treating MHE.

Dopamine Burden Triggers Cholesterol Overload Following Disruption of Synaptogenesis in Minimal Hepatic Encephalopathy.

The contribution of Dopamine (DA) to minimal hepatic encephalopathy (MHE) has been demonstrated. However, recent studies have revealed that cholesterol (CHO) treatment substantially increased the risk of dementia. The objectives of this study were to investigate whether CHO was induced by DA overload and its involvement in DA-induced cognitive impairment in MHE. Our study showed that DA treatment triggered CHO biosynthesis via the activation of JNK3/SREBP2 signaling pathway in primary cultured astrocytes. Conditioned media from DA-treated astrocytes increased CHO uptake by primary cultured neurons and disrupted synaptic formations; at the same time, inhibition of CHO synthesis and transportation from astrocytes diminished the disruption of synaptogenesis, which indicates the involvement of CHO in the perturbation of neural synaptogenesis in vitro. Secondary secretion of DA from primary cultured neurons was stimulated by CHO secreted from astrocytes. DA induced synergistic decreases of PPARγ/pERK/pCREB expressions in the presence of CHO in neurons, leading to synergistic synaptic impairment. Memory impairments were observed in MHE/DA-treated rats, which were partially rescued by atorvastatin (ATVS) treatment, confirming the involvement of CHO burden in vivo. Overall, our study suggests that DA overload triggers obvious CHO production from astrocytes. Excessive CHO in turn triggered neurons to secrete abundant DA and DA burden in combination with CHO overload elicit the cognitive decline and memory loss via PPARγ/ERK/CREB pathway in MHE.

Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury.

BACKGROUND: Studies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injured brain. It is well known that calpain activation plays a critical role in traumatic brain injury (TBI)-mediated inflammation and cell death; previous studies showed that inhibiting calpain activation is neuroprotective after TBI. Thus, we investigated whether preconditioning with the calpain inhibitor, MDL28170, could enhance the survival of BMSCs transplanted at 24 h post TBI to improve neurological function. METHODS: TBI rat model was induced by the weight-drop method, using the gravitational forces of a free falling weight to produce a focal brain injury. MDL28170 was injected intracranially at the lesion site at 30 min post TBI, and the secretion levels of neuroinflammatory factors were assessed 24 h later. BMSCs labeled with green fluorescent protein (GFP) were locally administrated into the lesion site of TBI rat brains at 24 h post TBI. Immunofluorescence and histopathology were performed to evaluate the BMSC survival and the TBI lesion volume. Modified neurological severity scores were chosen to evaluate the functional recovery. The potential mechanisms by which MDL28170 is involved in the regulation of inflammation signaling pathway and cell apoptosis were determined by western blot and immunofluorescence staining. RESULTS: Overall, we found that a single dose of MDL28170 at acute phase of TBI improved the microenvironment by inhibiting the inflammation, facilitated the survival of grafted GFP-BMSCs, and reduced the grafted cell apoptosis, leading to the reduction of lesion cavity. Furthermore, a significant neurological function improvement was observed when BMSCs were transplanted into a MDL28170-preconditioned TBI brains compared with the one without MDL28170-precondition group. CONCLUSIONS: Taken together, our data suggest that MDL28170 improves BMSC transplantation microenvironment and enhances the neurological function restoration after TBI via increased survival rate of BMSCs. We suggest that the calpain inhibitor, MDL28170, could be pursued as a new combination therapeutic strategy to advance the effects of transplanted BMSCs in cell-based regenerative medicine.

Baicalin reverses the impairment of synaptogenesis induced by dopamine burden via the stimulation of GABAAR-TrkB interaction in minimal hepatic encephalopathy.

BACKGROUND: It has been reported that D1 receptor (D1R) activation reduces GABAA receptor (GABAAR) current, and baicalin (BAI) displays therapeutic efficacy in diseases involving cognitive impairment. METHODS: We investigated the mechanisms by which BAI could improve DA-induced minimal hepatic encephalopathy (MHE) using immunoblotting, immunofluorescence, and co-immunoprecipitation. RESULTS: BAI did not induce toxicity on the primary cultured neurons. And no obvious toxicity of BAI to the brain was found in rats. DA activated D1R/dopamine and adenosine 3'5'-monophosphate-regulated phospho-protein (DARPP32) to reduce the GABAAR current; BAI treatment did not change the D1R/DARPP32 levels but blocked DA-induced reduction of GABAAR levels in primary cultured neurons. DA decreased the interaction of GABAAR with TrkB and the expression of downstream AKT, which was blocked by BAI treatment. Moreover, BAI reversed the decrease in the expression of GABAAR/TrkB/AKT and prevented the impairment of synaptogenesis and memory deficits in MHE rats. CONCLUSIONS: These results suggest that BAI has neuroprotective and synaptoprotective effects on MHE which are not related to upstream D1R/DARPP32 signaling, but to the targeting of downstream GABAAR signaling to TrkB.

Carnosine Inhibits the Proliferation of Human Cervical Gland Carcinoma Cells Through Inhibiting Both Mitochondrial Bioenergetics and Glycolysis Pathways and Retarding Cell Cycle Progression.

Carnosine has been demonstrated to play an antitumorigenic role in certain types of cancer. However, its underlying mechanism is unclear. In this study, the roles of carnosine in cell proliferation and its underlying mechanism were investigated in the cultured human cervical gland carcinoma cells HeLa and cervical squamous carcinoma cells SiHa. The results showed that carnosine exerted a significant inhibitory effect on the proliferation of HeLa cells, whereas its inhibitory action on the proliferation of SiHa cells was much weaker. Carnosine decreased the ATP content through inhibiting both mitochondrial respiration and glycolysis pathways in cultured HeLa cells but not SiHa cells. Carnosine reduced the activities of isocitrate dehydrogenase and malate dehydrogenase in TCA (tricarboxylic acid) cycle and the activities of mitochondrial electron transport chain complex I, II, III, and IV in HeLa cells but not SiHa cells. Carnosine also decreased the mRNA and protein expression levels of ClpP, which plays a key role in maintaining the mitochondrial function in HeLa cells. In addition, carnosine induced G1 arrest by inhibiting the G1-S phase transition in both HeLa and SiHa cells. Taken together, these findings suggest that carnosine has a strong inhibitory action on the proliferation of human cervical gland carcinoma cells rather than cervical squamous carcinoma cells. Mitochondrial bioenergetics and glycolysis pathways and cell cycle may be involved in the carnosine action on the cell proliferation in cultured human cervical gland carcinoma cells HeLa.