The 'Candidatus phytoplasma ziziphi' effectors SJP1 and SJP2 destabilise the bifunctional regulator ZjTCP7 to modulate floral transition and shoot branching.

Phytoplasmic SAP11 effectors alter host plant architecture and flowering time. However, the exact mechanisms have yet to be elucidated. Two SAP11-like effectors, SJP1 and SJP2, from 'Candidatus Phytoplasma ziziphi' induce shoot branching proliferation. Here, the transcription factor ZjTCP7 was identified as a central target of these two effectors to regulate floral transition and shoot branching. Ectopic expression of ZjTCP7 resulted in enhanced bolting and earlier flowering than did the control. Interaction and expression assays demonstrated that ZjTCP7 interacted with the ZjFT-ZjFD module, thereby enhancing the ability of these genes to directly bind to the ZjAP1 promoter. The effectors SJP1 and SJP2 unravelled the florigen activation complex by specifically destabilising ZjTCP7 and ZjFD to delay floral initiation. Moreover, the shoot branching of the ZjTCP7-SRDX transgenic Arabidopsis lines were comparable to those of the SJP1/2 lines, suggesting the involvement of ZjTCP7 in the regulation of shoot branching. ZjTCP7 interacted with the branching repressor ZjBRC1 to enhance suppression of the auxin efflux carrier ZjPIN3 expression. ZjTCP7 also directly bound to and upregulated the auxin biosynthesis gene ZjYUCCA2, thereby promoting auxin accumulation. Our findings confirm that ZjTCP7 serves as a bifunctional regulator destabilised by the effectors SJP1 and SJP2 to modulate plant development.

Atractylenolide I Suppresses A1 Astrocyte Activation to Improve Depression in Mice.

This work aimed to investigate the role of atractylenolide I (ATR) in resisting depression and its mechanism of action. The mouse model of depression was constructed through chronic unpredictable mild stress (CUMS) method. After ATR intervention, changes in the depression-related behaviors of mice were detected through open field test and elevated plus maze. In addition, enzyme-linked immunosorbent assay (ELISA) was conducted to detect inflammatory factor levels. Real-time fluorescence quantitative PCR (RT-qPCR) was performed to measure the mRNA levels of A1/A2 astrocyte markers. Furthermore, primary astrocytes were induced in vitro, and the A1 differentiation level was detected by ELISA and RT-qPCR assays. ATR improved the behaviors of CUMS mice and alleviated the depression symptoms. Moreover, it reduced tissue inflammation, inhibited the A1 differentiation of astrocytes, and decreased the mRNA levels of A1 markers. After NLRP3 knockout, the effects of ATR were suppressed. Similarly, in vitro experimental results also revealed that ATR suppressed the A1 differentiation of astrocytes. Based on molecular dynamics and small molecule-protein docking results, ATR mainly targeted NLRP3 and suppressed the NLRP3-mediated A1 differentiation. We discover that ATR can target NLRP3 to suppress A1 differentiation of astrocytes, restrain tissue inflammation, and improve the depression symptoms in mice.

Atractylenolide I improves behaviors in mice with depression-like phenotype by modulating neurotransmitter balance via 5-HT2A.

To explore the antidepressant effects and targets of atractylenolide I (ATR) through a network pharmacological approach. Relevant targets of ATR and depression analyzed by network pharmacology were scored (identifying 5-HT2A targets). Through elevated plus maze, open field, tail suspension, and forced swimming tests, the behavioral changes of mice with depression (chronic unpredictable mild stress [CUMS]) were examined, and the levels of neurotransmitters including serotonin, dopamine, and norepinephrine (5-HT, DA, and NE) were determined. The binding of ATR to 5-HT2A was verified by small molecular-protein docking. ATR improved the behaviors of CUMS mice, elevated their levels of neurotransmitters 5-HT, DA, and NE, and exerted a protective effect on their nerve cell injury. After 5-HT2A knockout, ATR failed to further improve the CUMS behaviors. According to the results of small molecular-protein docking and network pharmacological analysis, ATR acted as an inhibitor by binding to 5-HT2A. ATR can improve the behaviors and modulate the neurotransmitters of CUMS mice by targeting 5-HT2A.

Gastrodin improves nerve cell injury and behaviors of depressed mice through Caspase-3-mediated apoptosis.

AIM: We investigated the effects and target of gastrodin (GAS) for treating depression through network pharmacology combined with experimentation. METHODS: The therapeutic target and signal of GAS for depression were analyzed by network pharmacology. Depression in mice was mimicked with a chronic unpredictable mouse stress (CUMS) model. Through open field, elevated plus maze, forced swimming, and tail suspension tests, the effects of GAS on the CUMS mice behaviors were examined, and the levels of neurotransmitters were detected. The histopathological changes were assayed by H&E and IHC staining, and the protein expressions were detected by Western blotting. Small molecule-protein docking and molecular dynamics experiments were conducted to simulate the binding mode between GAS and Caspase-3. RESULTS: Network pharmacological analysis revealed that Caspase-3 was the action target of GAS. GAS could improve depression-like behaviors in CUMS mice, elevate their neurotransmitter levels, ameliorate their nerve cell injury, and inhibit their Caspase-3 expression. After knocking out Caspase-3, the effects of GAS were inhibited. Molecular dynamics simulation and small molecule-protein docking found that GAS bound to Caspase-3 at SER25, inhibiting the maturation and activation of Caspase-3. CONCLUSION: We find that GAS can act as a Caspase-3 inhibitor, which improves depression-like behaviors and nerve cell injury in CUMS mice by inhibiting Caspase-3-mediated apoptosis.

LncRNA-AC020978 Promotes Metabolic Reprogramming in M1 Microglial Cells in Postoperative Cognitive Disorder via PKM2.

The present work aimed to explore the role of long non-coding RNA (lncRNA)-AC020978 in postoperative cognitive disorder (POCD) and the underlying mechanism. The POCD mouse model was constructed through isoflurane anesthesia + abbreviated laparotomy. The AC020978 expression in brain tissue was silenced after lentivirus injection, then Morris water maze test was conducted to detect the cognitive disorder level, flow cytometry was performed to analyze M1 macrophage level, ELISA was carried out to measure inflammatory factor levels, H&E, Nissl and immunohistochemical staining was performed to detect the pathological changes in brain tissue, and Western blotting assay was adopted to detect protein expression. In addition, microglial cells were cultured in vitro, after lentivirus infection, the effect of AC020978 on the M1 polarization of microglial cells and glycolysis was observed. AC020978 overexpression promoted POCD progression and aggravated cognitive disorder in mice; in addition, the proportion of peripheral and central M1 cells increased, the inflammatory factor levels were upregulated, and microglial cells were activated. By contrast, AC020978 silencing led to cognitive disorder in mice and suppressed microglial cell activation and M1 polarization. In vitro experimental results indicated that AC020978 promoted the expression and phosphorylation of PKM2, which promoted inflammatory response through enhancing microglial cell glycolysis and M1 polarization. AC020978 interacts with PKM2 to promote the glycolysis and M1 polarization of microglial cells, thus regulating cognitive disorder and central inflammation in POCD.

Icariin improves cognitive impairment by inhibiting ferroptosis of nerve cells.

AIM: We investigated the effect and mechanism of Icariin (ICA) on improving neurobehavioral ability of mice with Alzheimer's disease (AD). METHODS: We selected 10-month-old APP/PS1 mice (AD) and wild-type C57BL/6J mice (Normal). After intragastric administration of ICA, Morris water maze was employed to detect neurobehavioral improvements, and to assay key ferroptosis indicators and oxidative stress levels. The common target of ICA for resisting ferroptosis and AD was predicted by network pharmacology. RESULTS: ICA could improve the neurobehavioral, memory and motor abilities of AD mice. It could lower the ferroptosis level and enhance the resistance to oxidative stress. After inhibition of MDM2, ICA could no longer improve the cognitive ability of AD mice, nor could it further inhibit ferroptosis. Network pharmacological analysis revealed that MDM2 might be the target of ICA action. CONCLUSIONS: We found that ICA can inhibit ferroptosis of nerve cells, thereby ameliorating neural damage in mice with AD.

Effect of low-calcium and standard-calcium dialysate on serum calcium, phosphorus and full-segment parathyroid hormone in patients on peritoneal dialysis: A retrospective observational study.

OBJECTIVE: To investigate the effects of low-calcium and standard-calcium dialysate in patients with chronic kidney disease on peritoneal dialysis, and find out which dialysate has less vascular calcification effect. METHODS: A total of 141 patients who had undergone peritoneal dialysis (PD) for 2 years in the PD centre from January 2012 to December 2017 were included and divided into two groups according to the calcium concentration of the PD fluid used. There were 79 cases in the low-calcium group, with a dialysate calcium concentration of 1.25 mmol/L and 62 cases in the standard-calcium group, with a dialysate calcium concentration of 1.75 mmol/L. The demographic characteristics and clinical information before initiation of PD were collected and compared between the two groups. Information on the serum calcium, phosphorus and PTH, systolic and diastolic blood pressures and the use of antihypertensive and phosphate-lowering drugs in the second year of dialysis was also collected and compared between the two groups. Vascular calcification was assessed in patients on PD treatment. RESULTS: The mean serum calcium concentrations before initiation of PD in the low- and standard-calcium groups were 1.94 ± 0.27 and 1.89 ± 0.28 mmol/L, respectively. The serum calcium concentrations after PD were 2.30 ± 0.21 and 2.41 ± 0.23 mmol/L, respectively. After PD, the serum calcium concentration in both groups was significantly increased (p < 0.05). The serum calcium concentration in the low-calcium group after PD treatment was lower than that in the standard-calcium group, and the difference was statistically significant (p < 0.05). Compared with the standard-calcium group, patients in the low-calcium group had significantly higher parathyroid hormone concentrations (p < 0.05). More types of phosphate-lowering drugs were used (59.49%) in the low-calcium group than that in the standard-calcium group (35.48%; p < 0.05). The number of antihypertensive drug usage were also higher in the low-calcium group, and the difference was statistically significant (p < 0.05). As for the vascular calcification effect, the two groups have shown no statistical difference in abdominal aortic calcification rate, carotid arteriosclerosis rate and aortic arch calcification rate (p < 0.05). CONCLUSION: We found that low-calcium PD fluid may increase the PTH level and the proportion of CKD patients using antihypertensive drug and phosphorus-lowering drug, but the vascular calcification effect of the low and standard calcium PD fluid needs further exploration. This paper provides new evidence for the choice of dialysate for PD, low-calcium dialysate has no outstanding advantages for long term dialysis.

Association between dialysis effluent leukocyte count after initial antibiotic treatment and outcomes of patients with peritoneal dialysis-associated peritonitis: a retrospective study.

BACKGROUND: Among patients with peritoneal dialysis-associated peritonitis (PDAP), It has been regarded as an indicator of deterioration of clinical condition that peritoneal dialysis effluent leukocyte count (PDELC) cannot be restored to normal after initial antibiotic therapy. However, the precise relationship between PDELC on day 5 and the clinical outcomes of PDAP episodes remains uncertain. AIMS: To explore the association between PDELC on day 5 and clinical outcomes of PDAP episodes. METHODS: This retrospective study was based on the medical chart database of the Affiliated Hospital of Guangdong Medical University. Multivariable regressions were used to evaluate the association between PDELC on day 5 and 60-day mortality, half-year mortality, treatment failure, and the length of stay in hospital with adjustment for confounding factors. RESULTS: A total of 549 PDAP episodes in 309 patients were enrolled. The total 60-day mortality, half-year mortality, and rate of treatment failure was 6.0%, 9.8%, and 14.2%, respectively. Compared with patients with normal PDELC, those with PDELC ≥2000 × 106/L on day 5 had significantly higher 60-day mortality (31.1% vs 2.7%), half-year mortality (35.6% vs 5.6%), and treatment failure (46.7% vs 5.7%). In multivariate adjusted regression, the ORs (95%CI) were 6.99 (2.33, 20.92; p = 0.001), 4.97(1.93, 12.77; p = 0.001), and 5.77 (2.07, 16.11; p = 0.001), respectively. Patients with PDELC were 100-2000 × 106/L on day 5 had a higher rate of treatment failure than those with normal PDELC (26.9% vs 5.7%) (OR = 3.03, 95%CI 1.42, 6.46; p = 0.004). After sensitivity analysis, the results remained robust. CONCLUSIONS: Among patients with PDAP, increased PDELC on day 5 was associated with a greater risk of 60-day mortality, half-year mortality, and treatment failure.

Paeoniflorin suppresses neuronal ferroptosis to improve the cognitive behaviors in Alzheimer's disease mice.

Aim of this research was to examine the impact of paeoniflorin (Pae) in suppressing the occurrence of ferroptosis in individuals with Alzheimer's disease (AD). The study utilized APP/PS1 mice with AD as the experimental subjects. Following the administration of Pae, the cognitive behaviors of mice were evaluated and the key indexes of ferroptosis were measured, as well as levels of oxidative stress (OS). For in-vitro experiments, Erastin was adopted for inducing the ferroptosis of PC12 cells, and the level of cell ferroptosis was detected after Pae treatment. Pae improved the cognitive ability of AD mice, reduced the level of ferroptosis, decreased the iron ion and MAD levels in brain tissues, and increased SOD expression. In PC12 cells, Pae suppressed the Erastin-induced ferroptosis, mitigated oxidative damage, and reduced the level of ROS. Based on the findings from our research, it was observed that Pae exhibited a specific binding affinity to P53, leading to the suppression of ferroptosis. This mechanism ultimately resulted in the improvement of nerve injury in mice with AD.

TL1A promotes the postoperative cognitive dysfunction in mice through NLRP3-mediated A1 differentiation of astrocytes.

AIM: We investigated the mechanism, whereby tumor necrosis factor-like ligand 1A (TL1A) mediates the A1 differentiation of astrocytes in postoperative cognitive dysfunction (POCD). METHODS: The cognitive and behavioral abilities of mice were assessed by Morris water maze and open field tests, while the levels of key A1 and A2 astrocyte factors were detected by RT-qPCR. Immunohistochemical (IHC) staining was used to examine the expression of GFAP, western blot was used to assay the levels of related proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory cytokines. RESULTS: The results showed that TL1A could promote the progression of cognitive dysfunction in mice. Astrocytes differentiated into A1 phenotype, while unobvious changes were noted in astrocyte A2 biomarkers. Knockout of NLRP3 or intervention with NLRP3 inhibitor could inhibit the effect of TL1A, improving the cognitive dysfunction and suppressing the A1 differentiation. CONCLUSION: Our results demonstrate that TL1A plays an important role in POCD in mice, which promotes the A1 differentiation of astrocytes through NLRP3, thereby exacerbating the progression of cognitive dysfunction.

Antcin K targets NLRP3 to suppress neuroinflammation and improve the neurological behaviors of mice with depression.

AIM: We aimed to explored the role of Antcin K in resisting depression and its targets. METHODS: LPS/IFN-γwas used to induce the activation of microglial BV2 cells. Following Antcin K pretreatment, the proportion of M1 cells was determined using flow cytometry (FCM), the expression of cytokines was measured through ELISA, and that of CDb and NLRP3 was analyzed by cell fluorescence staining. The protein levels were detected by Western-blot assay. After NLRP3 was knocked down in BV2 cells (BV2-nlrp3-/-), the M1 polarization level was detected with Antcin K treatment. The targeted binding relation of Antcin K with NLRP3 was confirmed through small molecule-protein docking and co-immunoprecipitation assay. The chronic unpredictable stress model (CUMS) was constructed to mimic the depression mice. After the administration of Antcin K, the neurological behavior of CUMS mice were detected by open-field test (OFT), elevated plus maze, forced swimming test (FST), and tail suspension test (TST). In addition, the expression of CD11b and IBA-1 was detected through histochemical staining, and the tissue pathological changes were detected by H&E staining. RESULTS: Antcin K suppressed the M1 polarization of BV2 cells and reduced the expression of inflammatory factors. Meanwhile, NLRP3 exhibited targeted binding relation with Antcin K, and Antcin K lost its effect after NLRP3 knockdown. In the CUMS mouse model, Antcin K improved the depression status and neurological behaviors in mice, and decreased central neuroinflammation and microglial cell polarization. CONCLUSION: Antcin K targets NLRP3 to suppress microglial cell polarization, alleviate central inflammation in mice and improve their neurological behaviors.

NADPH oxidase 4 regulate the glycolytic metabolic reprogramming of microglial cells to promote M1 polarization.

This work aimed to investigate the role and mechanism of NADPH oxidase 4 (NOX4) in the polarization of microglial cells. Microglial cells were transfected with the NOX4 overexpression plasmid (pGL3-NOX4), and later treated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) to induce its M1 polarization. Later, the F4/80 + CD86 + cell proportion was detected by flow cytometry (FCM), the inflammatory factor expression levels were analyzed through enzyme-linked immunosorbent assay (ELISA), while ionized calcium binding adapter molecule 1 (IBA-1) and PKM2 expression were measured by immunofluorescence (IF) staining. In addition, dichlorodihydrofluorescein diacetate probe was utilized to detect the reactive oxygen species (ROS) levels, glucose uptake, and glycolysis, as well as lactic acid level. The expression of glycolytic enzymes PKM2, HK2, and citrate (Si)-synthas (CS) was detected by Western-blot (WB) assay. Moreover, the polarization level of microglial cells was detected after ROS expression was suppressed by the ROS inhibitor N-acetylcysteine (NAC). In mouse experiments, LPS was applied in inducing central neuroinflammation in NOX4 knockdown mouse model (KO) and wild-type mice (WT). Thereafter, the inflammatory factor levels and lactic acid level in mouse tissues were detected; IBA-1 and CD86 expression in mice was measured by IF staining; and the expression of glycolytic enzymes PKM2, HK2, and CS in the central nervous system (CNS) was also detected. After NOX4 overexpression in microglial cells, the M1 polarization level was upregulated, the F4/80 + CD86 + cell proportion increased, and inflammatory factors were upregulated. At the same time, the expression of glycolytic enzymes PKM2, HK2, and CS was upregulated. NAC pretreatment suppressed the effects of NOX4, reduced the F4/80 + CD86 + cell proportion, and suppressed the expression of PKM2, HK2, and CS. In the mouse model, the expression levels of CD86 in KO group decreased, and the inflammatory factors were also downregulated. NOX4 promotes glycolysis of microglial cells via ROS, thus accelerating M1 polarization and inflammatory factor expression. In this regard, NOX4 is promising as a new target for the treatment of neuroinflammation.

Mechanism of neocryptotanshinone in protecting against cerebral ischemic injury: By suppressing M1 polarization of microglial cells and promoting cerebral angiogenesis.

AIM: This study explored the protective function and mechanism of neocryptotanshinone (NEO) on cerebral ischemia. METHODS: Lipopolysaccharide/γ-interferon(LPS/IFN-γ)was employed to mimic the polarization of mouse microglial cells BV2. After NEO treatment, the M1 polarization level of BV2 cells was identified using flow cytometry (FCM), fluorescent cell staining and enzyme linked immunosorbent assay(ELISA). Moreover, the mouse endothelial cells bEnd.3 were applied to be the study objects, which were intervened with NEO under the hypoxic condition. Thereafter, based on in-vitro tubule formation assay and fluorescence staining, the in-vitro tubule formation ability of bEnd.3 cells was detected. By adopting middle cerebral artery occlusion(MCAO) method, we constructed the mouse model of cerebral ischemia. After NEO intervention, the pathological changes of brain tissues were identified, while CD34 expression was measured by immunohistochemical (IHC) staining, nerve injury was detected by Nissl staining, and the changes in neurological behaviors of mice were also detected. RESULTS: Our results showed that NEO suppressed M1 polarization of BV2 cells, which exerted its effect through suppressing NF-κB and STAT3 signals, thereby decreasing the levels of iNOS, CD11b and inflammatory factors. NEO stimulated tubule formation in bEnd.3 cells based on the hypoxic situation, which exerted its effect through activating the Vascularendothelial growth factor-Vascular Endothelial Growth Factor Receptor 2-Notch homolog 1(VFGF-VEGFR2-Notch1) signal. Furthermore, NEO suppressed cerebral ischemia in mice and lowered the ischemic penumbra. NEO also improved the neurological behaviors of mice, increased the CD34 levels and decreased the expression of inflammatory factors. CONCLUSION: NEO has well protective effect against cerebral ischemia, and its mechanisms are related to suppressing M1 polarization of microglial cells and promoting cerebral angiogenesis, which are the mechanisms of NEO in treating ischemic encephalopathy.

Advanced Glycation End-Products (AGEs) Promote Endothelial Cell Pyroptosis Under Cerebral Ischemia and Hypoxia via HIF-1α-RAGE-NLRP3.

This work mainly aimed to explore the role and mechanism of advanced glycation end-products (AGEs) in inducing cerebrovascular endothelial cell pyroptosis under oxygen glucose deprivation (OGD) condition. The mouse cerebral microvascular endothelial cells (BMECs and bEnd.3) were used as the objects to construct the OGD model in vitro. Then, cells were pretreated with AGE-modified human serum albumin (AGE-HSA). Thereafter, CCK-8 assay was conducted to detect cell viability, and flow cytometry (FCM) was performed to measure cell pyroptosis level. Meanwhile, the expression of inflammatory factors was detected by enzyme-linked immunosorbent assay (ELISA). The expression of HIF-α, NLRP3, and RAGE was detected by fluorescence staining. The opening status of cell membrane pore was observed under the electron microscope, and the expression levels of FL-GSDMD, NT-GSDMD, and caspase-1 were measured through Western Blot (WB) assay. Moreover, bEnd.3 cells were treated with siRAN-silenced NLRP3 and HIF-α inhibitor, so as to observe the effect of AGEs on cell pyroptosis level. In the mouse model, the middle cerebral artery occlusion (MCAO) model was constructed by the suture-occluded method. After intraperitoneal injection of AGEs, the pathological changes in mouse brain tissues were detected; the expression levels of NLRP3, ZO-1, and CD31 were determined by histochemical staining, and the levels of inflammatory factors and pyroptosis-related proteins were also detected. Under OGD condition, AGEs induced the pyroptosis of bEnd.3 cells, and the cell pyroptosis rate increased, higher than that of the OGD group. Meanwhile, the levels of inflammatory factors were up-regulated; the expression of HIF-α, NLRP3, and RAGE in cells increased; and the levels of NT-GSDMD and caspase-1 were markedly higher than those of the control and OGD groups. siRNA-NLRP3 or HIF-α inhibitor treatment suppressed pyroptosis and reduced the inflammatory factor levels. In mouse experiments, AGE injection aggravated brain injury in the MCAO mouse model, decreased the expression of ZO-1 and CD31, and elevated the levels of NLRP3 and inflammatory factors. Under cerebral ischemia condition, AGEs can induce endothelial cell pyroptosis via HIF-α-RAGE-NLRP3, thereby further aggravating brain injury.

Aurantiamide suppresses the activation of NLRP3 inflammasome to improve the cognitive function and central inflammation in mice with Alzheimer's disease.

AIM: This study was aimed at exploring the mechanism by which aurantiamide (Aur) targeted NLRP3 to suppress microglial cell polarization. METHODS: The 7-month-old APP/PS1 mice and C57BL/6 mice were applied to be the study objects, and Aur was administered intragastrically to APP/PS1 mice at 10 mg/kg and 20 mg/kg. The changes in the neurocognitive function of mice were measured by Morris Water Maze (MWM) test. In the in vitro experiments, the mouse BV2 cells were employed as the study objects, which were subject to treatment with 10 µM and 20 µM Aur and induced with LPS and IFN-γ in order to activate BV2 cells and induce their M1 polarization. RESULTS: Aur was found to suppress the M1 polarization of mouse microglia, reduce central neuroinflammation, and improve the cognitive function in mice. Meanwhile, Aur suppressed the activation and the expression of NLRP3 inflammasome. The results of experiments in vitro demonstrated that Aur inhibited the activation and M1 polarization of BV2 cells. CONCLUSION: Aur targets NLRP3 and suppresses the activation of NLRP3 inflammasome.

Association Between the Variability of Glycated Hemoglobin and Retinopathy in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis.

Visit-to-visit variability of glycated hemoglobin (HbA1c) is a marker of long-term glycemic fluctuation, which has been related to increased risk of macrovascular complications in patients with type 2 diabetes mellitus (T2DM). The association between HbA1c variability and retinopathy in patients with T2DM, however, has been inconsistent in previous studies. In order to fully evaluate the above association, we conducted a meta-analysis. Observational studies related to the aim of the meta-analysis were identified by search of PubMed, Web of Science, and Embase databases. Studies with HbA1c variability evaluated as the standard deviation (SD) and/or the coefficients of variation (CV) of HbA1c were included. The results were analyzed using a random-effects model that incorporated potential heterogeneity between studies. Twelve observational studies involving 44 662 T2DM patients contributed to the meta-analysis. Overall, 5150 (11.5%) patients developed retinopathy. Pooled results showed that compared to patients with lower HbA1c variability, T2DM patients with higher HbA1c-SD (relative risk [RR]: 1.48, 95% confidence interval [CI]: 1.24 to 1.78, p<0.001, I2=34%) and higher HbA1c-CV (RR: 1.29, 95% CI: 1.05 to 1.59, p=0.02, I2=0%) were both associated with higher risk of DR. For studies with HbA1c-SD, the association was not significantly affected by study characteristics such as country, study design, mean age, disease duration, adjustment of mean HbA1c, or quality scores (p for subgroup difference all>0.05). In conclusion, higher HbA1c variability may be associated with an increased risk of retinopathy in patients with T2DM.

Aurantiamide promotes M2 polarization of microglial cells to improve the cognitive ability of mice with Alzheimer's disease.

This work aimed to investigate the effect of aurantiamide (Aur) in promoting the M2 polarization of microglial cells to improve the cognitive ability of mice with Alzheimer's disease (AD). The M2 polarization of BV2 cells was induced by interleukin-4 (IL-4) treatment.Aur promoted the M2 polarization of BV2 cells, and up-regulated the expression of CD206 and SOCS3. In the meantime, it increased TGF-ß1, Arg-1 and IL-10 levels, and promoted the polarization of JAK1-STAT6. Treatment with STAT6 inhibitor antagonized the effect of Aur. Besides, the cognitive ability of AD mice was improved after Aur treatment, meanwhile, the expression of CD206 was up-regulated, while that of IBA-1 was down-regulated. Aur promotes the M2 polarization of microglial cells to improve the cognitive ability of AD mice, and such effect is related to the STAT6 signal.

Tax preference, financing constraints and enterprise investment efficiency-Experience, of China's enterprises investment.

This paper takes the 2014 pilot project of accelerated depreciation of fixed assets as a quasi-natural experiment, and builds a Propensity Score Matching-Difference in Differences (PSM-DID) model based on the data of Chinese listed companies from 2000 to 2019 to test the impact of tax preference on enterprise investment efficiency and its mechanism. The results show that the policy inhibits supported enterprises investment efficiency significantly. Heterogeneity analysis shows that the policy causes greater investment efficiency losses for small and medium-sized enterprises, non-state-owned enterprises and asset-heavy enterprises. The mechanism test found the reason why the policy eased financing constraints but inhibited investment efficiency in short-term. After a variety of robustness tests, the above basic conclusions are still valid. Although the accelerated depreciation policy of fixed assets is conducive to expanding the scale of investment, the incentive effect on investment efficiency is not obvious, and even shows a restraining effect. Given the existence of heterogeneity, the design of the policy should not only distinguish industries, but also pay attention to the differences between different enterprises in the same industry. Strengthening research and development (R&D) innovation and improving the matching mechanism between human capital and fixed investment will help give full play to the incentive effect of this policy. The research in this paper helps to deepen the understanding of the microeconomic effects of tax policy and identify the internal mechanism, which not only enriches the relevant literature, but also provides a reference for the government to better use tax policy to promote the high-quality development of enterprises.

Hepcidin regulates neuronal ferroptosis: A mechanism for postoperative cognitive dysfunction.

Toll-like receptor 4 (TLR4) is a signaling molecule responsible for the expression of hepcidin (Hepc), while myeloid differentiation protein 2 (MD2) is one major accessory protein of TLR4. This study focuses on exploring the neurocyte ferroptosis mediated through the regulation of Hepc expression by MD2, which is also one of the mechanisms for postoperative cognitive dysfunction (POCD). An experimental study was carried out using aged wild-type (Wt) and MD2 transgenic (Tg) mice. The neurocyte ferroptosis and POCD in the mice were assessed following splenectomy. Morris water maze was utilized to assess the neurocognitive abilities, hematoxylin and eosin (H&E) assay was performed to examine histopathology, and Nissl staining was used to evaluate the neurocyte damage. The Fe2+ , superoxide dismutase(SOD), malondialdehyde (MDA), glutathione(GSH), and glutathione peroxidase 4 (GPX4) levels were determined with kits. The expressions of transferrin receptor (TFR), Hepc, and MD2 were measured by Western blotting, while the expressions of TFR and GPX4 were measured by immunohistochemical staining. In Tg mice, we observed neurocyte ferroptosis and POCD following treatment with an MD2 inhibitor. PC12 cells were used as a neurocyte model. Ferroptosis was induced after treatment with an MD2 inhibitor, and the cell viability was assayed by Cell Counting Kit-8. Immunofluorescent staining was used to measure the TFR and GPX4 expressions. Meanwhile, the intracellular levels of Fe2+ , SOD, MDA, GSH, GPX4, and Hepc were also measured. POCD occurred among aged Wt and Tg mice. The Tg-POCD mice had more apparent POCD than the Wt-POCD mice. Nissl and H&E staining revealed neurocyte damage in brain tissues. Besides this, the Fe2+ and MDA expressions were upregulated, while the SOD, GSH, and GPX4 expressions were downregulated. Elevations in tissue levels of TFR, Hepc, and MD2 were observed, which were higher than those of Wt-POCD mice. After treatment with an MD2 inhibitor, the POCD could be prominently ameliorated in Tg-POCD mice, the Fe2+ and MDA levels could be reduced, while the SOD, GSH, and GPX4 levels could be elevated. In the PC12 model, ferroptosis could be suppressed by inhibiting the expression of MD2. MD2 is capable of regulating neurocyte ferroptosis by promoting Hepc expression, which has great potential as a novel target for POCD therapy.