KLF13 promotes VSMCs phenotypic dedifferentiation by directly binding to the SM22α promoter.

Krüppel-like factor 13 (KLF13), a zinc finger transcription factor, is considered as a potential regulator of cardiomyocyte differentiation and proliferation during heart morphogenesis. However, its precise role in the dedifferentiation of vascular smooth muscle cells (VSMCs) during atherosclerosis and neointimal formation after injury remains poorly understood. In this study, we investigated the relationship between KLF13 and SM22α expression in normal and atherosclerotic plaques by bioanalysis, and observed a significant increase in KLF13 levels in the atherosclerotic plaques of both human patients and ApoE-/- mice. Knockdown of KLF13 was found to ameliorate intimal hyperplasia following carotid artery injury. Furthermore, we discovered that KLF13 directly binds to the SM22α promoter, leading to the phenotypic dedifferentiation of VSMCs. Remarkably, we observed a significant inhibition of platelet-derived growth factor BB-induced VSMCs dedifferentiation, proliferation, and migration when knocked down KLF13 in VSMCs. This inhibitory effect of KLF13 knockdown on VCMC function was, at least in part, mediated by the inactivation of p-AKT signaling in VSMCs. Overall, our findings shed light on a potential therapeutic target for treating atherosclerotic lesions and restenosis after vascular injury.

Skin mottling score assesses peripheral tissue hypoperfusion in critically ill patients following cardiac surgery.

BACKGROUND: Skin mottling is a common manifestation of peripheral tissue hypoperfusion, and its severity can be described using the skin mottling score (SMS). This study aims to evaluate the value of the SMS in detecting peripheral tissue hypoperfusion in critically ill patients following cardiac surgery. METHODS: Critically ill patients following cardiac surgery with risk factors for tissue hypoperfusion were enrolled (n = 373). Among these overall patients, we further defined a hypotension population (n = 178) and a shock population (n = 51). Hemodynamic and perfusion parameters were recorded. The primary outcome was peripheral hypoperfusion, defined as significant prolonged capillary refill time (CRT, > 3.0 s). The characteristics and hospital mortality of patients with and without skin mottling were compared. The area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of SMS in detecting peripheral hypoperfusion. Besides, the relationships between SMS and conventional hemodynamic and perfusion parameters were investigated, and the factors most associated with the presence of skin mottling were identified. RESULTS: Of the 373-case overall population, 13 (3.5%) patients exhibited skin mottling, with SMS ranging from 1 to 5 (5, 1, 2, 2, and 3 cases, respectively). Patients with mottling had lower mean arterial pressure, higher vasopressor dose, less urine output (UO), higher CRT, lactate levels and hospital mortality (84.6% vs. 12.2%, p < 0.001). The occurrences of skin mottling were higher in hypotension population and shock population, reaching 5.6% and 15.7%, respectively. The AUROC for SMS to identify peripheral hypoperfusion was 0.64, 0.68, and 0.81 in the overall, hypotension, and shock populations, respectively. The optimal SMS threshold was 1, which corresponded to specificities of 98, 97 and 91 and sensitivities of 29, 38 and 67 in the three populations (overall, hypotension and shock). The correlation of UO, lactate, CRT and vasopressor dose with SMS was significant, among them, UO and CRT were identified as two major factors associated with the presence of skin mottling. CONCLUSION: In critically ill patients following cardiac surgery, SMS is a very specific yet less sensitive parameter for detecting peripheral tissue hypoperfusion.

Carnosol alleviates sepsis-induced pulmonary endothelial barrier dysfunction by targeting nuclear factor erythroid2-related factor 2/sirtuin-3 signaling pathway to attenuate oxidative damage.

Excessive reactive oxygen species production during acute lung injury (ALI) will aggravate the inflammatory process and endothelial barrier dysfunction. Carnosol is a natural phenolic diterpene with antioxidant and anti-inflammatory properties, but its role in treating sepsis-induced ALI remains unclear. This study aims to explore the protective effects and underlying mechanisms of carnosol in sepsis-induced ALI. C57BL/6 mouse were preconditioned with carnosol for 1 h, then the model of lipopolysaccharide (LPS)-induced sepsis was established. The degree of pulmonary edema, oxidative stress, and inflammation were detected. Endothelial barrier function was evaluated by apoptosis and cell junctions. In vitro, Mito Tracker Green probe, JC-1 staining, and MitoSOX staining were conducted to investigate the effect of carnosol on mitochondria. Finally, we investigated the role of nuclear factor-erythroid 2-related factor (Nrf2)/sirtuin-3 (SIRT3) in carnosol against ALI. Carnosol alleviated LPS-induced pulmonary oxidative stress and inflammation by inhibiting excess mitochondrial reactive oxygen species production and maintaining mitochondrial homeostasis. Furthermore, carnosol also attenuated LPS-induced endothelial cell barrier damage by reducing vascular endothelial cell apoptosis and restoring occludin, ZO-1, and vascular endothelial-Cadherin expression in vitro and in vivo. In addition, carnosol increased Nrf2 nuclear translocation to promote SIRT3 expression. The protective effects of carnosol on ALI were largely abolished by inhibition of Nrf2/SIRT3. Our study has provided the first evidence that the Nrf2/SIRT3 pathway is a protective target of the endothelial barrier in ALI, and carnosol can serve as a potential therapeutic candidate for ALI by utilizing its ability to target this pathway.

Hypoglycaemia aggravates impaired endothelial-dependent vasodilation in diabetes by suppressing endothelial nitric oxide synthase activity and stimulating inducible nitric oxide synthase expression.

BACKGROUND: Diabetes exacerbates vascular injury by triggering endothelial dysfunction. Endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) both play major roles in endothelial dysfunction. However, effects of hypoglycaemia, the main complication of the insulin therapy to the glycemic control in diabetes, on eNOS activity and iNOS expression, and underlying mechanisms in diabetes remain unknown. Hence, we aimed to determine the effects of hypoglycaemia on eNOS activity and iNOS expression in different arterial beds of diabetic rats. METHODS: Sprague-Dawley rats were subjected to Streptozotocin (STZ) combined with high fat diet (HFD) to induce diabetes and then received insulin injection to attain acute and recurrent hypoglycaemia. Immunoblotting was used to analyse the phosphorylation and O-glycosylation status of eNOS and iNOS level from thoracic aorta and mesenteric artery tissue. Indicators of oxidative stress from plasm were determined, and endothelial-dependent vasodilation was detected via wire myograph system. RESULTS: Hypoglycaemia was associated with a marked increase in eNOS O-GlcNAcylation and decrease in Serine (Ser)-1177 phosphorylation from thoracic aortas and mesenteric arteries. Moreover, hypoglycaemia resulted in elevated phosphorylation of eNOS at Threonine (Thr)-495 site in mesenteric arteries. Besides, changes in these post-translational modifications were associated with increased O-GlcNAc transferase (OGT), decreased phosphorylation of Akt at Ser-473, and increased protein kinase C α subunit (PKCα). iNOS expression was induced in hypoglycaemia. Furthermore, endothelial-dependent vasodilation was impaired under insulin-induced hypoglycaemia, and further in recurrent hypoglycaemia. CONCLUSIONS: Conclusively, these findings strongly indicate that hypoglycaemia-dependent vascular dysfunction in diabetes is mediated through altered eNOS activity and iNOS expression. Therefore, this implies that therapeutic modulation of eNOS activity and iNOS expression in diabetics under intensive glucose control may prevent and treat adverse cardiovascular events.

Postoperative glucocorticoids in patients with acute type A aortic dissection (GLAD): study protocol for a prospective, single-center, randomized controlled trial.

BACKGROUND: Patients receiving surgical treatment of acute type A Aortic Dissection (aTAAD) are common to suffer organ dysfunction in the intensive care unit due to overwhelming inflammation. Previous studies have revealed that glucocorticoids may reduce complications in certain patient groups, but evidence between postoperative glucocorticoids administration and improvement in organ dysfunction after aTAAD surgery are lacking. METHODS: This study will be an investigator-initiated, prospective, single-blind, randomized, single-center study. Subjects with confirmed diagnosis of aTAAD undergoing surgical treatment will be enrolled and 1:1 randomly assigned to receive either glucocorticoids or normal treatment. All patients in the glucocorticoids group will be given methylprednisolone intravenously for 3 days after enrollment. The primary endpoint will be the amplitude of variation of Sequential Organ Failure Assessment score on post-operative day 4 compared to baseline. DISCUSSION: The trial will explore the rationale for postoperative application of glucocorticoids in patients after aTAAD surgery. TRIAL REGISTRATION: This study has been registered on ClinicalTrials.gov (NCT04734418).

Effect of glucocorticoid for patients with type A aortic dissection undergoing surgical repair with deep hypothermic circulatory arrest: A single-center, retrospective study.

BACKGROUND: Postoperative patients with Type A aortic dissection (TAAD) often experience severe inflammatory responses caused by multiple factors perioperatively. However, the effect of postoperative glucocorticoid (GC) use, which is a potent anti-inflammatory agent, on complications or all-cause mortality is unclear. METHODS: Patients with TAAD who underwent surgical repair requiring deep hypothermic circulatory arrest between January 2020 and December 2021 were included in the study. Characteristics of patients treated with and without GCs were compared. The primary outcome was in-hospital mortality, and a composite secondary outcome was defined as in-hospital death or any major complications. Propensity score matching was used to balance baseline differences between groups. Kaplan-Meier curves were used to compare survival probability. RESULTS: A total of 393 postoperative patients with TAAD were included in the study. Forty of them (10.2%) received GC treatment at a median daily methylprednisolone-equivalent dose of 0.6 mg/kg (0.4-0.7) for a median period of 2 (1-3) days. Patients on GCs had more intraoperative blood transfusions, higher postoperative APACHE II (12 vs 9, p = .004) and SOFA (9 vs 6, p < .001) scores, worse perioperative hepatic, renal and cardiac function. The in-hospital mortality in the matched cohort did not differ between groups [GC n = 11/40 (27.5%) versus Non-GC n = 19/80 (23.8%); p = .661]. CONCLUSIONS: The propensity to use GCs correlated with the critical status of the patient. However, low dose and short-term postoperative GC treatment did not reduce in-hospital mortality rates among patients with TAAD. A more appropriate regimen should be further investigated.

Honokiol improves endothelial function in type 2 diabetic rats via alleviating oxidative stress and insulin resistance.

We aimed to examine the effect of Honokiol (HKL) on endothelial dysfunction in type 2 diabetic rats and its possible mechanism. A high-fat diet and streptozotocin (STZ) were used to establish the type 2 diabetic model in rats. Part of these rats were intraperitoneally injected with HKL 10 mg/kg daily. Then the expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS), eNOS, and CD31, vasodilation function, insulin signaling, indicators of oxidative stress and relative signaling pathway were measured. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanism of the effect of HKL on high glucose-related endothelial injury in vitro. The data showed that HKL could reverse the decline of the expression of p-eNOS and CD31, endothelium-related vasodilation dysfunction, insulin resistance and activation of oxidative stress induced by type 2 diabetes in vivo. The similar results were obtained in vitro. In summary, our study demonstrates that HKL improves endothelial function and diminishes insulin resistance and oxidative stress, suggesting that HKL could be used as a treatment option for diabetes in the future.

NLRP3 inflammasome contributes to endothelial dysfunction in angiotensin II-induced hypertension in mice.

AIMS: Inflammation is a key feature of endothelial dysfunction induced by angiotensin (Ang) II. The purpose of this study was to explore the role of Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in endothelial dysfunction in Ang II-induced hypertension. MATERIALS AND METHODS: We analyzed blood pressure and vascular function of wild-type (WT) and Nlrp3 knockout (Nlrp3-/-) mice, treated with Ang II. In vitro, we mainly tested the endothelial nitric oxide synthase (eNOS) phosphorylation expression of human umbilical vein endothelial cells (HUVECs). KEY FINDINGS: Here we showed that 14-day Ang II infusion into mice resulted in the elevation of blood pressure, NLRP3 expression, serum interleukin (IL)-1ß level, and the decline of endothelium-dependent relaxation function, p-eNOS-Ser1177 expression in aortas. Nlrp3 deficiency reduced Ang II-induced blood pressure elevation and endothelial dysfunction. In vitro, NLRP3 was involved in the effect of Ang II on reducing p-eNOS-Ser1177 expression. Moreover, the direct effect of IL-1ß on vascular endothelial injury could be observed in both vivo and vitro. SIGNIFICANCE: Our result demonstrates that the NLRP3 inflammasome is critically involved in the detrimental effects of Ang II on vascular endothelium in hypertension via the activation of IL-1ß, placing NLRP3 as a potential target for therapeutic interventions in conditions with endothelial dysfunction in hypertension.

Remifentanil versus Dexmedetomidine in Cardiac Surgery Patients with Noninvasive Ventilation Intolerance: Protocol for the REDNIVI Trial.

BACKGROUND: Respiratory failure is one of the most common complications following cardiac surgery. Although noninvasive ventilation (NIV) has been an effective treatment, it has a high rate of intolerance. Both remifentanil and dexmedetomidine are used as sedatives in cardiac surgery (CS) patients with NIV intolerance. However, no randomized controlled trials have compared the effects of these drugs in relieving the intolerance. METHODS: REDNIVI will be a multicenter, prospective, single-blind, randomized controlled trial carried out in six clinical sites in China. Subjects with NIV intolerance will be randomized to receive remifentanil or dexmedetomidine in a ratio of 1:1. Primary outcomes of intolerance remission rate at different timings (15 minutes, 1, 3, 6, 12, 24, 36, 48, 60, 72 hours after initiation of treatment) and 72 h average remission rate will be determined. In addition, secondary outcomes such as mortality, duration of intensive care unit (ICU) stay, duration of mechanical ventilation (MV), the need for endotracheal intubation, hemodynamic changes, and delirium incidence will also be determined. CONCLUSIONS: This trial will provide evidence to determine the effects of remifentanil and dexmedetomidine in patients with NIV intolerance after cardiac surgery. CLINICAL TRIAL REGISTRATION: This study has been registered on ClinicalTrials.gov (NCT04734418).

Early prediction of noninvasive ventilation failure after extubation: development and validation of a machine-learning model.

BACKGROUND: Noninvasive ventilation (NIV) has been widely used in critically ill patients after extubation. However, NIV failure is associated with poor outcomes. This study aimed to determine early predictors of NIV failure and to construct an accurate machine-learning model to identify patients at risks of NIV failure after extubation in intensive care units (ICUs). METHODS: Patients who underwent NIV after extubation in the eICU Collaborative Research Database (eICU-CRD) were included. NIV failure was defined as need for invasive ventilatory support (reintubation or tracheotomy) or death after NIV initiation. A total of 93 clinical and laboratory variables were assessed, and the recursive feature elimination algorithm was used to select key features. Hyperparameter optimization was conducted with an automated machine-learning toolkit called Neural Network Intelligence. A machine-learning model called Categorical Boosting (CatBoost) was developed and compared with nine other models. The model was then prospectively validated among patients enrolled in the Cardiac Surgical ICU of Zhongshan Hospital, Fudan University. RESULTS: Of 929 patients included in the eICU-CRD cohort, 248 (26.7%) had NIV failure. The time from extubation to NIV, age, Glasgow Coma Scale (GCS) score, heart rate, respiratory rate, mean blood pressure (MBP), saturation of pulse oxygen (SpO2), temperature, glucose, pH, pressure of oxygen in blood (PaO2), urine output, input volume, ventilation duration, and mean airway pressure were selected. After hyperparameter optimization, our model showed the greatest accuracy in predicting NIV failure (AUROC: 0.872 [95% CI 0.82-0.92]) among all predictive methods in an internal validation. In the prospective validation cohort, our model was also superior (AUROC: 0.846 [95% CI 0.80-0.89]). The sensitivity and specificity in the prediction group is 89% and 75%, while in the validation group they are 90% and 70%. MV duration and respiratory rate were the most important features. Additionally, we developed a web-based tool to help clinicians use our model. CONCLUSIONS: This study developed and prospectively validated the CatBoost model, which can be used to identify patients who are at risk of NIV failure. Thus, those patients might benefit from early triage and more intensive monitoring. TRIAL REGISTRATION: NCT03704324. Registered 1 September 2018, https://register. CLINICALTRIALS: gov .

Cartesian coordinates scaffold stable spatial perception over time.

Visual systems exploit temporal continuity principles to achieve stable spatial perception, manifested as the serial dependence and central tendency effects. These effects are posited to reflect a smoothing process whereby past and present information integrates over time to decrease noise and stabilize perception. Meanwhile, the basic spatial coordinate-Cartesian versus polar-that scaffolds the integration process in two-dimensional continuous space remains unknown. The spatial coordinates are largely related to the allocentric and egocentric reference frames and presumably correspond with early and late processing stages in spatial perception. Here, four experiments consistently demonstrate that Cartesian outperforms polar coordinates in characterizing the serial bias-serial dependence and central tendency effect-in two-dimensional continuous spatial perception. The superiority of Cartesian coordinates is robust, independent of task environment (online and offline task), experimental length (short and long blocks), spatial context (shape of visual mask), and response modality (keyboard and mouse). Taken together, the visual system relies on the Cartesian coordinates for spatiotemporal integration to facilitate stable representation of external information, supporting the involvement of allocentric reference frame and top-down modulation in spatial perception over long time intervals.

Effects of different intensities of continuous training on vascular inflammation and oxidative stress in spontaneously hypertensive rats.

We aimed to study the effects and underlying mechanism of different intensities of continuous training (CT) on vascular inflammation and oxidative stress in spontaneously hypertensive rats (SHR). Rats were divided into five groups (n = 12): Wistar-Kyoto rats sedentary group (WKY-S), sedentary group (SHR-S), low-intensity CT group (SHR-L), medium-intensity CT group (SHR-M) and high-intensity CT group (SHR-H). Changes in body mass, heart rate and blood pressure were recorded. The rats were euthanized after 14 weeks, and blood and vascular tissue samples were collected. Haematoxylin and Eosin staining was used to observe the aortic morphology, and Western blot was used to detect the expression of mesenteric artery proteins. After CT, the mean arterial pressures improved in SHR-L and SHR-M and increased in SHR-H compared with those in SHR-S. Vascular inflammation and oxidative stress levels significantly subsided in SHR-L and SHR-M (p < 0.05), whereas in SHR-H, only vascular inflammation significantly subsided (p < 0.05), and oxidative stress remained unchanged (p > 0.05). AMPK and SIRT1/3 expressions in SHR-L and SHR-M were significantly up-regulated than those in SHR-S (p < 0.05). These results indicated that low- and medium-intensity CT can effectively reduce the inflammatory response and oxidative stress of SHR vascular tissue, and high-intensity CT can improve vascular tissue inflammation but not oxidative stress.

Tubeimoside I improves endothelial function in sepsis via activation of SIRT3.

Sepsis is life-threatening organ dysfunction caused by a deregulated host response to infection. Endothelial dysfunction is the initial factor leading to organ dysfunction and it is associated with increased mortality. There is no effective drug to treat sepsis-induced endothelial dysfunction. In this study, we detected a favorable effect of tubeimoside I (TBM) in ameliorating sepsis-induced endothelial dysfunction. To unveil the mechanism how TBM protects against sepsis-induced endothelial dysfunction, we examined TBM's effects on oxidative stress and apoptosis both in vivo and in vitro. TBM treatment alleviated oxidative stress by decreasing NOX2 and Ac-SOD2/SOD2 and decreased apoptosis by inhibiting cleaved caspse3 and Bax/Bcl-2. Notably, sepsis induced a significant decrease of SIRT3 expression in vascular endothelium, while TBM treatment reversed SIRT3 expression. To clarify whether TBM provides protection via SIRT3, we knockdown SIRT3 using siRNA before TBM treatment. Then, the cytoprotective effects of TBM were largely abolished by siSIRT3. This suggests that SIRT3 plays an essential role in TBM's endothelial protective effects and TBM might be a potential drug candidate to treat sepsis-induced endothelial dysfunction.

Diacerein attenuates vascular dysfunction by reducing inflammatory response and insulin resistance in type 2 diabetic rats.

AIM: To examine the effect of diacerein on vascular dysfunction in type 2 diabetic rats and elucidate the mechanism of diacerein. METHODS: In a rat model, type 2 diabetes was induced by high-fat diet and streptozotocin. Vascular function was assessed in vascular reactivity experiment. The effect of diacerein (10 or 20 mg/kg/day) on blood glucose, inflammation and insulin signaling, and modulators in vascular tissue in diabetic rats were investigated by molecular and biochemical approaches. RESULTS: In this study, diacerein inhibited diabetes-induced vascular dysfunction. Diacerein treatment normalized blood glucose, insulin tolerance test, inflammatory cytokine levels and nitric oxide synthases expression in diabetic rats. Moreover, diacerein inhibited NF-κB and NLRP3 pathways and activated insulin signaling pathway related proteins IRS-1 and AKT in diabetic rats. CONCLUSION: Diacerein improved vascular function effectively in diabetic rats by suppressing inflammation and reducing insulin resistance. These results suggest that diacerein may represent a novel therapy for patients with diabetes.

Progesterone promotes endothelial nitric oxide synthase expression through enhancing nuclear progesterone receptor-SP-1 formation.

Progesterone exerts antihypertensive actions partially by modulating endothelial nitric oxide synthase (eNOS) activity. Here, we aimed to investigate the effects and mechanisms of progesterone on eNOS expression. First, human umbilical vein endothelial cells (HUVECs) were exposed to progesterone and then the eNOS transcription factor specificity protein-1 (SP-1) and progesterone receptor (PRA/B) expression were assessed by Western blotting and qRT-PCR. The interaction between SP-1 and PRA/B was next determined through coimmunoprecipitation assay. The chromatin immunoprecipitation assay and luciferase assay were used to investigate the relationship of PRA/B, SP-1, and eNOS promoter. At last, rats were intraperitoneally injected with progesterone receptor antagonist RU-486, and then the expression of eNOS and vasodilation function in thoracic aorta and mesenteric artery were measured. The results showed that progesterone could increase eNOS expression in HUVECs. Further study showed that progesterone increased PRA-SP-1 complex formation and facilitated PRA/B and SP-1 binding to eNOS promoter. Mutating SP-1 or PR-binding motif on eNOS promoter abolished the effect of progesterone on eNOS gene transcription. We also observed that progesterone receptor antagonist RU-486 reduced eNOS expression and impaired vasodilation in rats. Those results suggest that progesterone modulates eNOS expression through promoting PRA-SP-1 complex formation, and progesterone antagonist attenuates eNOS expression, leading to the loss of vascular relaxation.NEW & NOTEWORTHY Progesterone directly upregulated endothelial nitric oxide synthase (eNOS) expression in human endothelial cells. Progesterone augmented eNOS promoter activity through a progesterone receptor A- and specificity protein-1-dependent manner. Antagonism of the progesterone receptor reduced eNOS expression and impaired vasodilation in rats.

RING finger protein 10 attenuates vascular restenosis by inhibiting vascular smooth muscle cell hyperproliferation in vivo and vitro.

Vascular smooth muscle cell (VSMC) hyperproliferation is the main pathological process in various cardiovascular diseases, such as vascular restenosis. This process may be repressed by RING finger protein 10 (RNF10) in metabolic syndrome (MetS) rats. The aim of this study is to evaluate the inhibitory effects and molecular mechanisms of RNF10 on VSMC hyperproliferation. Neointimal hyperplasia in MetS and high-glucose-induced VSMC hyperproliferation were measured after infection with adenoviruses encoding RNF10 (Ad-RNF10), short hairpin RNF10 (Ad-shRNF10), or green fluorescent protein (Ad-GFP). In vivo and in vitro, we found that overexpression of RNF10 significantly affected neointima formation and VSMC proliferation, and displayed further inhibitory activity by promoting mesenchyme homeobox 2 (Meox2) and suppressing activating protein 1 (AP-1). In contrast, Ad-shRNF10 had an opposite effect on neointimal hyperplasia and VSMC hyperproliferation in vivo and in vitro. Our study indicated that RNF10 inhibited the hyperproliferation with the activities of Meox2 and AP-1 proteins. RNF10 may be a next drug target for treating vascular restenosis and other related cardiovascular diseases. © 2018 IUBMB Life, 71(5):632-642, 2019.

Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton's tyrosine kinase inhibitors.

A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07µM. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.

Dapagliflozin ameliorates myocardial infarction injury through AMPKα-dependent regulation of oxidative stress and apoptosis.

Dapagliflozin (DAPA) has been demonstrated to reduce cardiovascular mortality and heart failure hospitalization rates in diabetic patients. However, the mechanism underlying its cardio-protective effect in non-diabetic patients remains unclear. Our study aimed to explore the cardio-protective impact of DAPA on myocardial infarction in non-diabetic mice. We induced myocardial infarction in C57BL/6 mice by ligating the descending branch of the left coronary artery. After surgery, the animals were randomly treated with either saline or DAPA. We employed echocardiography, Western blot analysis, and tissue staining to assess post-infarction myocardial injury. Additionally, we investigated the mechanism of action through cell experiments. Compared to the myocardial infarction group, DAPA treatment significantly attenuated ventricular remodeling and improved cardiac function. By mitigating myocardial oxidative stress and apoptosis, DAPA may activate the AMPKα signaling pathway, thereby exerting a protective effect. These findings suggest that DAPA could serve as a novel therapeutic approach for patients with cardiac infarction.

Unveiling cytokine charge disparity as a potential mechanism for immune regulation.

Cytokines are small signaling proteins that regulate the immune responses to infection and tissue damage. Surface charges of cytokines determine their in vivo fate in immune regulation, e.g., half-life and distribution. The overall negative charges in the extracellular microenvironment and the acidosis during inflammation and infection may differentially impact cytokines with different surface charges for fine-tuned immune regulation via controlling tissue residential properties. However, the trend and role of cytokine surface charges has yet to be elucidated in the literature. Interestingly, we have observed that most pro-inflammatory cytokines have a negative charge, while most anti-inflammatory cytokines and chemokines have a positive charge. In this review, we extensively examined the surface charges of all cytokines and chemokines, summarized the pharmacokinetics and tissue adhesion of major cytokines, and analyzed the link of surface charge with cytokine biodistribution, activation, and function in immune regulation. Additionally, we identified that the general trend of charge disparity between pro- and anti-inflammatory cytokines represents a unique opportunity to develop precise immune modulation approaches, which can be applied to many inflammation-associated diseases including solid tumors, chronic wounds, infection, and sepsis.