Diminished nuclear-localized ß-adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy.

BACKGROUND AND PURPOSE: Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), which is characterized by mesangial matrix expansion that involves dysfunctional mesangial cells (MCs). However, the underlying mechanisms remain unclear. This study aims to delineate the spatiotemporal contribution of adrenergic signalling in diabetic kidney fibrosis to reveal potential therapeutic targets. EXPERIMENTAL APPROACH: A model of diabetic nephropathy was induced by in db/db mice. Gene expression in kidneys was profiled by RNA-seq analyses, western blot and immunostaining. Subcellular-localized fluorescence resonance energy transfer (FRET) biosensors determined adrenergic signalling microdomains in MCs. Effects of oral rolipram, a phosphodiesterase 4 (PDE4) inhibitor, on the model were measured. KEY RESULTS: Our model exhibited impaired kidney function with elevated expression of adrenergic and fibrotic genes, including Adrb1, PDEs, Acta2 and Tgfß. RNA-seq analysis revealed that MCs with dysregulated YAP pathway were crucial to the extracellular matrix secretion in kidneys from diabetic nephropathy patients. In cultured MCs, TGF-ß promoted profibrotic gene transcription, which was regulated by nuclear-localized ß-adrenoceptor signalling. Mechanistically, TGF-ß treatment diminished nuclear-specific cAMP signalling in MCs and reduced PKA-dependent phosphorylation of YAP, leading to its activation. In parallel, db/db mouse kidneys showed increased expressions of PDE4B and PDE4D. Treatment with oral rolipram alleviated kidney fibrosis in db/db mice. CONCLUSION AND IMPLICATIONS: Diabetic nephropathy impaired nuclear-localized ß1-adrenoceptor-cAMP signalling microdomain through upregulating PDE4 expression, promoting fibrosis in MCs via PKA dephosphorylation-dependent YAP activation. Our results suggest PDE4 inhibition as a promising strategy for alleviating kidney fibrosis in diabetic nephropathy.

N-butanol extract of Broussonetia papyrifera (L.) L'Hér. ex Vent root bark alleviates atopic dermatitis by targeting E3 ubiquitin ligase WWP1 to promote NLRP3 degradation.

BACKGROUND: Broussonetia papyrifera (L.) L'Hér. ex Vent (B. papyrifera) is a deciduous tree widely distributed in Asia. Previous studies have revealed that leaves of B. papyrifera ameliorated atopic dermatitis (AD)-like symptoms and inflammatory response. However, the impact and underlying mechanism of other parts of B. papyrifera on AD remain elusive. METHODS: The AD mice induced by 1-Chloro-2,4-dinitrochlorobenzene were used to observe the histopathological alterations in the skin tissues using hematoxylin-eosin staining and toluidine blue staining techniques. Serum levels of inflammatory factors were quantified utilizing ELISA. Pyroptosis was analyzed by lactate dehydrogenase release and flow cytometry in human keratinocytes. The activation of Nod-like receptor protein 3 (NLRP3) inflammasome was analyzed by western blots. Furthermore, the mechanism underlying the inhibition of NLRP3 inflammasome by N-butanol extracts of B. papyrifera root bark (NE-BPRB) was investigated using cellular thermal shift assay and surface plasmon resonance techniques. RESULTS: Treatment with NE-BPRB significantly ameliorated symptoms of AD mice and reduced serum levels of pro-inflammatory factors. NE-BPRB intervention exhibited inhibitory effects on NLRP3 inflammasome activation and pyroptosis in vitro and in vivo. NE-BPRB and its primary bioactive constituent chlorogenic acid (CA) promote the K48-linked ubiquitination of NLRP3, leading to its proteasomal degradation by binding WW domain containing E3 ubiquitin protein ligase 1 (WWP1). CONCLUSIONS: The NE-BPRB and its primary bioactive constituent, CA, effectively inhibit the formation of the NLRP3 inflammasome and impede cell pyroptosis by promoting K48-linked ubiquitin-dependent proteasomal degradation of NLRP3 through binding to the E3 ubiquitin ligase WWP1, thereby resulting in improved AD.

Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). ß-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac ß-adrenoceptors (ßARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local ßAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different ßAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by ß1AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca2+) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced ß1AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the ß1AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with ß1AR were observed. Stimulating ß1AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament ß1AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

Turbulent flow field in maglev centrifugal blood pumps of CH-VAD and HeartMate III: secondary flow and its effects on pump performance.

Secondary flow path is one of the crucial aspects during the design of centrifugal blood pumps. Small clearance size increases stress level and blood damage, while large clearance size can improve blood washout and reduce stress level. Nonetheless, large clearance also leads to strong secondary flows, causing further blood damage. Maglev blood pumps rely on magnetic force to achieve rotor suspension and allow more design freedom of clearance size. This study aims to characterize turbulent flow field and secondary flow as well as its effects on the primary flow and pump performance, in two representative commercial maglev blood pumps of CH-VAD and HeartMate III, which feature distinct designs of secondary flow path. The narrow and long secondary flow path of CH-VAD resulted in low secondary flow rates and low disturbance to the primary flow. The flow loss and blood damage potential of the CH-VAD mainly occurred at the secondary flow path, as well as the blade clearances. By contrast, the wide clearances in HeartMate III induced significant disturbance to the primary flow, resulting in large incidence angle, strong secondary flows and high flow loss. At higher flow rates, the incidence angle was even larger, causing larger separation, leading to a significant decrease of efficiency and steeper performance curve compared with CH-VAD. This study shows that maglev bearings do not guarantee good blood compatibility, and more attention should be paid to the influence of secondary flows on pump performance when designing centrifugal blood pumps.

Leptin combined with withaferin A boost posthemorrhagic neurogenesis via activation of STAT3/SOCS3 pathway.

Neurogenesis as a potential strategy to improve the consequences of intracerebral hemorrhage (ICH). The current study investigates the effects of withaferin A (WFA) in combination with leptin (LEP) on ICH and neurogenesis mechanisms. LEP levels were dramatically reduced on days 7 and 14 following ICH insults in mice, but continuous WFA therapy significantly improved the potency of intrinsic LEP on day 14 after ICH. Furthermore, WFA combined with LEP enhances intrinsic neurogenesis and lessen motor deficits and long-term cognitive outcomes after ICH. In parallel, leptin deficiency in ob/ob mice limits enhancement of neurogenesis following ICH in response to WFA combined with LEP treatment. Importantly, the functional recovery conferred by WFA combined with LEP after ICH was inhibited by neurogenesis suppression. Mechanistically, this study unveiled that the signal transducer and activator of transcription-3 (STAT3) / suppressor of cytokine signaling-3 (SOCS3) pathway is a critical signaling pathway through which WFA combined with LEP treatment promotes intrinsic neurogenesis after ICH. Collectively, the results of this study elucidate the neuroprotective effects of WFA and LEP in ICH, and highlight a potential approach for ICH cell therapy.

ßIV-Spectrin in Cardiac Fibroblasts: Implications for Fibrosis and Therapeutic Targeting in Cardiac Diseases. Comment on Nassal et al. Spectrin-Based Regulation of Cardiac Fibroblast Cell-Cell Communication. Cells 2023, 12, 748.

Fibroblasts in the heart, traditionally recognized as interstitial cells, have long been overlooked in the study of cardiac physiology and pathology [...].

Temporal trends of breast cancer burden in the Western Pacific Region from 1990 to 2044: Implications from the Global Burden of Disease Study 2019.

INTRODUCTION: Breast cancer (BC) is a malignant disease that occurs worldwide and poses serious health burden. OBJECTIVES: To assess the prevalence of BC burden in the Western Pacific region (WPR) from 1990 to 2019, and to predict trends from 2020 to 2044. To analyze the driving factors and put forward the region-oriented improvement. METHODS: Based on the Global Burden of Disease Study 2019, BC cases, deaths, disability-adjusted life years (DALYs) cases, age-standardized incidence rate (ASIR), age-standardized death rate (ASDR), and age-standardized DALYs rate in WPR from 1990 to 2019 was obtained and analysed. Age-period-cohort (APC) model was used to analyze age, period, and cohort effects in BC, and Bayesian APC (BAPC) was used to predict trends over the next 25 years. RESULTS: In conclusion, BC incidence and deaths in the WPR have increased rapidly over the past 30 years and are expected to continue to increase between 2020 and 2044. Among behavioral and metabolic factors, high body-mass index was the main risk factor for BC mortality in middle-income countries, whereas alcohol use was the main risk factor in Japan. Age is a key factor in the development of BC, with 40 years being the critical point. Incidence trends coincide with the course of economic development. CONCLUSIONS: The BC burden remains an essential public health issue in the WPR and will increase substantially in the future. More efforts should be made in middle-income countries to prompt the health behavior and minimize the burden of BC because these nations accounts for the majority of BC burden in the WPR.

Spatial effects of public health laboratory emergency testing institutions under COVID-19 in China.

BACKGROUND: The transmission of 2019 novel coronavirus (COVID-19) has caused global panic in the past three years. Countries have learned an important lesson in the practice of responding to COVID-19 pandemic: timely and accurate diagnosis is critical. As an important technology of virus diagnosis, nucleic acid testing (NAT) is also widely used in the identification of other infectious diseases. However, geographic factors often constrain the provision of public health services such as NAT services, and the spatial nature of their resource allocation is a significant problem. METHODS: We used OLS, OLS-SAR, GWR, GWR-SAR, MGWR, and MGWR-SAR models to identify the determinants of spatial difference and spatial heterogeneity affecting NAT institutions in China. RESULTS: Firstly, we identify that the distribution of NAT institutions in China shows a clear spatial agglomeration, with an overall trend of increasing distribution from west to east. There is significant spatial heterogeneity in Chinese NAT institutions. Secondly, the MGWR-SAR model results show that city level, population density, number of tertiary hospitals and number of public health emergency outbreaks are important factors influencing the spatial heterogeneity of NAT institutions in China. CONCLUSIONS: Therefore, the government should allocate health resources rationally, optimise the spatial layout of testing facilities, and improve the ability to respond to public health emergencies. Meanwhile, third-party testing facilities need to focus on their role in the public health emergency response system as a market force to alleviate the inequitable allocation of health resources between regions. By taking these measures to prepare adequately for possible future public health emergencies.

Point-of-Care Testing for Norovirus Typing Using CRISPR/Cas12a Combined with Reverse Transcription Recombinase Polymerase Amplification.

Noroviruses (NoVs) are one of the leading causes of acute gastroenteritis in humans. This study combined reverse transcription recombinase polymerase amplification (RT-RPA) with a clustered regularly interspaced short palindromic repeat/CRISPR-associated protein (CRISPR/Cas) nucleic acid detection system to develop a point-of-care testing (POCT) technology for typing NoVs. The detection can be completed within 35 min at 37 °C, covering each genotype of genogroup I (GI) and II (GII) NoVs. The sensitivity of this method is 10 copies/µL for GI and 1 copy/µL for GII NoV plasmids. For the detection of clinical samples, the detection results of this method for NoV infected samples are consistent with the RT-qPCR detection method in the laboratory, and this detection method has no cross-reactivity with rotavirus and adenovirus. Therefore, the detection method established in this study enables the diagnosis and screening of suspected patients and close contacts by POCT, which is important for the timely identification and control of NoV outbreaks. In addition, the typing detection of GI and GII NoVs can achieve a precise diagnosis and treatment of patients infected with NoVs.

Hyperhomocysteinemia activates NLRP3 inflammasome to cause hepatic steatosis and insulin resistance via MDM2-mediated ubiquitination of HSF1.

Hyperhomocysteinemia (HHcy) is associated with nonalcoholic fatty liver disease (NAFLD) and insulin resistance (IR). However, the underlying mechanism is still unknown. Recent studies have demonstrated that NLRP3 inflammasome activation plays a vital role in NAFLD and IR. Our study aimed to explore whether NLRP3 inflammasome contributed to HHcy-induced NAFLD and IR as well as dissected the underlying mechanism. C57BL/6 mice were fed a high-methionine diet (HMD) for 8 weeks to establish the HHcy mouse model. Compared with a chow diet, HMD induced hepatic steatosis (HS) and IR as well as activation of hepatic NLRP3 inflammasome. Moreover, HHcy-induced NAFLD and IR characterization disclosed that NLRP3 inflammasome activation occurred in liver tissue of HMD-fed mice, but was very marginal in either NLRP3-/- or Caspase-1-/- mice. Mechanistically, high levels of homocysteine (Hcy) up-regulated the expression of mouse double minute 2 homolog (MDM2), which directly ubiquitinates heat shock transcription factor 1 (HSF1) and consequently activated hepatic NLRP3 inflammasome in vivo and in vitro. In addition, in vitro experiments showed P300-mediated HSF1 acetylation at K298 hindered MDM2-mediated ubiquitination of HSF1 at K372, which plays important role in determining the HSF1 level. Importantly, either inhibition of MDM2 by JNJ-165 or activation of HSF1 by HSF1A reversed HMD-induced hepatic NLRP3 inflammasome, and consequently alleviated HS and IR in mice. This study demonstrates that NLRP3 inflammasome activation contributes to HHcy-induced NAFLD and IR, and further identified that HSF1 as a new substrate of MDM2 and its decrease on MDM2-mediated ubiquitination at K372 modulates NLRP3 inflammasome activation. These findings may provide novel therapeutic strategies aimed at halting HS or IR.

Application of spatial transcriptome technologies to neurological diseases.

Spatial transcriptome technology acquires gene expression profiles while retaining spatial location information, it displays the gene expression properties of cells in situ. Through the investigation of cell heterogeneity, microenvironment, function, and cellular interactions, spatial transcriptome technology can deeply explore the pathogenic mechanisms of cell-type-specific responses and spatial localization in neurological diseases. The present article overviews spatial transcriptome technologies based on microdissection, in situ hybridization, in situ sequencing, in situ capture, and live cell labeling. Each technology is described along with its methods, detection throughput, spatial resolution, benefits, and drawbacks. Furthermore, their applications in neurodegenerative disease, neuropsychiatric illness, stroke and epilepsy are outlined. This information can be used to understand disease mechanisms, pick therapeutic targets, and establish biomarkers.

Determining the spatial non-stationarity underlying social and natural environment in thyroid cancer in China.

BACKGROUND: Light at night (LAN) is a physiological environmental factor related to thyroid cancer (TC). The spatial relationship between the number of TC incident cases, LAN, air pollution and other macro social factors and stationarity needs to be further examined to provide evidence for regional control of TC. METHODS: Spatial econometrics methods for spatial nonstationarity were used to explore the impacts of LAN, air pollutants, economic factors, and population size on the number of TC incident cases in 182 Chinese prefecture-level cities and the local coefficients were further tested for nonstationarity. Temporally weighted regression (TWR), geographically weighted regression (GWR), and geographically and temporally weighted regression (GTWR) were compared in this study for model selection. RESULTS: Based on the ordinary least squares (OLS), LAN, air pollutants, and urbanization all significantly affected the number of TC incident cases. GWR had the best goodness of fit, and the coefficients of all the variables passed the nonstationarity test. The strong positive impact of LAN was mainly concentrated in North China, air pollutants in Central China and neighboring regions, and urbanization in the eastern coast of China. CONCLUSIONS: The locational factors of the prefecture-level city influence the spatial pattern of the number of TC incident cases. Governments should pay attention to this influence, adhere to the Health in All Policies principle, and formulate region-specific policies based on regional characteristics, which this study provides updated evidence for.

Influence of Inlet Boundary Conditions on the Prediction of Flow Field and Hemolysis in Blood Pumps Using Large-Eddy Simulation.

Inlet boundary conditions (BC) are one of the uncertainties which may influence the prediction of flow field and hemolysis in blood pumps. This study investigated the influence of inlet BC, including the length of inlet pipe, type of inlet BC (mass flow rate or experimental velocity profile) and turbulent intensity (no perturbation, 5%, 10%, 20%) on the prediction of flow field and hemolysis of a benchmark centrifugal blood pump (the FDA blood pump) and a commercial axial blood pump (Heartmate II), using large-eddy simulation. The results show that the influence of boundary conditions on integral pump performance metrics, including pressure head and hemolysis, is negligible. The influence on local flow structures, such as velocity distributions, mainly existed in the inlet. For the centrifugal FDA blood pump, the influence of type of inlet BC and inlet position on velocity distributions can also be observed at the diffuser. Overall, the effects of position of inlet and type of inlet BC need to be considered if local flow structures are the focus, while the influence of turbulent intensity is negligible and need not be accounted for during numerical simulations of blood pumps.

Withaferin A inhibits ferroptosis and protects against intracerebral hemorrhage.

Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage (ICH). Withaferin A (WFA), a natural compound, exhibits a positive effect on a number of neurological diseases. However, the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown. In this study, we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis. We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH. WFA was injected intracerebroventricularly at 0.1, 1 or 5 µg/kg once daily for 7 days, starting immediately after ICH operation. WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage. Through in vitro experiments, cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury. Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde, an oxidative stress marker, and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH. Western blot assay, quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling axis, promoted translocation of Nrf2 from the cytoplasm to nucleus, and increased HO-1 expression. Silencing Nrf2 with siRNA completely reversed HO-1 expression, oxidative stress and protective effects of WFA. Furthermore, WFA reduced hemin-induced ferroptosis. However, after treatment with an HO-1 inhibitor, the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened. MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell injury. Our findings reveal that WFA treatment alleviated ICH injury-induced ferroptosis and oxidative stress through activating the Nrf2/HO-1 pathway, which may highlight a potential role of WFA for the treatment of ICH.

Time tracking and multidimensional influencing factors analysis on female breast cancer mortality: Evidence from urban and rural China between 1994 to 2019.

Background: There are huge differences in female breast cancer mortality between urban and rural China. In order to better prevent breast cancer equally in urban and rural areas, it is critical to trace the root causes of past inequities and predict how future differences will change. Moreover, carcinogenic factors from micro-individual to macro-environment also need to be analyzed in detail. However, there is no systematic research covering these two aspects in the current literature. Methods: Breast cancer mortality data in urban and rural China from 1994 to 2019 are collected, which from China Health Statistical Yearbook. The Age-Period-Cohort model is used to examine the effects of different age groups, periods, and birth cohorts on breast cancer mortality. Nordpred project is used to predict breast cancer mortality from 2020 to 2039. Results: The age effect gradually increases and changes from negative to positive at the age of 40-44. The period effect fluctuates very little and shows the largest difference between urban and rural areas in 2019. The birth cohort effect gradually decreases with urban-rural effects alternating between strong and weak. In the predicted results, the urban-rural mortality gap becomes first narrow and then wide and shows a trend of younger death. Conclusions: From the perspective of a temporal system, the changing trend of breast cancer mortality is highly consistent with the history of social and economic structural changes in China. From the perspective of the theory of social determinants of health, individuals, families, institutions and governments need to participate in the prevention of breast cancer.

Government drivers of breast cancer prevention: A spatiotemporal analysis based on the association between breast cancer and macro factors.

Background: Currently, breast cancer (BC) is ranked among the top malignant tumors in the world, and has attracted widespread attention. Compared with the traditional analysis on biological determinants of BC, this study focused on macro factors, including light at night (LAN), PM2.5, per capita consumption expenditure, economic density, population density, and number of medical beds, to provide targets for the government to implement BC interventions. Methods: A total of 182 prefecture-level cities in China from 2013 to 2016 were selected as the sample of the study. The geographically and temporally weighted regression (GTWR) model was adopted to describe the spatiotemporal correlation between the scale of BC and macro factors. Results: The results showed that the GTWR model can better reveal the spatiotemporal variation. In the temporal dimension, the fluctuations of the regression coefficients of each variable were significant. In the spatial dimension, the positive impacts of LAN, per capita consumption expenditure, population density and number of medical beds gradually increased from west to east, and the positive coefficient of PM2.5 gradually increased from north to south. The negative impact of economic density gradually increased from west to east. Conclusion: The fact that the degree of effect of each variable fluctuates over time reminds the government to pay continuous attention to BC prevention. The spatial heterogeneity features also urge the government to focus on different macro indicators in eastern and western China or southern and northern China. In other words, our research helps drive the government to center on key regions and take targeted measures to curb the rapid growth of BC.

Characterization of Chlamydia muridarum TC0668 Protein: Localization, Expression, and Inflammation-Inducing Effects on Host Cell.

The objective of this study is to elucidate the basic biological properties and function of TC0668 in vitro. Laser confocal microscopy and immune-electron microscopy were used to detect localization of TC0668 in Chlamydia-infected human epithelial cells, while the expression phase was investigated by qRT-PCR and western blot analysis. Protein array technology was employed to evaluate differences in cytokine secretion between cells infected with tc0668 single mutants and those infected with tc0668 null mutants. We found that TC0668 is restricted to the chlamydial inclusion. Translation and transcription of TC0668 were detected at 4 h and peaked at 16 h during the life cycle of Chlamydia in vitro. The cytokines produced by tc0668 single mutant infected cultures compared with tc0668 null mutant group indicated that 36 cytokines were downregulated, while 10 were up-regulated significantly. C. muridarum bearing a single tc0668 gene mutation have decreased urogenital pathogenicity that is explained by the effects of the mutation on the regulation of inflammation-related cytokine secretion.

Leptin Promotes Angiogenesis via Pericyte STAT3 Pathway upon Intracerebral Hemorrhage.

Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin potentiates angiogenesis and plays a beneficial role in stroke. However, the proangiogenic effect of leptin on ICH has not been adequately explored. Moreover, leptin triggers post-ICH angiogenesis through pericyte, an important component of forming new blood vessels, which remains unclear. Here, we reported that exogenous leptin infusion dose-dependent promoted vascular endothelial cells survival and proliferation at chronic stage of ICH mice. Additionally, leptin robustly ameliorated pericytes loss, enhanced pericytes proliferation and migration in ICH mice in vivo, and in ICH human brain microvascular pericytes (HBVPC) in vitro. Notably, we showed that pericytes-derived pro-angiogenic factors were responsible for enhancing the survival, proliferation and tube formation followed leptin treatment in human brain microvascular endothelial cells (HCMEC/D3)/HBVPC co-culture models. Importantly, considerable improvements in neurobehavioral function and hostile microenvironment were observed in leptin treatment ICH mice, indicating that better vascular functionality post ICH improves outcome. Mechanistically, this study unveiled that leptin boost post-ICH angiogenesis potentially through modulation of leptin receptor (leptinR)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pericyte. Thus, leptin may be a lucrative option for the treatment of ICH.

Palbociclib Induces the Apoptosis of Lung Squamous Cell Carcinoma Cells via RB-Independent STAT3 Phosphorylation.

Lung squamous cell carcinoma (LUSC) treatment response is poor and treatment alternatives are limited. Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients and applied in multiple preclinical models, but its use for LUSC therapy remains elusive. Here, we investigated whether palbociclib induced cell apoptosis and dissected the underlying mechanism in LUSC. We found that palbociclib induced LUSC cell apoptosis through inhibition of Src tyrosine kinase/signal transducers and activators of transcription 3 (STAT3). Interestingly, palbociclib reduced STAT3 signaling in LUSC cells interfered by retinoblastoma tumor-suppressor gene (RB), suggesting that pro-apoptosis effect of palbociclib was independent of classic CDK4/6-RB signaling. Furthermore, palbociclib could suppress IL-1ß and IL-6 expression, and therefore blocked Src/STAT3 signaling, which were rescued by either recombinant human IL-1ß or IL-6. Moreover, Myc mediated the sensitivity of LUSC cells to palbociclib. Our discoveries demonstrated that palbociclib induces apoptosis of LUSC cells through the Src/STAT3 axis in an RB-independent manner, and provided a reliable experimental basis of clinical studies in LUSC patients.

Hemorrhage-Induced Sphingosine Kinase 1 Contributes to Ferroptosis-Mediated Secondary Brain Injury in Intracerebral Hemorrhage.

The pathogenic processes of brain injury after intracerebral hemorrhage (ICH) have not yet been fully elucidated. Increasing evidence suggests that ferroptosis activation aggravates injury after ICH, but the underlying mechanism remains unclear. Sphingosine kinase 1 (Sphk1) is a key enzyme in the regulation of sphingosine metabolism involved in the ferroptosis pathway, but its role in ICH needs clarification. In this study, transcriptional changes in ICH patients were assessed by microarray data, exposing Sphk1 as a highly upregulated gene during ICH. Furthermore, Sphk1 chemical inhibitors and siRNA were used to inhibit ICH-induced Sphk1 upregulation in in vivo and in vitro models, showing that Sphk1 inhibition after protects against ferroptosis and attenuates secondary brain injury and cell death. Mechanistically, this study unveiled that sphingosine kinase 1/sphingosine 1-phosphate/extracellular-regulated protein kinases/phosphorylated extracellular-regulated protein kinases (Sphk1/S1p/ERK/p-ERK) pathway is responsible for regulation of ferroptosis leading to secondary brain injury and cell death following ICH. Collectively, this study demonstrates that ferroptosis is closely associated with ICH, and that Sphk1 has a critical role in this lethal process. These results suggest a novel unique and effective therapeutic approach for ICH prevention and treatment.