HSP27 Alleviates Cardiac Aging in Mice via a Mechanism Involving Antioxidation and Mitophagy Activation

Aging-induced cardiac dysfunction is a prominent feature of cardiac aging. Heat shock protein 27 (HSP27) protects cardiac function against ischemia or chemical challenge. We hypothesized that HSP27 attenuates cardiac aging. Transgenic (Tg) mice with cardiac-specific expression of the HSP27 gene and wild-type (WT) littermates were employed in the experiments. Echocardiography revealed a significant decline in the cardiac function of old WT mice compared with young WT mice. In striking contrast, the aging-induced impairment of cardiac function was attenuated in old Tg mice compared with old WT mice. Levels of cardiac aging markers were lower in old Tg mouse hearts than in old WT mouse hearts. Less interstitial fibrosis and lower contents of reactive oxygen species and ubiquitin-conjugated proteins were detected in old Tg hearts than in old WT hearts. Furthermore, old Tg hearts demonstrated lower accumulation of LC3-II and p62 than old WT hearts. Levels of Atg13, Vps34, and Rab7 were also higher in old Tg hearts than in old WT hearts. Additionally, old Tg hearts had higher levels of PINK1 and Parkin than old WT hearts, suggesting that mitophagy was activated in old Tg hearts. Taken together, HSP27 alleviated cardiac aging and this action involved antioxidation and mitophagy activation

HSPA12B Attenuated Acute Myocardial Ischemia/reperfusion Injury via Maintaining Endothelial Integrity in a PI3K/Akt/mTOR-dependent Mechanism

Endothelial damage is a critical mediator of myocardial ischemia/reperfusion (I/R) injury. HSPA12B is an endothelial-cell-specifically expressed heat shock protein. However, the roles of HSPA12B in acute myocardial I/R injury is unknown. Here we reported that myocardial I/R upregulated HSPA12B expression in ventricular tissues, and endothelial overexpression of HSPA12B in transgenic mice (Tg) limited infarct size, attenuated cardiac dysfunction and improved cardiomyocyte survival compared with their wild type littermates. These improvements were accompanied with the diminished myocardial no-reflow phenomenon, decreased microvascular leakage, and better maintained endothelial tight junctions. The I/R-evoked neutrophil infiltration was also suppressed in Tg hearts compared with its wild type (WT) littermates. Moreover, Tg hearts exhibited the enhanced activation of PI3K/Akt//mTOR signaling following I/R challenge. However, pharmacological inhibition of PI3K abolished the HSPA12B-induced cardioprotection against myocardial I/R injury. The data demonstrate for the first time that the endothelial HSPA12B protected hearts against myocardial I/R injury. This cardioprotective action of HSPA12B was mediated, at least in part, by improving endothelial integrity in a PI3K/Akt/mTOR-dependent mechanism. Our study suggests that targeting endothelial HSPA12B could be an alternative approach for the management of patients with myocardial I/R injury

HSPA12A Is Required for Adipocyte Differentiation and Diet-Induced Obesity Through a Positive Feedback Regulation With PPARγ

Obesity is one of the most serious public health problems. Peroxisome proliferator-activated receptor γ (PPARγ) plays the master role in adipocyte differentiation for obesity development. However, optimum anti-obesity drug has yet been developed, mandating more investigation to identify novel regulator in obesity pathogenesis. Heat shock protein 12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that obese patients showed increased adipose HSPA12A expression, which was positively correlated with increase of body mass index. Intriguingly, knockout of HSPA12A (Hspa12a−/−) in mice attenuated high-fat diet (HFD)-induced weight gain, adiposity, hyperlipidemia, and hyperglycemia compared to their wild type (WT) littermates. Increased insulin sensitivity was observed in Hspa12a−/− mice compared to WT mice. The HFD-induced upregulation of PPARγ and its target adipogenic genes in white adipose tissues (WAT) of Hspa12a−/− mice were also attenuated. Loss- and gain-of-function studies revealed that the differentiation of primary adipocyte precursors, as well as the expression of PPARγ and target adipogenic genes during the differentiation, was suppressed by HSPA12A deficiency whereas promoted by HSPA12A overexpression. Importantly, PPARγ inhibition by GW9662 reversed the HSPA12A-mediated adipocyte differentiation. On the other hand, HSPA12A expression was downregulated by PPARγ inhibition but upregulated by PPARγ activation in primary adipocytes. A direct binding of PPARγ to the PPAR response element in the Hspa12a promoter region was confirmed by chromatin immunoprecipitation assay, and this binding was increased after differentiation of primary adipocytes. These findings indicate that HSPA12A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. HSPA12A inhibition might represent a viable strategy for the management of obesity in humans

HSPA12A Attenuates Lipopolysaccharide-Induced Liver Injury Through Inhibiting Caspase-11-Mediated Hepatocyte Pyroptosis via PGC-1α-Dependent Acyloxyacyl Hydrolase Expression

Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A (HSPA12A) is a novel member of the HSP70 family. Here, we report that LPS increased HSPA12A nuclear translocation in hepatocytes, while knockout of HSPA12A (Hspa12a−/−) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMDNterm (markers of pyroptosis) were greater in livers of Hspa12a−/− mice compared with its wild type controls. Loss- and gain-of-function studies showed that HSPA12A deficiency promoted, whereas HSPA12A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMDNterm generation in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by HSPA12A deficiency, whereas AOAH overexpression reversed the HSPA12A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that HSPA12A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed HSPA12A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte HSPA12A represents a viable strategy for the management of liver injury in sepsis patients

HSPA12B Promotes Functional Recovery After Ischaemic Stroke Through an eNOS-Dependent Mechanism

Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Stroke is the leading cause of disability worldwide. HSPA12B, a heat-shock protein recently identified expression specifically in endothelial cells, is able to promote angiogenesis. Here, we have investigated its effects on functional recovery at chronic phase of ischaemic stroke. Ischaemic stroke was induced by 60 min. of middle cerebral artery occlusion in transgenic mice with overexpression of HSPA12B (HSPA12B Tg) and wild-type littermates (WT). HSPA12B Tg mice demonstrated a significant higher survival rate than WT mice within 28 days post-stroke. Significant improved neurological functions, increased spontaneous locomotor activity and decreased anxiety were detected inHSPA12B Tg mice compared with WT controls within 21 days post-stroke. Stroke-induced hippocampal degeneration was attenuated in HSPA12B Tg mice examined at day 28 post-stroke. Interestingly, HSPA12B Tg mice showed enhanced peri-infarct angiogenesis (examined 28 days post-stroke) and hippocampal neurogenesis (examined 7 days post-stroke), respectively, compared to WT mice. The stroke-induced eNOS phosphorylation and TGF-β1 expression were augmented in HSPA12B Tg mice. However, administration with eNOS inhibitor L-NAME diminished the HSPA12B-induced protection in neurological functional recovery and mice survival post-stroke. The data suggest that HSPA12B promoted functional recovery and survival after stroke in an eNOS-dependent mechanism. Targeting HSPA12B expression may have a therapeutic potential for the stroke-evoked functional disability and mortality

HSPA12A Unstabilizes CD147 to Inhibit Lactate Export and Migration in Human Renal Cell Carcinoma

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Background: Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. Methods: HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. Results: RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Conclusion: Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis

A review of different ventilation methods for controlling the transmission of the virus during the COVID-19 pandemic

With the COVID-19 pandemic sweeping worldwide, much attention has been paid to infectious viruses. Because of the different sizes of pathogen-carrying droplets exhaled by individuals infected with COVID-19, the influence of gravity and inertia on the droplets varies, which leads to different modes of transmission of the virus. Ventilation changes the air distribution in a room, and affects virus transmission. An appropriate ventilation method that reduces the floating time of viruses and the exposure rate of the human body should be selected. Although previous studies have extensively reviewed methods to reduce the airborne transmission of viruses, research on ventilation methods remain limited. This review aimed to explore a ventilation mode that could ensure the thermal comfort and maintain low exposure and infection rates in the human body. This study investigated the transmission modes of the virus and the importance of particle size. The effects of mixing ventilation, displacement ventilation, impinging jet ventilation, and stratum ventilation on the removal of different particle sizes and applications at various locations were compared. The results of this study can contribute to reducing the indoor virus concentrations during the COVID-19 pandemic

Research on radiation characteristics of dipole antenna modulation by sub-wavelength inhomogeneous plasma layer

The modulation and enhancement effect of sub-wavelength plasma structures on compact antennas exhibits obvious technological advantage and considerable progress. In order to extend the availability of this technology under complex and actual environment with inhomogeneous plasma structure, a numerical simulation analysis based on finite element method has been conducted in this paper. The modulation function of the antenna radiation with sub-wavelength plasma layer located at different positions was investigated, and the inhomogeneous plasma layer with multiple electron density distribution profiles were employed to explore the effect of plasma density distribution on the antenna radiation. It has been revealed that the optical near-field modulated distance and reduced plasma distribution are more beneficial to enhance the radiation. On the basis above, an application-focused research about communication through the plasma sheath surrounding a hypersonic vehicle has been carried out aiming at exploring an effective communication window. The relevant results devote guiding significance in the field of antenna radiation modulation and enhancement, as well as the development of communication technology in hypersonic flight

MOFs-Derived Porous NiFe2O4 Nano-Octahedrons with Hollow Interiors for an Excellent Toluene Gas Sensor

Toluene is extensively used in many industrial products, which needs to be effectively detected by sensitive gas sensors even at low-ppm-level concentrations. Here, NiFe2O4 nano-octahedrons were calcinated from NiFe-bimetallic metal-organic framework (MOFs) octahedrons synthesized by a facile refluxing method. The co-existence of p-Phthalic acid (PTA) and 3,3-diaminobenzidine (DAB) promotes the formation of smooth NiFe-bimetallic MOFs octahedrons. After subsequent thermal treatment, a big weight loss (about 85%) transformed NiFe2O4 nanoparticles (30 nm) into NiFe2O4 porous nano-octahedrons with hollow interiors. The NiFe2O4 nano-octahedron based sensor exhibited excellent gas sensing properties for toluene with a nice stability, fast response, and recovery time (25 s/40 s to 100 ppm toluene), and a lower detection limitation (1 ppm) at 260 °C. The excellent toluene-sensing properties can not only be derived from the hollow interiors combined with porous nano-octahedrons to favor the diffusion of gas molecules, but also from the efficient catalytic activity of NiFe2O4 nanoparticles