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Aims  Increased myofilament contractility is recognized as a crucial factor in the pathogenesis of hypertrophic cardiomyopathy (HCM). Direct myofilament desensitization might be beneficial in preventing HCM disease progression. Here, we tested whether the small molecule fropofol prevents HCM phenotype expression and disease progression by directly depressing myofilament force development. Methods and results  Force, intracellular Ca2+, and steady-state activation were determined in isolated trabecular muscles from wild-type (WT) and transgenic HCM mice with heterozygous human α-myosin heavy chain R403Q mutation (αMHC 403/+). αMHC 403/+ HCM mice were treated continuously with fropofol by intraperitoneal infusion for 12 weeks. Heart tissue was analysed with histology and real-time PCR of prohypertrophic and profibrotic genes. Fropofol decreased force in a concentration-dependent manner without significantly altering [Ca2+]i in isolated muscles from both WT and αMHC 403/+ HCM mouse hearts. Fropofol also depressed maximal Ca2+-activated force and increased the [Ca2+]i required for 50% activation during steady-state activation. In whole-animal studies, chronic intra-abdominal administration of fropofol prevented hypertrophy development and diastolic dysfunction. Chronic fropofol treatment also led to attenuation of prohypertrophic and profibrotic gene expression, reductions in cell size, and decreases in tissue fibrosis. Conclusions  Direct inhibition of myofilament contraction by fropofol prevents HCM disease phenotypic expression and progression, suggesting that increased myofilament contractile force is the primary trigger for hypertrophy development and HCM disease progression. [ABSTRACT FROM AUTHOR]

Background/Aims: We have reported the neuroprotective properties of Heat shock protein B8(HSPB8) against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury by inhibiting the mitochondrial apoptotic pathway. However, the exact underlying mechanism of its protective effect on mitochondrial function remains unknown. Here we examined whether the beneficial effect of HSPB8 on OGD/R-induced cell death is associated with mitophagy in mouse neuroblastoma Neuro2a (N2a) cells. Methods: Using the mouse transient middle cerebral artery occlusion (tMCAO) model and mouse neuroblastoma Neuro2a (N2a) cell cultures subjected to OGD/R, we employed western-blot, RT-PCR and immunostaining to analyze the change of expression pattern of HSPB8 and mitophagic flux after brain I/R both in vivo and in vitro. Moreover, via overexpressing HSPB8 or knocking down HSPB8 expression with siRNA in N2a cell, we evaluated the effect of HSPB8 on mitochondrial function during OGD/R. The impact of HSPB8 on mitophagic pathway was also assessed. Finally, mitotophagy inhibitors (CQ and Mdivi-1) were adopted to verify the involvement of mitophagy in HSPB8- induced neuroprotection. Results: HSPB8 could be up-regulated by brain I/R both in vivo and in vitro. Mitophagy enhancement coincided with induction of HSPB8 during I/R. Overexpression of HSPB8 reinforced I/R-induced mitophagy in OGD/R-treated mouse N2a cells and HSPB8 silence suppressed mitophagy process. Inhibition of mitophagy compromised neuroprotection conferred by HSPB8 overexpression. Conclusions: HSPB8 promoted OGD/R-induced mitophagy, which restored the mitochondrial function and contributed to the decrease in cell apoptosis after OGD/R. Therefore, HSPB8 could be a favorable neuroprotective agent for cerebral I/R related disorders. [ABSTRACT FROM AUTHOR]

HSPB6(Heat shock protein B6), is also referred to as P20/HSP20. Unlike other many other members of sHSP(small Heat shock protein) family, which tend to form high-molecular-mass oligomers, in solution, human HSPB6 only forms dimers. However, it still exhibits chaperon-like activity comparable with that of HSPB5. It is expressed ubiquitously, with high and constitutive expression in muscular tissues. sHSPs characteristically function as molecular chaperones and HSPB6 also has a molecular chaperone activity. HSPB6 is up-regulated in response to diverse cellular stress or damage and protect cells from otherwise lethal conditions. HSPB6 is widely recognized as a principle mediator of cardioprotective signaling and recent studies have unraveled the protective role of HSPB6 in disease or injury to the central nervous system. Moreover, accumulating evidence has implicated HSPB6 as a key mediator of diverse vital physiological processes, such as smooth muscle relaxation, platelet aggregation. The versatility of HSPB6 can be explained by its direct involvement in regulating different client proteins and its ability to form heterooligomer with other sHSPs, which seems to be dependent on HSPB6 phosphorylation. This review focuses on the properties including expression and regulation pattern, phosphorylation, chaperon activity, multiple cellular targets of HSPB6, as well as its possible role in physical and pathological conditions. [ABSTRACT FROM AUTHOR]

The incidence of intrahepatic cholangiocarcinoma (ICC) is steadily rising, and it is associated with a high mortality rate. Clinical samples were collected to detect the expression of HSPB8 and BAG3 in ICC tissues. ICC cells were cultured and transfected with plasmids that overexpressed or silenced specific genes to investigate the impact of gene expression alterations on cell function. qPCR and Western blot techniques were utilized to measure gene and protein expression levels. A wound healing assay was conducted to assess cell migration ability. The Transwell assay was used to assess cell invasion ability. Co-IP was used to verify the binding relationship between HSPB8 and BAG3. The effects of HSPB8 and BAG3 on lung metastasis of tumors in vivo were verified by constructing a metastatic tumor model. Through the above experiments, we discovered that the expressions of HSPB8 and BAG3 were up-regulated in ICC tissues and cells, and their expressions were positively correlated. The metastatic ability of ICC cells could be promoted or inhibited by upregulating or downregulating the expression of BAG3. Furthermore, the HSPB8-BAG3 chaperone complex resulted in the abnormal degradation of Filamin A by activating autophagy. Increased expression of Filamin A inhibits the migration and invasion of ICC cells. Overexpression of HSPB8 and BAG3 in vivo promoted the lung metastasis ability of ICC cells. The HSPB8-BAG3 chaperone complex promotes ICC cell migration and invasion by regulating CASA-mediated degradation of Filamin A, offering insights for enhancing ICC therapeutic strategies.

Background: Geranylgeranylacetone (GGA) has been recently reported to be centrally active after oral administration and protect against ischemic brain injury. This study was aimed to investigate the underlying mechanism of the protective effect of GGA., Methods: In this study, transient middle cerebral artery occlusion (tMCAO) was established. Neurological score and brain water content were adopted to investigate the role of GGA in vivo . Evans-blue (EB), western blot and immunofluorescence staining of tight junction proteins were performed to evaluate blood brain barrier (BBB) permeability. Inflammation response was assessed by immunofluorescence staining of MPO and Iba-1 and quantitative real-time polymerase chain reaction (qRT-PCR) of proinflammatory cytokines. In in vitro experiment, after oxygen-glucose deprivation (OGD), transepithelial electrical resistance (TEER) and endothelial cell monolayer permeability assay were conducted to examine the effects of GGA on barrier integrity. Furthermore, heat shock protein (HSP) 70 expression was knockdown by RNA interference in bEnd.3 cells to verify the involvement of HSP70 in the action of GGA. TEER, endothelial cell monolayer permeability, CCK8 and flow cytometry were performed. Expression of caspase-3 was detected by western blot and immunofluorescence staining., Results: Our results indicated that pretreatment with a single oral GGA dose (800 mg/kg) reduced the infarct volume and prevented the neurological impairments after tMCAO. Importantly, GGA ameliorated cerebral ischemia/reperfusion (I/R) induced BBB breakdown and rescued tight junction proteins (TJPs). GGA also profoundly decreased neutrophil infiltration, inhibited glial activation and reduced the expression of proinflammatory cytokines. Consistently, GGA significantly decreased OGD-induced BBB hyper-permeability in vitro . Consistent with the previous studies, GGA promoted HSP70 induction after I/R insult. Mechanistic study showed that GGA inhibited OGD-induced apoptosis of bEnd.3 cells. Genetic inhibition of HSP70 attenuated GGA's anti-apoptotic effect and reversed the protective effects of GGA., Competing Interests: None., (AJTR Copyright © 2021.)

Heat-shock protein B8 (HSPB8) has been recently reported to confer neuroprotection against ischemia/reperfusion (I/R)-induced cerebral injury in vivo and in vitro. However, the molecular mechanism is still elusive. This study focused on the effect of intracerebroventricular (i.c.v) delivery of lenti-HSPB8 virus against neurological injury in a rat model of cerebral I/R and explored the underlying mechanism. We found that lentivirus i.c.v injection-induced HSPB8 over-expression strongly alleviated infarct volume, improved neurobehavioral outcomes, and reduced brain edema in rat middle cerebral artery occlusion/reperfusion (MCAO/R) model. Concomitantly, HSPB8 over-expression noticeably prevented blood-brain barrier (BBB) disruption after cerebral I/R injury as indicated by the reduction in Evans blue leakage and IgG detection in the ipsilateral hemisphere compared with the vehicle group. Moreover, immunoblotting and immunofluorescence staining of tight junction proteins claudin-5 and occludin showed that HSPB8 over-expression prevented the degradation of these proteins induced by MCAO/R, which indicated the protective effect of HSPB8 on BBB. Western blotting and immunostaining techniques were also utilized to analyze the expression of the markers of autophagy. We found that HSPB8 over-expression promoted autophagic flux, evidenced by increased ratio of LC3 I/II, accumulation of Beclin-1 expression and enhanced p62 degradation. i.c.v injection of 15 μg autophagy inhibitor 3-methyladenine (3-MA) was applied at the onset of reperfusion. The results showed that 3-MA elicited a significant loss of the protective effect of HSPB8 against MCAO/R-induced neurological defect, Evans blue extravasation, and the loss tight junction proteins, suggesting that the BBB protective role of HSPB8 was, at least in part, mediated through autophagy. Collectively, HSPB8 may represent a potential therapeutic agent for preserving BBB integrity following cerebral I/R injury. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Cover Image for this issue: doi: 10.1111/jnc.14488., (© 2018 International Society for Neurochemistry.)

Purpose: This study was designed to compare the long-term outcomes of patients with gastric carcinoma after open or laparoscopic total gastrectomy., Methods: A case-matched controlled prospective analysis of 136 patients who underwent laparoscopic total gastrectomy for stage I-III gastric carcinoma from 2007 to 2014 was performed. Patients who at the same period underwent open total gastrectomy were matched to the laparoscopy group at the ratio of 1:1 for comparison. The perioperative clinical outcomes, postoperative pathology, and survival were compared between the 2 groups, Results: The patient characteristics between the two groups were comparable. Laparoscopic resection resulted in less blood loss, shorter postoperative hospital stay, and longer operating time. The two groups had similar complication rates. Pathological data were similar for both procedures. Cumulative incidence of recurrence, disease-free, or overall survival rates were statistically similar., Conclusion: This study showed that laparoscopic total gastrectomy for gastric carcinoma is acceptable in terms of short-term clinical outcomes and long-term survival results.

As worldwide life expectancy rises, the number of candidates for surgical treatment of gastric carcinoma over 70 years will increase. This study aims to examine outcomes after gastric carcinoma in elderly patients. This study is a retrospective review of 697 patients undergoing gastrectomy with radical intent for gastric carcinoma during January 2007 to January 2013. A total of 534 patients were less than 70 years old (group A), and 163 patients 70 years or greater (group B). We analyzed the effect of age on short and long-term variables including overall survival and disease-free survival. Major morbidity was observed to occur in 19 patients of group A, and 15 of group B. Mortality, both 30-day and 90-day was observed in 1 and 3 of group A, and 3 and 6 of group B. Five-year overall survival and disease-free survival was 61% and 60% for group A, 50% and 43% for group B respectively. Gastrectomy should be carefully considered in patients 70 years old and can be justified with low mortality and acceptable long-term outcomes.