Search

We systematically reviewed published clinical trials to evaluate the effectiveness of virtual reality (VR) technology on functional improvement, pain relief, and reduction of mental distress among burn patients undergoing rehabilitation.Systematic searches were conducted in 4 databases, including PubMed, the Cochrane Library, Embase, and Web of Science, from inception to August 2021.Randomized controlled trials (RCTs) evaluating any type of VR for the rehabilitation in burn patients with dysfunction were included.Two reviewers evaluated the eligibility, and another 2 reviewers used the Cochrane risk of bias assessment tool to assess the risk of bias. The extracted data included the main results of rehabilitation evaluation (quality of life [QOL], work performance, range of motion [ROM] of joints, hand grip and pinch strength, pain, fun, anxiety), the application performance of VR (realness and presence), adverse effects (fatigue and nausea), and characteristics of the included studies. Heterogeneity was evaluated using the chi-square tests and ISixteen RCTs with 535 burn patients were included. VR-based interventions were superior to usual rehabilitation in QOL and work performance of burn patients and produced positive effect on the average gain of ROM (SMD=0.72) as well. VR was not associated with improved hand grip and pinch strength (SMD=0.50, 1.22, respectively) but was associated with reduced intensity, affective, and cognitive components of pain (SMD=-1.26, -0.71, -1.01, respectively) compared with control conditions. Ratings of fun in rehabilitation therapy were higher (SMD=2.38), and anxiety scores were lower (SMD=-0.73) than in control conditions.VR-based burn rehabilitation significantly improves the QOL and work performance of burn patients, increases the ROM gain in the joints, reduces the intensity and unpleasantness of pain and the time spent thinking about pain, increases the fun in the rehabilitation therapy, reduces the anxiety caused by the treatment, and has no obvious adverse effects. However, it did not significantly improve hand grip or pinch strength.

We previously showed that wound-induced hypoxia is related to keratinocyte migration. The ability of keratinocytes within wound healing to undergo epithelial to mesenchymal transition (EMT) contributes significantly to the acquisition of migratory properties. However, the effect of hypoxia on keratinocyte EMT on wound healing and the potential mechanism are poorly documented. This study first demonstrated that reactive oxygen species (ROS) appear to be an essential signalling mediator in keratinocytes with increased EMT and migration subjected to hypoxic conditions. Next, we showed that the expression of sex-determining region Y-box 2 (SOX2), a stemness-associated molecule, is ROS-dependent under hypoxia and that SOX2 inhibition in keratinocytes dramatically prevented hypoxia-induced EMT and migration. In addition, β-catenin was found to be a potential molecular target of SOX2, and the activation of Wnt/β-catenin was required for hypoxia-induced EMT and migration. Using an in vitro skin culture model and an in vivo skin wound model, our study further reinforced the critical role of ROS in inducing EMT through SOX2 expression and subsequent activation of Wnt/β-catenin, allowing for rapid reepithelialization of the wound area. Taken together, our findings reveal a previously unknown mechanism by which hypoxia promotes wound healing by promoting reepithelialization through the production of ROS, inducing keratinocyte EMT and migration via the enhancement of SOX2 and activation of Wnt/β-catenin.

Phosphorylation of MAP4 (p-MAP4) causes cardiac remodeling, with the cardiac microvascular endothelium being considered a vital mediator of this process. In the current study, we investigated the mechanism underlying p-MAP4 influences on cardiac microvascular density. We firstly confirmed elevated MAP4 phosphorylation in the myocardium of MAP4 knock-in (KI) mice. When compared with the corresponding control group, we detected the decreased expression of CD31, CD34, VEGFA, VEGFR2, ANG2, and TIE2 in the myocardium of MAP4 KI mice, accompanied by a reduced plasma concentration of VEGF. Moreover, we observed apoptosis and mitochondrial disruption in the cardiac microvascular endothelium of MAP4 KI animals. Consistently, we noted a decreased cardiac microvascular density, measured by CD31 and lectin staining, in MAP4 KI mice. To explore the underlying mechanism, we targeted the NLRP3-related pyroptosis and found increased expression of the corresponding proteins, including NLRP3, ASC, mature IL-1β, IL-18, and GSDMD-N in the myocardium of MAP4 KI mice. Furthermore, we utilized a MAP4 (Glu) adenovirus to mimic cellular p-MAP4. After incubating HUVECs with MAP4 (Glu) adenovirus, the angiogenic ability was inhibited, and NLRP3-related pyroptosis were significantly activated. Moreover, both cytotoxicity and PI signal were upregulated by the MAP4 (Glu) adenovirus. Finally, NLRP3 inflammasome blockage alleviated the inhibited angiogenic ability induced by MAP4 (Glu) adenovirus. These results demonstrated that p-MAP4 reduced cardiac microvascular density by activating NLRP3-related pyroptosis in both young and aged mice. We thus managed to provide clues explaining MAP4 phosphorylation-induced cardiac remodeling and enriched current knowledge regarding the role of MAP4.

Background: Calcium homeostasis imbalance is one of the important pathological mechanisms in heart failure. Sarco /endoplasmic reticulum Ca2+-ATPase (SERCA2a), a calcium ATPase on the sarcoplasmic reticulum in cardiac myocytes, is a myocardial systolic-diastolic Ca2+ homeostasis regulating enzyme that is not only involved in cardiac diastole but also indirectly affects cardiac myocyte contraction. SERCA2a expression was found to be decreased in myocardial tissue in heart failure, and SERCA2a gene therapy may be a potential target for patients with heart failure; however, there are few reports on serum SERCA2a expression in patients with heart failure, and this study was designed to investigate whether serum SERCA2a levels are associated with the occurrence of adverse events after discharge in patients hospitalized with heart failure.Methods: Patients with heart failure hospitalized in the cardiovascular department of the Second Affiliated Hospital of Guangdong Medical University, China, from July 2018 to July 2019 were included in this study, and serum SERCA2a concentrations were measured; each enrolled patient was followed up by telephone after 6 months (6 ± 1 months) for general post-discharge patient status. The correlation between serum SERCA2a levels and the occurrence of adverse events (death or readmission due to heart failure) after hospital discharge was assessed using univariate analysis and trend analysis.Results: Seventy-one patients with heart failure were finally included in this study, of whom 38 (53.5%) were men and 33 (46.5%) were women. Univariate analysis revealed no correlation between serum SERCA2a levels and the occurrence of adverse events in the total study population and in male patients, but serum SERCA2a levels were associated with the occurrence of adverse outcome events after hospital discharge in female patients (OR=1.02, P=0.047). Further analysis using a trend analysis yielded a 4.0% increase in the risk of adverse outcomes after hospital discharge for each unit increase in SERCA2a in female patients (OR=1.04; P=0.02), while no significant difference was seen in men.Conclusions: This study suggests that serum SERCA2a levels at admission are associated with the occurrence of post-discharge adverse events in female patients hospitalized with heart failure and that serum SERCA2a may be a potential serologic predictor of post-discharge adverse events in patients with heart failure.

Background Diabetic nephropathy (DN) involves various structural and functional changes because of chronic glycemic assault and kidney failure. Proteinuria is an early clinical manifestation of DN, but the associated pathogenesis remains elusive. This study aimed to investigate the role of microtubule associated protein 4 (MAP4) phosphorylation (p-MAP4) in proteinuria in DN and its possible mechanisms. Methods In this study, the urine samples of diabetic patients and kidney tissues of streptozotocin (STZ)-induced diabetic mice were obtained to detect changes of p-MAP4. A murine model of hyperphosphorylated MAP4 was established to examine the effect of MAP4 phosphorylation in DN. Podocyte was applied to explore changes of kidney phenotypes and potential mechanisms with multiple methods. Results Our results demonstrated elevated content of p-MAP4 in diabetic patients’ urine samples, and increased kidney p-MAP4 in streptozocin (STZ)-induced diabetic mice. Moreover, p-MAP4 triggered proteinuria with aging in mice, and induced epithelial-to-mesenchymal transition (EMT) and apoptosis in podocytes. Additionally, p-MAP4 mice were much more susceptible to STZ treatment and showed robust DN pathology as compared to wild-type mice. In vitro study revealed high glucose (HG) triggered elevation of p-MAP4, rearrangement of microtubules and F-actin filaments with enhanced cell permeability, accompanied with dedifferentiation and apoptosis of podocytes. These effects were significantly reinforced by MAP4 hyperphosphorylation, and were rectified by MAP4 dephosphorylation. Notably, pretreatment of p38/MAPK inhibitor SB203580 reinstated all HG-induced pathological alterations. Conclusions The findings indicated a novel role for p-MAP4 in causing proteinuria in DN. Our results indicated the therapeutic potential of MAP4 in protecting against proteinuria and related diseases.

Previously, we and other investigators have demonstrated that phosphorylated microtubule-associated protein 4 (p-MAP4) impacts myocardial hypertrophy and ischemic heart failure. However, the detailed mechanism behind this remains under elucidated. Published studies have suggested that impaired mitophagy contributes to hypoxia-induced myocardial damage, hence the involvement of p-MAP4 in mitophagy in cardiomyocytes was investigated. The results herein revealed that there was increased degradation of mitochondria, accumulated mitophagosomes and disrupted autophagic flux in both neonatal and adult ones of MAP4-knockin (KI) mice. This indicated that p-MAP4 persistently degraded mitochondria through activating mitophagy. Next, Tom70 was found as the importer of p-MAP4 in the context of mitochondrial translocation. And, the LC3-interacting region (LIR) motif (47–50aa) caused p-MAP4-induced mitochondrial engulfment, and the ubiquitin-interacting motif (UIM) domain determined the characteristics of p-MAP4-induced mitophagosomes, which were structure and membrane potential-independent. Moreover, p-MAP4 enhanced hypoxia-induced mitophagic flux impairment, and p-MAP4 LIR (47–50aa) mutation decreased hypoxia-induced autophagy both in MAP4 knockout and wildtype cardiomyocytes. Overall, this study identified that p-MAP4 as a novel mediator and cargo receptor in mitophagy, and that the degradation of the MAP4 PJ domain as a promising therapeutic target for improving the cardiac function of hypoxia-related heart failure or cardiac remodelling.

Background Developing an ideal wound dressing that meets the multiple demands of safe and practical, good biocompatibility, superior mechanical property and excellent antibacterial activity is highly desirable for wound healing. Bacterial cellulose (BC) is one of such promising class of biopolymers since it can control wound exudates and can provide moist environment to a wound resulting in better wound healing. However, the lack of antibacterial activity has limited its application. Methods and results We prepared a flexible dressing based on a bacterial cellulose membrane and then modified it by chemical crosslinking to prepare in situ synthesis of nZnO/BCM via a facile and eco-friendly approach. Scanning electron microscopy (SEM) results indicated that nZnO/BCM membranes were characterized by an ideal porous structure (pore size: 30~ 90 μm), forming a unique string-beaded morphology. The average water vapor transmission of nZnO/BCM was 2856.60 g/m2/day, which improved the moist environment of nZnO/BCM. ATR-FITR further confirmed the stepwise deposition of nano-zinc oxide. Tensile testing indicated that our nanocomposites were flexible, comfortable and resilient. Bacterial suspension assay and plate counting methods demonstrated that 5wt. % nZnO/BCM possessed excellent antibacterial activity against S.aureus and E. coli, while MTT assay demonstrated that they had no measurable cytotoxicity toward mammalian cells. Moreover, skin irritation test and histocompatibility examination supported that 5wt. % nZnO/BCM had no stimulation to skin and had acceptable biocompatibility with little infiltration of the inflammatory cells. Finally, by using a bacteria-infected (S. aureus and E. coli) murine wound model, we found that nZnO/BCM could prevent in vivo bacterial infections and promote wound healing via accelerating the re-epithelialization and wound contraction, and these membranes had no obvious toxicity toward normal tissues. Conclusion Therefore, the constructed nZnO/BCM has great potential for biomedical applications as an efficient antibacterial wound dressing.

Endogenous electric fields (EFs) direct the migration (electrotaxis) of keratinocytes in skin wounds, and the exogenous application of EFs may therefore improve wound healing, but the potential benefits are limited by the side effects of constant direct current (DC) passing through tissues. In contrast, with pulsed DC (characterized by intermittent output), parameters can be adjusted to minimize the adverse effects of electric currents. However, it remains unknown whether pulsed DC can reliably induce keratinocyte electrotaxis. In this study, using primary keratinocytes in an electrotaxis chamber, we found that a pulsed DCEF at physiological strength (EF = 150 mV/mm, duty cycle = 60%, frequency = 0.1 Hz) could induce robust electrotaxis. This effect was dependent on both voltage and duty cycle, but not on frequency. As predicted, fewer electrochemical reactions and cytotoxic reactions were detected with pulsed DCEF than with constant DCEF. In summary, we here demonstrate for the first time, that pulsed DCEF can trigger keratinocyte electrotaxis comparable to that induced by constant DCEF, while minimizing the electrochemical side effects. These findings support the future development of a pulsed DCEF device to improve wound healing in human patients.

The exact relationships and detailed mechanisms between autophagy and necroptosis remain obscure. Here, we demonstrated the link between accumulated autophagosome and necroptosis by intervening with autophagic flux. We first confirmed that the LC3 interacting region (LIR) domain is present in the protein sequences of RIPK1 and RIPK3. Mutual effects among LC3, RIPK1, and RIPK3 have been identified in myocardium and cardiomyocytes. Direct LC3-RIPK1 and LC3-RIPK3 interactions were confirmed by pull-down assays, and their interactions were deleted after LIR domain mutation. Moreover, after disrupting autophagic flux under normoxia with bafilomycin A1 treatment, or with LC3 or ATG5 overexpression adenovirus, RIPK1, RIPK3, p-RIPK3, and p-MLKL levels increased, suggesting necroptosis activation. Severe disruptions in autophagic flux were observed under hypoxia and bafilomycin A1 co-treated cardiomyocytes and myocardium and led to more significant activation of necroptosis. Conversely, after alleviating hypoxia-induced autophagic flux impairment with LC3 or ATG5 knockdown adenovirus, the effects of hypoxia on RIPK1 and RIPK3 levels were reduced, which resulted in decreased p-RIPK3 and p-MLKL. Furthermore, necroptosis was inhibited by siRNAs against RIPK1 and RIPK3 under hypoxia or normoxia. Based on our results, LIR domain mediated LC3-RIPK1 and LC3-RIPK3 interaction. Besides, autophagosome accumulation under hypoxia lead to necrosome formation and, in turn, necroptosis, while when autophagic flux was uninterrupted, RIPK1 and RIPK3 were cleared through an autophagy-related pathway which inhibited necroptosis. These findings provide novel insights for the role of LC3 in regulating cardiomyocyte necroptosis, indicating its therapeutic potential in the prevention and treatment of hypoxic myocardial injury and other hypoxia-related diseases.

Visceral organs are the participants and maintainers of various life activities of the body. Various injuries such as trauma, surgery, organ transplantation, inflammatory bowel disease, and other serious diseases will cause damage to internal organs. The main reason is the double impact of ischemia and reperfusion, which in turn causes the activation of complement-phagocytic-lymphocyte in the body, causing local and systemic inflammatory reactions, dysfunction of coagulation system, hypermetabolic status, etc., eventually leading to multiple organ dysfunction syndrome (MODS), and even multiple systemic organ failure (MSOF) also called multiple organ failure (MOF). Visceral organ damage, especially multiple organ function damage, is an important feature of the aggravation of traumatic injury and the occurrence of complications. For open wounds, damaged organs can be repaired and reconstructed by surgery. However, for closed injury such as ischemia-reperfusion injury to intestine, liver, kidney, and lung; ischemic injury of donors during organ transplantation; and multiple organ damage after traumatic (burn) injury, especially the occult shock of the intestinal tract, etc., the organ itself has ischemic damage that is difficult to distinguish with the naked eye; the pathogenesis of such damage is complex, wide, and concealed; there is a lack of effective prosthetic measures; and the repair after injury is often not easy to attract people’s attention, thus leading to the death of patients. According to experts’ statistics, more than half of all deaths are caused by visceral complications after severe burns; two-thirds of the injured in serious traffic accidents are accompanied by visceral injury, which is the primary cause of disability and death. MODS is also ranked first in the cause of death in the intensive care unit. In general, the death of the visceral injury after severe trauma is mainly divided into two stages: early death, which is closely related to shock or severe brain injury; and late death, which is mainly caused by MODS or multiple system organ failure (MSOF), and its occurrence is associated with systemic inflammatory response syndrome (SIRS), ischemia-reperfusion injury, and endotoxemia. Among them, organ ischemia-reperfusion injury and microcirculatory dysfunction (the second hit) are one of the central links of visceral complications after severe trauma. For visceral injury, previous studies focused on the pathogenesis of visceral injury and initially clarified the role of infection, uncontrolled inflammatory response, and oxygen-free radical activation in the occurrence of severe visceral injury. However, it is worth noting that previous studies have focused too much on the pathogenesis of organ damage, while there is a lack of in-depth discussion on the outcome of damaged organs. Therefore, it is essential to strengthen the prevention and treatment of visceral injuries and promote the early repair and reconstruction of damaged organs to guarantee life safety. How to accelerate and promote the repair of damaged internal organs has become the key to determine the success of serious trauma treatment, especially to prevent MODS and MSOF.

Modified Meek micrografting is a common method for treating severe burn patients. This study was to analyze the factors affecting the survival of modified Meek micrografting, thereby improving the survival rate of skin grafts. Eighty-three patients who underwent modified Meek micrografting were analyzed. According to the survival rate of skin graft after operation, the patients were divided into good skin survival group (GSSG, survival rate ≥ 70%, 47 cases) and poor skin survival group (PSSG, survival rate < 70%, 36 cases). The baseline data, surgical information, perioperative laboratory indicators, and prognosis of the patients were statistically analyzed. The univariate analysis and repeated measurement showed the burn severity, Meek skin graft area, duration of anesthesia, the postoperative sepsis shock, the mortality, the neutrophils percentage on the third day after surgery (NEU3), and the growth rate of neutrophils percentage from the first to third day after surgery (NEU3-1%) in the GSSG were significantly lower than those in the PSSG, whereas the perioperative average albumin levels and the perioperative average pre-albumin levels were higher. Receiver operating characteristic curve showed that the NEU3 had a good predictive value for the survival of skin slices. Maintaining perioperative albumin levels at a high level, controlling perioperative infection, and shortening the operation time as much as possible may improve the survival rate of modified Meek micrografting.

BNIP3 is an atypical BH3-only member of the Bcl-2 family with pro-death, pro-autophagic, and cytoprotective functions, depending on the type of stress and cellular context. Recently, we demonstrated that BNIP3 stimulates the migration of epidermal keratinocytes under hypoxia. In the present study found that autophagy and BNIP3 expression were concomitantly elevated in the migrating epidermis during wound healing in a hypoxia-dependent manner. Inhibition of autophagy through lysosome-specific chemicals (CQ and BafA1) or Atg5-targeted small-interfering RNAs greatly attenuated the hypoxia-induced cell migration, and knockdown of BNIP3 in keratinocytes significantly suppressed hypoxia-induced autophagy activation and cell migration, suggesting a positive role of BNIP3-induced autophagy in keratinocyte migration. Furthermore, these results indicated that the accumulation of reactive oxygen species (ROS) by hypoxia triggered the activation of p38 and JNK mitogen-activated protein kinase (MAPK) in human immortalized keratinocyte HaCaT cells. In turn, activated p38 and JNK MAPK mediated the activation of BNIP3-induced autophagy and the enhancement of keratinocyte migration. These data revealed a previously unknown mechanism that BNIP3-induced autophagy occurs through hypoxia-induced ROS-mediated p38 and JNK MAPK activation and supports the migration of epidermal keratinocytes during wound healing.

Background Smoke inhalation injury increases overall burn mortality. Locally applied heparin attenuates lung injury in burn animal models of smoke inhalation. It is uncertain whether local treatment of heparin is benefit for burn patients with inhalation trauma. We systematically reviewed published clinical trial data to evaluate the effectiveness of nebulized heparin in treating burn patients with inhalation injury. Methods A systematic search was undertaken in PubMed, the Cochrane Library, Embase, Web of Science, the Chinese Journals Full-text Database, the China Biomedical Literature Database and the Wanfang Database to obtain clinical controlled trails evaluating nebulized heparin in the treatment of burn patients with inhalation injury. Patient and clinical characteristics, interventions and physiological and clinical outcomes were recorded. Cochrane Risk of Bias Evaluation Tool and the Newcastle–Ottawa Scale were used to evaluate data quality. Potential publication bias was assessed by Egger’s test. A sensitivity analysis was conducted to assess the stability of the results. The meta-analysis was conducted in R 3.5.1 software. Results Nine trials were eligible for the systematic review and meta-analysis. Nebulized heparin can reduce lung injury and improve lung function in burn patients with inhalation injury without abnormal coagulation or bleeding, but the findings are still controversial. Mortality in the heparin-treated group was lower than that of the traditional treatment group (relative risk (RR) 0.75). The duration of mechanical ventilation (DOMV) was shorter in the heparin-treated group compared to the traditional treatment group (standardized mean difference (SMD) −0.78). Length of hospital stay was significantly shorter than that in the traditional treatment group (SMD −0.42), but incidence rates of pneumonia and unplanned reintubation were not significantly different in the study groups (RRs 0.97 and 0.88, respectively). No statistically significant publication biases were detected for the above clinical endpoints (p > 0.05). Conclusions Based on conventional aerosol therapy, heparin nebulization can further reduce lung injury, improve lung function, shorten DOMV and length of hospital stay, and reduce mortality, although it does not reduce the incidence of pneumonia and/or the unplanned reintubation rate., Nebulized heparin can significantly reduce the comprehensive scores of lung injury, including on chest roentgenogram, oxygenation capacity, respiratory resistance, and compliance, among others, and does not cause coagulation disorders or changes in platelet count. Compared with patients in the traditional treatment group (N-acetylcysteine + Salbutamol), mortality was significantly reduced in the heparin-treated group (heparin + N-acetylcysteine + Salbutamol). And the duration of mechanical ventilation (DOMV) and length of hospital stay were significantly shortened. There were no significant differences in the incidence rates of pneumonia and unplanned reintubation between the heparin-treated and traditional treatment groups.

CD9 is a trans-membrane protein, and has recently been implicated in different physiological and cellular processes, such as cell migration and adhesion. According to previous study, down-regulation of CD9 contributes to keratinocyte migration, critical for wound re-epithelialization. Nevertheless, it is widely believed that tetraspanin CD9 does not have ligands or function as the cell surface receptor, rather it is thought to associate with other transmembrane molecules, thereby mediate keratinocyte migration. Little is known about how CD9 associates with transmembrane molecules in migratory keratinocytes. Here, using confocal microscopy, we observed that tetraspanin CD9 and ADAM17 co-localized on the surface of keratinocytes in the course of wound repair in vivo and in vitro. Co-immunoprecipitation experiments demonstrated a direct association between CD9 and ADAM17 in HaCaT cells and C57-MKs. Functional studies revealed that down-regulation or over-expression of CD9 exerted negative regulatory effects on ADAM17 sheddase activity. This activity is involved in CD9-regulated cell motility and migration. Further studies found that ADAM17 inhibitor-TAPI-2 or siADAM17 significantly abolished the enhanced effect of keratinocyte migration induced by CD9 down-regulation. Meanwhile, the sheddase activity of ADAM17 was inhibited by TAPI-2, which decreased this release of AREG and HB-EGF in CD9-silenced HaCat cells and C57-MKs. Importantly, neutralizing antibody against HB-EGF significant weakened keratinocyte migration and motility in CD9-silenced keratinocytes, and the inhibition of CD9-regulated keratinocyte migration by siADAM17 was rescued by addition of recombinant HB-EGF, activating EGFR/ERK pathway. Collectively, our results suggest that ADAM17 sheddase activity is activated by down-regulation of CD9, thereby mediating shedding of HB-EGF and activation of EGFR/ERK signaling, which crucially affects the keratinocyte migration and wound healing.

Autophagy is a highly conserved self-protection mechanism that plays a crucial role in cardiovascular diseases. Cardiomyocyte hypoxic injury promotes oxidative stress and pathological alterations in the heart, although the interplay between these effects remains elusive. The transient receptor potential vanilloid 1 (TRPV1) ion channel is a nonselective cation channel that is activated in response to a variety of exogenous and endogenous physical and chemical stimuli. Here, we investigated the effects and mechanisms of action of TRPV1 on autophagy in hypoxic cardiomyocytes. In this study, primary cardiomyocytes isolated from C57 mice were subjected to hypoxic stress, and their expression of TRPV1 and adenosine 5′-monophosphate-activated protein kinase (AMPK) was regulated. The autophagy flux was assessed by Western blotting and immunofluorescence staining, and the cell viability was determined through Cell counting kit-8 assay and Lactate dehydrogenase assays. In addition, the calcium influx after the upregulation of TRPV1 expression in cardiomyocytes was examined. The results showed that the number of autophagosomes in cardiomyocytes was higher under hypoxic stress and that the blockade of autophagy flux aggravated hypoxic damage to cardiomyocytes. Moreover, the expression of TRPV1 was induced under hypoxic stress, and its upregulation by capsaicin improved the autophagy flux and protected cardiomyocytes from hypoxic damage, whereas the silencing of TRPV1 significantly attenuated autophagy. Our observations also revealed that AMPK signaling was activated and involved in TRPV1-induced autophagy in cardiomyocytes under hypoxic stress. Overall, this study demonstrates that TRPV1 activation mitigates hypoxic injury in cardiomyocytes by improving autophagy flux through the AMPK signaling pathway and highlights TRPV1 as a novel therapeutic target for the treatment of hypoxic cardiac disease.

Autophagy protects cardiomyocytes in various pathological and physiological conditions; however, the molecular mechanisms underlying its influence and the promotion of autophagic clearance are not completely understood. The present study aimed to explore the role of H(+)/Cl(−) exchange transporter 7 (CLC-7) in cardiomyocyte autophagy. In this study, rapamycin was used to induce autophagy in mouse cardiomyocytes, and the changes in CLC-7 were investigated. The expression levels of CLC-7 and autophagy-related proteins, such as microtubule associated protein 1 light chain 3, autophagy related 5 and Beclin 1, were detected using western blotting or immunofluorescence. Autolysosomes were observed and analyzed using transmission electron microscopy and immunofluorescence following CLC-7 silencing with small interfering RNAs. Cellular viability was assessed using Cell Counting Kit-8 and lactate dehydrogenase assays. Lysosomal acidification was measured using an acidification indicator. Increased CLC-7 co-localization with lysosomes was identified during autophagy. CLC-7 knockdown weakened the acidification of lysosomes, which are the terminal compartments of autophagy flux, and consequently impaired autophagy flux, ultimately resulting in cell injury. Collectively, the present study demonstrated that in cardiomyocytes, CLC-7 may contribute to autophagy via regulation of lysosomal acidification. These findings provide novel insights into the role of CLC-7 in autophagy and cytoprotection.

Endogenous wound electric fields (EFs), an important and fundamental occurrence of wound healing, profoundly influence the directed migration of keratinocytes. Although numerous studies have unveiled the signals responsible for EF-biased direction, the mechanisms by which EFs promote keratinocyte motility remains to be elucidated. In our study, EFs enhanced the directed migratory speed of keratinocytes by inducing autophagic activity, thereby facilitating skin barrier restoration. Initially, we found that electrical signals directed keratinocytes to the cathode with enhanced motility parameters [ i.e., trajectory distance, trajectory speed, displacement distance, and displacement speed ( Td/ t)] and more efficient migration (directionality and Td/ t along the x axis, among others). Meanwhile, EFs induced a time-dependent increase in autophagic activity in keratinocytes, with constant autophagic flux, accompanied by increased transcription of numerous autophagy-related genes. Deficiency in Atg5, a key protein necessary for autophagosome formation, led to significant reduction of autophagy, which was accompanied by a substantial reduction in EF-stimulated directed motility. These results demonstrated a causal relationship between autophagy and EF-directed migratory speed. In addition, both cell migration under normal conditions and EF-biased directionality were autophagy independent. Thus, our findings define autophagy as an important functional regulator of electrically enhanced directed motility, adding to a growing understanding of EFs.-Yan, T., Jiang, X., Lin, G., Tang, D., Zhang, J., Guo, X., Zhang, D., Zhang, Q., Jia, J., Huang, Y. Autophagy is required for the directed motility of keratinocytes driven by electric fields.

Empathy among teaching professionals is highly valued in the field of education. However, there is no suitable instrument to measure teachers' empathy in relation to their pupils. This paper describes the development and validation of an empathy scale for teachers (EST). The initial pool of items for the EST was generated by an open-ended survey of teachers. Exploratory and confirmatory factor analyses were employed to identify and confirm, respectively, the factor structure of the EST. The results show that the EST includes three dimensions: cognitive empathy, negative affective empathy and positive affective empathy, and the internal consistency reliability of the three subscales is satisfactory. In addition, the EST is positively correlated with perspective taking, empathic concern, prosocial behaviour and teacher-student relationships. Our study suggests that the EST could be an effective tool to measure the empathy of primary, middle and high school teachers in relation to their pupils.

Lysosomal membrane permeabilization (LMP) has recently been recognized as an important cell death pathway in various cell types. However, studies regarding the correlation between LMP and cardiomyocyte death are scarce. Lysosomal membrane-associated protein 2 (Lamp2) is an important component of lysosomal membranes and is involved in both autophagy and LMP. In the present study, we found that the protein content of Lamp2 gradually decreased in response to oxygen, glucose and serum deprivation (OGD) treatment in vitro. To further elucidate its role in ischemic cardiomyocytes, particularly with respect to autophagy and LMP, we infected cardiomyocytes with adenovirus carrying full-length Lamp2 to restore its protein level in cells. We found that OGD treatment resulted in the occurrence of LMP and a decline in the viability of cardiomyocytes, which were remarkably reversed by Lamp2 restoration. Exogenous expression of Lamp2 also significantly alleviated the autophagic flux blockade induced by OGD treatment by promoting the trafficking of cathepsin B (Cat B) and cathepsin D (Cat D). Through drug intervention and gene regulation to alleviate and exacerbate autophagic flux blockade respectively, we found that impaired autophagic flux in response to ischemic injury contributed to the occurrence of LMP in cardiomyocytes. In conclusion, our present data suggest that Lamp2 overexpression can improve autophagic flux blockade probably by promoting the trafficking of cathepsins and consequently conferring cardiomyocyte resistance against lysosomal cell death (LCD) that is induced by ischemic injury. These results may indicate a new therapeutic target for ischemic heart damage.

Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in CD38–/– mice and CD38–/– neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression., Graphical Abstract CD38 inhibits transcription of the Plekhm1 gene and Rab7 gene. CD38 mediates autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner.

miR-186-5p has been reported to be implicated in tumorigenesis and paclitaxel resistance in non-small-cell lung cancer cells (NSCLCs). However, it remains undisclosed whether miR-186-5p takes a part in chemoresistance against diaminodichloroplatinum (cisplatin, DDP) in lung cancers, including NSCLC. Expression of miR-186-5p and sine oculis homeobox 1 (SIX1) was detected using RT-qPCR and western blot. In vitro, 50% inhibitory concentration (IC50) of DDP and cell proliferation were measured by MTT assay. The rate of apoptosis and abilities of migration and invasion were evaluated with flow cytometry and Transwell assay. The target binding between miR-186-5p and SIX1 was predicted on Diana tools software and confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. In vivo experiments, xenogeneic transplantation was conducted to monitor the tumor growth. Expression of miR-186-5p was downregulated in DDP resistant NSCLC tissues and cells (A549/DDP and H1299/DDP). Functionally, miR-186-5p overexpression could inhibit cell proliferation, migration and invasion, and promoted apoptosis rate in A549/DDP and H1299/DDP cells. Mechanically, SIX1 was identified as a downstream target for miR-186-5p and was highly expressed in A549/DDP and H1299/DDP cells. Similarly, SIX1 knockdown could also suppress DDP resistant NSCLC cell proliferation, migration and invasion, and promote apoptosis rate, which was reversed by miR-186-5p downregulation. Moreover, xenograft tumors induced by A549/DDP cells exerted cisplatin resistance, and miR-186-5p overexpression could inhibit tumor growth under DDP treatment. In conclusion, upregulation of miR-186-5p suppresses cisplatin resistance in DDP resistant NSCLC cells both in vitro and in vivo presumably by targeting SIX1.