FPR1: A critical gatekeeper of the heart and brain.

G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.

Construction and verification of risk predicting models to evaluate the possibility of hydrocephalus following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Hydrocephalus following a ruptured aneurysm portends a poor prognosis. The authors aimed to establish a nomogram to predict the risk of hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A total of 421 patients with aSAH who were diagnosed by digital subtraction angiography in The General Hospital of Northern Theater Command center from January 2020 to June 2021 were screened to establish the training cohort. An additional 135 patients who enrolled between July 2021 and May 2022 were used for the validation cohort. Variate difference analysis and stepwise logistic regression (model A) and univariate and multivariate logistic regressions (model B) were respectively used to construct two models. Then, the net reclassification improvement (NRI), integrated discrimination improvement (IDI), and receiver operating characteristic (ROC) curve were used to compare the predictive abilities of the two models. Finally, two nomograms were constructed and externally validated. RESULTS: After screening, 556 patients were included. The area under the ROC curve of models A and B in the training cohort were respectively 0.884 (95 % confidence interval [CI]: 0.847-0.921) and 0.834 (95 % CI: 0.787-0.881). The prediction ability of the model A was superior to model B (NRI > 0, IDI > 0, p < 0.05). The C-index of models A and B was 0.8835 and 0.8392, respectively. Regarding clinical usefulness, the two models offered a net benefit with a threshold probability of between 0.12 and 1 in the decision curve analysis, suggesting that the two models can accurately predict hydrocephalus events. CONCLUSIONS: Both models have good prediction accuracy. Compared with model B, model A has better discrimination and calibration. Further, the easy-to-use nomogram can help neurosurgeons to make rapid clinical decisions and apply early treatment measures in high-risk groups, which ultimately benefits patients.

SRY-related high-mobility-group box 4: Crucial regulators of the EMT in cancer.

The epithelial-mesenchymal transition (EMT) is a process of cell transformation under certain physiological and pathological states in which epithelial cells are transformed into mesenchymal cells with fibroblast-like properties, which confers upon them the increased invasion and migration capabilities of cancer cells. Previous studies have demonstrated that SRY-related high-mobility-group box 4 (Sox4) protein coordinates EMT-related pathways and EMT-related transcription factors, thereby regulating the EMT process. The focus of this review is to evaluate recent advances regarding the role of Sox4 protein in the cancer EMT. First, we provide an overview of the general background of Sox4 (structure and function) and the EMT in cancer. Next, we introduce the interactions between Sox4 protein and various factors during cancer EMT. Finally, we suggest directions for future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information on the subject matter and contribute to the design of other research and future efforts to develop therapeutic strategies that target the Sox4 protein.

Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings.

Melatonin has demonstrated a potential protective effect in central nervous system. Thus, it is interesting to determine whether pre-ischemia melatonin administration could protect against cerebral ischemia/reperfusion (IR)-related injury and the underlying molecular mechanisms. In this study, we revealed that IR injury significantly activated endoplasmic reticulum (ER) stress and autophagy in a middle cerebral artery occlusion mouse model. Pre-ischemia melatonin treatment was able to attenuate IR-induced ER stress and autophagy. In addition, with tandem RFP-GFP-LC3 adeno-associated virus, we demonstrated pre-ischemic melatonin significantly alleviated IR-induced autophagic flux. Furthermore, we showed that IR induced neuronal apoptosis through ER stress related signalings. Moreover, IR-induced autophagy was significantly blocked by ER stress inhibitor (4-PBA), as well as ER-related signaling inhibitors (PERK inhibitor, GSK; IRE1 inhibitor, 3,5-dibromosalicylaldehyde). Finally, we revealed that melatonin significantly alleviated cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency, which were remarkably abolished by tunicamycin (ER stress activator) and rapamycin (autophagy activator), respectively. In summary, our study provides strong evidence that pre-ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress-dependent autophagy. Our findings shed light on the novel preventive and therapeutic strategy of daily administration of melatonin, especially among the population with high risk of cerebral ischemic stroke.

The impact of resilience on psychological outcomes in women with threatened premature labor and spouses: a cross-sectional study in Southwest China.

BACKGROUND: Threatened premature labor (TPL) is a severe obstetric complication which affects the mental and physical health of both the mother and fetus. Family resilience may have protective role against psychological distress in women experiencing these pregnancy complications. There may be resilience related risk factors in TPL women, and interplays may exist among psychological variables and within couples. This study aims to examine psychological outcomes influenced by different levels of resilience, and explore psychological interactions in TPL women, spouses, and between women and spouses. METHODS: Six validated questionnaires were used to measure the psychological outcomes (Connor-Davidson resilience scale CD-RISC, Edinburgh postnatal depression scale EPDS, positive and negative affect scale PANAS, pregnancy pressure scale PPS, simplified coping style questionnaire SCSQ, social support rating scale SSRS) in 126 TPL women hospitalized in three tertiary hospitals and 104 spouses in Southwest China. RESULTS: Low resilient women had significantly more complicated placenta praevia, longer pediatric observation, more pressure than high resilient women. They also had significantly less active coping and positive affect, more negative affect and depression compared to high resilient women and their spouses. Although the socio-demographic characteristics of both TPL women and spouses and psychometric parameters of spouses had no significant differences, the prevalence rates of depression in spouses were notable. Compared with spouses, TPL women had a more complex interaction among these psychometric factors, with women's resilience negatively associated with their partners' negative affect, and their pressure positively correlated with pressure and negative affect of spouses. CONCLUSIONS: Pregnancy complicated with placenta praevia and pediatric observation may be risk factors for resilience of women with TPL. Maternal resilience has an important impact on the psychological outcomes in TPL women. A screening for resilience, depression and other psychological outcomes in couples with TPL and early psychological intervention of low resilient couples may be appropriate to promote resilience and well-being of these families.

SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury.

Ischemia reperfusion (IR) injury is harmful to skeletal muscles and causes mitochondrial oxidative stress. Pterostilbene (PTE), an analogue of resveratrol, has organic protective effects against oxidative stress. However, no studies have investigated whether PTE can protect against IR-related skeletal muscular injury. In this study, we sought to evaluate the protective effect of PTE against IR-related skeletal muscle injury and to determine the mechanisms in this process. Male Sprague-Dawley rats were pretreated with PTE for a week and then underwent limb IR surgery. The IR injury induced segmental necrosis and apoptosis, myofilament disintegration, thicker interstitial spaces, and inflammatory cell infiltration. Furthermore, mitochondrial respiratory chain activity in the muscular tissue was inhibited, methane dicarboxylic aldehyde concentration and myeloperoxidase activity were up-regulated, and superoxide dismutase was down-regulated after IR. However, these effects were significantly inhibited by PTE in a dose-dependent manner. The mechanism underlying IR injury is attributed to the down-regulation of silent information regulator 1 (SIRT1)-FOXO1/p53 pathway and the increase of the Bax/Bcl2 ratio, Cleaved poly ADP-ribose polymerase 1, Cleaved Caspase 3, which can be reversed with PTE. Furthermore, EX527, an SIRT1 inhibitor, counteracted the protective effects of PTE on IR-related muscle injury. In conclusion, PTE has protective properties against IR injury of the skeletal muscles. The mechanism of this protective effect depends on the activation of the SIRT1-FOXO1/p53 signaling pathway and the decrease of the apoptotic ratio in skeletal muscle cells.

Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB/STAT3 pathway after ischemic stroke in mice.

BACKGROUND: Astrocyte-mediated neuroinflammation plays a critical role in ischemic stroke-induced secondary cerebral injury. Previous studies have suggested that the dopamine D2 receptor (DRD2) acts as a key target in regulating the neuroinflammatory response. However, the underlying molecular mechanisms are still unknown, and effective DRD2 agonists are lacking. In the present study, we examined the anti-inflammatory and neuroprotective effects of sinomenine (Sino), a monomeric compound with potential immunoregulatory properties in nervous system. METHODS: TTC staining, apoptosis assay, evaluation of brain edema, and neurological assessment were performed in the middle cerebral artery occlusion (MCAO) mouse model. Primary astrocytes exposed to oxygen glucose deprivation (OGD) were used in the in vitro experiments. Quantitative PCR was applied to assess the levels of inflammatory cytokines. Multi-labeling immunofluorescence, Western blot, co-immunoprecipitation, and electrophoretic mobility shift assay (EMSA) were also used to investigate the molecular mechanisms underlying the Sino-mediated anti-inflammatory effects in vivo and in vitro. RESULTS: Sino remarkably attenuated the cerebral infarction and neuronal apoptosis, reduced the levels of inflammatory cytokines, and alleviated neurological deficiency in MCAO mice. Sino significantly inhibited astrocytic activation and STAT3 phosphorylation as well as increased DRD2 and αB-crystallin (CRYAB) expression after MCAO. In vitro, Sino blocked OGD-induced activation of STAT3 and generation of pro-inflammatory cytokines in primary astrocytes, and these effects were significantly abolished by either DRD2 or CRYAB knockdown. Additionally, Sino induced up-regulation and nuclear translocation of CRYAB in astrocytes and enhanced the interaction between CRYAB and STAT3, which further inhibited the activation and DNA-binding activity of STAT3. CONCLUSIONS: Our study demonstrates that Sino activates astrocytic DRD2 and thereby suppresses neuroinflammation via the CRYAB/STAT3 pathway, which sheds some light on a promising therapeutic strategy for ischemic stroke.

Rutin Inhibits Neuroinflammation and Provides Neuroprotection in an Experimental Rat Model of Subarachnoid Hemorrhage, Possibly Through Suppressing the RAGE-NF-κB Inflammatory Signaling Pathway.

As is known to all, neuroinflammation plays a vital role in early brain injury pathogenesis following subarachnoid hemorrhage (SAH). It has been shown that rutin have a property of inhibiting inflammation in many kinds of animal models. However, the effect of rutin on neuroinflammation after SAH remains uninvestigated. In this study, we investigated the potential effects of rutin on neuroinflammation and the underlying mechanism in an experimental rat model of SAH performed by endovascular perforation. Adult male SD rats were randomly divided into three groups, including sham group, SAH + vehicle group and SAH + rutin group (50 mg/kg) intraperitoneally (i.p.) administered at 30 min after SAH. After sacrificed at 24 h after SAH, all rats were examined by following tests, including neurologic scores, blood-brain barrier permeability, brain water content and neuronal cell death in cerebral cortex. The level of inflammation in brain was estimated by means of multiple molecules, including RAGE, NF-κB, and inflammation cytokines. Our results indicated that rutin could significantly downregulate the increased level of REGE, NF-κB and inflammatory cytokines in protein level. In addition, rutin could also ameliorate a series of secondary brain injuries such as brain edema, destruction of blood-brain barrier, neurological deficits and neuronal death. This study indicated that rutin administration had a neuroprotective effect in an experimental rat model of SAH, possibly through inhibiting RAGE-NF-κB mediated inflammation signaling pathway.

Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy.

Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy.

Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling.

Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation associated with the upregulation of apoptotic signaling pathway has been implicated in various inflammatory diseases including hemorrhagic insults. Melatonin is reported to possess substantial anti-inflammatory properties, which is beneficial for early brain injury (EBI) after SAH. However, the molecular mechanisms have not been clearly identified. This study was designed to investigate the protective effects of melatonin against EBI induced by SAH and to elucidate the potential mechanisms. The adult mice were subjected to SAH. Melatonin or vehicle was injected intraperitoneally 2 hr after SAH. Melatonin was neuroprotective, as shown by increased survival rate, as well as elevated neurological score, greater survival of neurons, preserved brain glutathione levels, and reduced brain edema, malondialdehyde concentrations, apoptotic ratio, and blood-brain barrier (BBB) disruption. Melatonin also attenuated the expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, interleukin-1ß (IL-1ß), and interleukin-6 (IL-6); these changes were also associated with an increase in the anti-apoptotic factor (Bcl2) and reduction in the pro-apoptotic factor (Bim). In summary, our results demonstrate that melatonin treatment attenuates the EBI following SAH by inhibiting NLRP3 inflammasome-associated apoptosis.

Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice.

Silent information regulator 1 (SIRT1), a type of histone deacetylase, is a highly effective therapeutic target for protection against ischemia reperfusion (IR) injury (IRI). Previous studies showed that melatonin preserves SIRT1 expression in neuronal cells of newborn rats after hypoxia-ischemia. However, the definite role of SIRT1 in the protective effect of melatonin against cerebral IRI in adult has not been explored. In this study, the brain of adult mice was subjected to IRI. Prior to this procedure, the mice were given intraperitoneal with or without the SIRT1 inhibitor, EX527. Melatonin conferred a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema, and increased neurological scores. The melatonin-induced upregulation of SIRT1 was also associated with an increase in the anti-apoptotic factor, Bcl2, and a reduction in the pro-apoptotic factor Bax. Moreover, melatonin resulted in a well-preserved mitochondrial membrane potential, mitochondrial Complex I activity, and mitochondrial cytochrome c level while it reduced cytosolic cytochrome c level. However, the melatonin-elevated mitochondrial function was reversed by EX527 treatment. In summary, our results demonstrate that melatonin treatment attenuates cerebral IRI by reducing IR-induced mitochondrial dysfunction through the activation of SIRT1 signaling.

Genetic association of CHEK2, GSTP1, and ERCC1 with glioblastoma in the Han Chinese population.

Glioblastoma (GBM), a deadly brain tumor, is the most malignant glioma. It mainly occurs in adults and occurs significantly more in males than in females. We genotyped 19 tag single nucleotide polymorphisms (tSNPs) from 13 genes in a case-control study of the Han Chinese population to identify genetic factors contributing to the risk of GBM. These tSNPs were genotyped by Sequenom MassARRAY RS1000. Statistical analysis was performed using χ(2) test and SNPStats, a website software. Using χ(2) test, we found that the distribution of two tSNPs (rs2267130 in checkpoint kinase 2 (CHEK2), p = 0.040; rs1695 in GSTP1, p = 0.023) allelic frequencies had significant difference between cases and controls. When we analyzed all of the tSNPs using the SNPStats software, we found that rs1695 in GSTP1 decreased the risk of GBM in log-additive model (OR = 0.56, 95% CI, 0.34-0.94, p = 0.022). Besides, we found that there is an interaction between rs3212986 in excision repair cross-complementing group 1 (ERCC1) and gender under codominant and recessive models. The gene polymorphisms in CHEK2, GSTP1, and ERCC1 may be involved in GBM in the Han Chinese population. Since our sample size is small, further investigation needs to be performed.

Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage.

Quercetin has been demonstrated to play an important role in altering the progression of ischemic brain injuries and neurodegenerative diseases by protecting against oxidative stress. The effects of quercetin on brain damage after subarachnoid hemorrhage (SAH), however, have not been investigated. This study was designed to explore the effects of quercetin on oxidative stress and brain edema after experimental SAH using four equal groups (n = 16) of adult male Sprague-Dawley (SD) rats, including a sham group, an SAH + vehicle group, an SAH + quercetin10 group, and an SAH + quercetin50 group. The rat SAH model was induced by injection of 0.3 ml of non-heparinised arterial blood into the prechiasmatic cistern. In the SAH + quercetin10 and SAH + quercetin50 groups, doses of 10 mg/kg and 50 mg/kg quercetin, respectively, were directly administered by intraperitoneal injection at 30 min, 12 h, and 24 h after SAH induction. Cerebral tissue samples were extracted for enzymatic antioxidant determination, lipid peroxidation assay, caspase-3 activity and water content testing 48 h after SAH. Treatment with a high dose (50 mg/kg) of quercetin markedly enhanced the activities of copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px), and treatment with this dose significantly reduced the level of malondialdehyde (MDA). Caspase-3 and brain edema was ameliorated and neurobehavioral deficits improved in rats that received the high dose of quercetin. The findings suggest that the early administration of optimal dose of quercetin may ameliorate brain damage and provide neuroprotection in the SAH model, potentially by enhancing the activity of endogenous antioxidant enzymes and inhibiting free radical generation.

Heat stroke: Pathogenesis, diagnosis, and current treatment.

Recently, the incidence of heat-related illnesses has exhibited a steadily upward trend, which is closely associated with several environmental factors such as climate change and air pollution. The progression of heat-related illnesses is a continuous process and can progress to the terminal period when it transforms into heat stroke, the most severe form. Heat stroke is markedly by a core body temperature above 40°C and central nervous system dysfunction. Current knowledge suggests that the pathogenesis of heat stroke is complex and varied, including inflammatory response, oxidative stress, cell death, and coagulation dysfunction. This review consolidated recent research progress on the pathophysiology and pathogenesis of heat stroke, with a focus on the related molecular mechanisms. In addition, we reviewed common strategies and sorted out the drugs in various preclinical stages for heat stroke, aiming to offer a comprehensive research roadmap for more in-depth researches into the mechanisms of heat stroke and the reduction in the mortality of heat stroke in the future.

Involvement of a chromatin modifier in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell injury: probably an indirect action via the regulation of NFκB/FasL circuitry.

The Fas/FasL signaling pathway, controlled by nuclear factor-κB (NFκB) at the transcriptional level, is critical for triggering germ cell apoptosis in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell (SC) injury, but the exact regulation mechanism remain unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), a component of the Mi-2/nucleosome remodeling and deacetylase complex, was upregulated in SCs during the early recovery after MEHP exposure. This expression change was in line with the dynamic changes in germ cell apoptosis in response to MEHP treatment. Furthermore, a knockdown of MTA1 by RNAi in SCs was found to impair the MEHP-induced early activation of NFκB pathway and abolish the recruitment of NFκB onto FasL promoter, which consequently diminished the MEHP-triggered FasL induction. Considering that Fas/FasL is a well characterized apoptosis initiating signaling during SCs injury, our results point to a potential "switch on" effect of MTA1, which may govern the activation of NFκB/FasL cascade in MEHP-insulted SCs. Overall, the MTA1/NFκB/FasL circuit may serve as an important defensive/repairing mechanism to help to control the germ cell quality after SCs injury.

YES1 activation elicited by heat stress is anti-apoptotic in mouse pachytene spermatocytes.

Deregulated expression of protein tyrosine phosphorylation has been implicated in testicular response to different stimuli. Herein, YES1, a nonreceptor protein tyrosine kinase, was found to be significantly up-regulated in pachytene spermatocytes (PS) during early recovery from a transient testicular heat stress. Coculture of PS with Sertoli cells (SCs) could enhance the hyperthermia-induced YES1 activation, indicative of a positive regulation of the paracrine signaling. Moreover, SU6656, a selective YES1 inhibitor, was shown to effectively block YES1 activity, thereafter resulting in a dramatic increase of heat stress-induced apoptosis in primary cultured PS. Mechanistically, the antiapoptotic effect of YES1 activation in response to testicular heat insult may mediate via the regulation of extracellular signal-regulated kinase (ERK)/metastasis-associated 1 (MTA1) cascade. From a clinical standpoint, a notably higher level of YES1 expression was observed in the pathological testis from varicocele patients as compared to a negligible staining in the control group. Taken together, our present results provide the first evidence that the YES1/ERK/MTA1/p53 cascade may serve as a naturally occurring, indispensable self-defensive mechanism maintaining apoptotic balance during meiotic heat stress. Our study may have also partially answered the question of how activation of signal pathways at the cell membrane surface interacts with the key regulatory events occurring in the nucleus during testicular heat shock.

Curcumin attenuates diabetic neuropathic pain by downregulating TNF-α in a rat model.

The mechanisms involved in diabetic neuropathic pain are complex and involve peripheral and central pathophysiological phenomena. Proinflammatory tumour necrosis factor α (TNF-α) and TNF-α receptor 1, which are markers of inflammation, contribute to neuropathic pain. The purpose of this experimental study was to evaluate the effect of curcumin on diabetic pain in rats. We tested 24 rats with diabetes induced by a single intraperitoneal injection of streptozotocin and 24 healthy control rats. Twelve rats in each group received 60 mg/kg oral curcumin daily for 28 days, and the other 12 received vehicle. On days 7, 14, 21, and 28, we tested mechanical allodynia with von Frey hairs and thermal hyperalgesia with radiant heat. Markers of inflammation in the spinal cord dorsal horn on day 28 were estimated with a commercial assay and Western blot analysis. Compared to control rats, diabetic rats exhibited increased mean plasma glucose concentration, decreased mean body weight, and significant pain hypersensitivity, as evidenced by decreased paw withdrawal threshold to von Frey hairs and decreased paw withdrawal latency to heat. Curcumin significantly attenuated the diabetes-induced allodynia and hyperalgesia and reduced the expression of both TNF-α and TNF-α receptor 1. Curcumin seems to relieve diabetic hyperalgesia, possibly through an inhibitory action on TNF-α and TNF-α receptor 1.

Effects of PEMF on microcirculation and angiogenesis in a model of acute hindlimb ischemia in diabetic rats.

Hindlimb ischemia is a major complication of diabetic patients due to poor neovascularization. Therapy with pulsed electromagnetic fields (PEMF) can promote angiogenesis in ischemic lesions. However, the efficacy and therapeutic mechanisms of PEMF in diabetes-related hindlimb ischemia are unclear. Sprague-Dawley rats were injected with streptozocin to induce diabetes, and 10 weeks later diabetic rats were subjected to surgical induction of acute hindlimb ischemia. The rats were randomized and treated with PEMF, and the blood perfusion of individual rats was determined longitudinally by laser Doppler perfusion imaging (LDPI). The neovascular density was examined using immunofluorescent analysis of CD31 expression and alkaline phosphatase (AP) staining. The levels of VEGF, VEGFR, FGF-2, and FGFR1 expression, and ERK 1/2 and P38 phosphorylation in the muscles were characterized using enzyme-linked immunosorbent assay (ELISA) and Western blot assays. The values of LDPI in the PEMF-treated rats at 14 and 28 days post surgery were significantly greater than those in the controls, accompanied by significantly elevated levels of anti-CD31 and AP staining. The relative levels of FGF-2 and FGFR1, but not VEGF and VEGFR expression, and ERK1/2, but not P38 phosphorylation, in the muscles of the PEMF-treated rats were significantly higher than those in the controls. Our data indicated that PEMF enhanced acute hindlimb ischemia-related perfusion and angiogenesis, associated with up-regulating FGF-2 expression and activating the ERK1/2 pathway in diabetic rats. Therefore, PEMF may be valuable for the treatment of diabetic patients with ischemic injury.

The role of dynamin-related protein 1 in cerebral ischemia/hypoxia injury.

Mitochondrial dysfunction, especially in terms of mitochondrial dynamics, has been reported to be closely associated with neuronal outcomes and neurological impairment in cerebral ischemia/hypoxia injury. Dynamin-related protein 1 (Drp1) is a cytoplasmic GTPase that mediates mitochondrial fission and participates in neuronal cell death, calcium signaling, and oxidative stress. The neuroprotective role of Drp1 inhibition has been confirmed in several central nervous system disease models, demonstrating that targeting Drp1 may shed light on novel approaches for the treatment of cerebral ischemia/hypoxia injury. In this review, we aimed to highlight the roles of Drp1 in programmed cell death, oxidative stress, mitophagy, and mitochondrial function to provide a better understanding of mitochondrial disturbances in cerebral ischemia/hypoxia injury, and we also summarize the advances in novel chemical compounds targeting Drp1 to provide new insights into potential therapies for cerebral ischemia/hypoxia injury.

Identification of PIK3CG as a hub in septic myocardial injury using network pharmacology and weighted gene co-expression network analysis.

Sepsis causes multiple organ injuries, among which the heart is one most severely damaged organ. Melatonin (MEL) alleviates septic myocardial injury, although a systematic and comprehensive approach is still lacking to understand the precise protective machinery of MEL. This study aimed to examine the underlying mechanisms of MEL on improvement of septic myocardial injury at a systematic level. This study integrated three analytic modalities including database investigations, RNA-seq analysis, and weighted gene co-expression network analysis (WCGNA), in order to acquire a set of genes associated with the pathogenesis of sepsis. The Drugbank database was employed to predict genes that may serve as pharmacological targets for MEL-elicited benefits, if any. A pharmacological protein-protein interaction network was subsequently constructed, and 66 hub genes were captured which were enriched in a variety of immune response pathways. Notably, PIK3CG, one of the hub genes, displayed high topological characteristic values, strongly suggesting its promise as a novel target for MEL-evoked treatment of septic myocardial injury. Importantly, molecular docking simulation experiments as well as in vitro and in vivo studies supported an essential role for PIK3CG in MEL-elicited effect on septic myocardial injury. This study systematically clarified the mechanisms of MEL intervention in septic myocardial injury involved multiple targets and multiple pathways. Moreover, PIK3CG-governed signaling cascade plays an important role in the etiology of sepsis and septic myocardial injury. Findings from our study provide valuable information on novel intervention targets for the management of septic myocardial injury. More importantly, this study has indicated the utility of combining a series of techniques for disease target discovery and exploration of possible drug targets, which should shed some light on elucidation of experimental and clinical drug action mechanisms systematically.