Multifaceted functions of Drp1 in hypoxia/ischemia- induced mitochondrial quality imbalance: from regulatory mechanism to targeted therapeutic strategy

Hypoxic-ischemic injury is a common pathological dysfunction in clinical settings.Mitochondria are sensitive organelles that are readily damaged following ischemia and hypoxia.Dynamin-related protein 1(Drp1)regulates mitochondrial quality and cellular functions via its oligomeric changes and multiple modifications,which plays a role in mediating the induction of multiple organ damage during hypoxic-ischemic injury.However,there is active controversy and gaps in knowledge regarding the modification,protein interaction,and functions of Drp1,which both hinder and promote development of Drp1 as a novel therapeutic target.Here,we summarize recent findings on the oligomeric changes,modification types,and protein interactions of Drp1 in various hypoxic-ischemic diseases,as well as the Drp1-mediated regulation of mitochondrial quality and cell functions following ischemia and hypoxia.Additionally,potential clinical translation prospects for targeting Drp1 are discussed.This review provides new ideas and targets for proactive interventions on multiple organ damage induced by various hypoxic-ischemic diseases.

Multi-Organ Pathogenesis and Therapeutic Strategies for Cystic Fibrosis

Cystic Fibrosis (CF) is the most common lethal autosomal inherited disorder that affects all races and ethnicities in the United States. However, it is mostly predominant in the Caucasian populace accounting for about 80% of all CF cases. CF most severe complication can be referred to as pulmonary bronchiectasis and infections of the airways, nonetheless, the devastating effects of the disease have far-reaching consequences beyond lung damage. CF is a heterogeneous disease that is caused by mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The impairment or absence of this gene can affect multiple organs and systems and is characterized not only by chronic lung blockage, infections, and inflammation but also by exocrine gland dysfunction, intestinal obstruction, liver pathology, elevated sweat chloride concentration, and in males, infertility due to the congenital bilateral absence of the vas deferens. To this end, we briefly explore the pathological effects of CF and how CF mediates the destruction of several critical organs in the body and some of the gene therapeutical approaches such as gene editing and viral-based strategies available for the treatment of this multi-organ disease.

Metabolic syndrome in hypertensive patients:An unholy alliance

For many years, it has been recognized that hypertension tends to cluster with various anthropometric and metabolic abnormalities including abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, glucose intolerance, insulin resistance and hyperuricemia. This constellation of various conditions has been transformed from a pathophysiological concept to a clinical entity, which has been defined metabolic syndrome(MetS). The consequences of the MetS have been difficult to assess without commonly accepted criteria to diagnose it. For this reason, on 2009 the International Diabetes Federation, the American Heart Association and other scientific organizations proposed a unified MetS definition. The incidence of the MetS has been increasing worldwide in parallel with an increase in overweight and obesity. The epidemic proportion reached by the MetS represents a major public health challenge, because several lines of evidence showed that the MetS, even without type 2 diabetes, confers an increased risk of cardiovascular morbidity and mortality in different populations including also hypertensive patients. It is likely that the enhanced cardiovascular risk associated with MetS in patients with high blood pressure may be largely mediated through an increased prevalence of preclinical cardiovascular and renal changes, such as left ventricular hypertrophy, early carotid atherosclerosis, impaired aortic elasticity, hypertensive retinopathy and microalbuminuria. Indeed, many reports support this notion, showing that hypertensive patients with MetS exhibit, more often than those without it, these early signs of end organ damage, most of which are recognized as significant independent predictors of adverse cardiovascular outcomes.

Association of blood pressure variability with target organ damage in older patients with essential hypertension

Background:Although multiple measures of blood pressure variability(BPV)have been proposed,whether they are better than mean blood pressure in predicting target organs is unclear.We aimed to determine the relationship between short term BPV and target organ injury.Methods:This study was a retrospective study,and 635 inpatients in the Department of Cardiology from 2015 to 2020 were selected.We divided participants into four groups on the basis of the quartiles of BPV.One-way analysis of variance was used to compare the differences between the groups,and linear regression was used to analyze the relationship between BPV and target organ damage.Results:The average age of 635 patients was 74.36±6.50 years old.Among them,354 of 627 patients had diminished renal function(56.5%),221of 604 patients had associated left ventricular hypertrophy(36.6%),and 227 of 231 patients had carotid plaque formation(98.3%).The baseline data indicated significant differences in fasting glucose,total cholesterol,low-density lipoprotein,creatinine,glomerular filtration rate,sex,calcium channel blocker use,and the rate of diminished renal function.Multiple linear regression analysis showed that BPV was negatively correlated with renal injury(creatinine:r=0.306,p<0.01;estimated glomerular filtration rate:r=0.058,p<0.01),and BPV is positively correlated with cardiac injury(r=0.083,p<0.01).Elevated BPV was not found to be associated with vascularinjury.Conclusion:Renal function decreases with increasing BPV and left ventricular mass increases with increasing BPV.

Effect of airplane transport of donor livers on post-liver transplantation survival

AIM To evaluate the effect of long haul airplane transport of donor livers on post-transplant outcomes. METHODS A retrospective cohort study of patients who received a liver transplantation was performed in Perth, Australia from 1992 to 2012. Donor and recipient characteristics information were extracted from Western Australian liver transplantation service database. Patients were followed up for a mean of six years. Patient and graft survival were evaluated and compared between patients who received a local donor liver and those who received an airplane transported donor liver. Predictors of survival were determined by univariate and multivariate analysis using cox regression.RESULTS One hundred and ninety-three patients received alocal donor liver and 93 patients received an airplane transported donor liver. Airplane transported livers had a significantly lower alanine transaminase(mean: 45 U/L vs 84 U/L, P = 0.035), higher donor risk index(mean: 1.88 vs 1.42, P < 0.001) and longer cold ischemic time(CIT)(mean: 10.1 h vs 6.4 h, P < 0.001). There was a weak correlation between CIT and transport distance(r2 = 0.29, P < 0.001). Mean follow up was six years and 93 patients had graft failure. Multivariate analysis found only airplane transport retained significance for graft loss(HR = 1.92, 95%CI: 1.16-3.17). One year graft survival was 0.88 for those with a local liver and was 0.71 for those with an airplane transported liver. One year graft loss was due to primary graft non-function or associated with preservation injury in 20.8% of recipients of an airplane transported liver compared with 4.6% in those with a local liver(P = 0.027). CONCLUSION Airplane transport of donor livers was independently associated with reduced graft survival following liver transplantation.

End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899

AIM: To compare the therapeutic efficacy of SAR407899 with the current standard treatment for hypertension [an angiotensin converting enzyme(ACE)-inhibitor and a calcium channel blocker] and compare the frequency and severity of the hypertension-related end-organ damage. METHODS: Long-term pharmacological characterization of SAR407899 has been performed in two animal models of hypertension, of which one is sensitive to ACE-inhibition and the other is insensitive [deoxycorticosterone acetate(DOCA)]. SAR407899 efficiently lowered high blood pressure and significantly reduced late-stage end organ damage as indicated by improved heart, kidney and endothelial function and reduced heart and kidney fibrosis in both models of chronic hypertension. RESULTS: Long term treatment with SAR407899 has been well tolerated and dose-dependently reduced elevated blood pressure in both models with no signs of tachyphylaxia. Blood pressure lowering effects and protective effects on hypertension related end organ damage of SAR407899 were superior to ramipril and amlodipine in the DOCA rat. Typical end-organ damage was significantly reduced in the SAR407899-treated animals. Chronic administration of SAR407899 significantly reduced albuminuria in both models. The beneficial effect of SAR407899 was associated with a reduction in leukocyte/macrophage tissue infiltration. The overall protective effect of SAR407899 was superior or comparable to that of ACE-inhibition or calciumchannel blockade. Chronic application of SAR407899 protects against hypertension and hypertension-induced end organ damage, regardless of the pathophysiological mechanism of hypertension. CONCLUSION: Rho-kinases-inhibition by the SAR407899 represents a new therapeutic option for the treatment of hypertension and its complications.

Biomarkers of graft-vs-host disease:Understanding and applications for the future

Hematopoietic stem cell transplantation(HSCT)is widely performed as a treatment for malignant blood disorders,such as leukemia.To achieve good clinical outcomes in HSCT,it is necessary to minimize the unfavorable effects of acute graft-vs-host disease(GVHD)and induce the more tolerable,chronic form of the disease.For better management of GVHD,sensitive and specific biomarkers that predict the severity and prognosis of the disease have been intensively investigated using proteomics,transcriptomics,genomics,cytomics,and tandem mass spectrometry methods.Here,I will briefly review the current understanding of GVHD biomarkers and future prospects.

Mechanisms of multiple organ damages in acute necrotizing pancreatitis

Abstract:Objective To determine the role of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), and evaluate the progress from SIRS to MODS and the therapeutic strategies for acute necrotizing pancreatitis (ANP).Methods Rat ANP models were made by retrograde injection of 3.5% sodium taurocholate 2.5?ml/kg into the pancreatic duct. Serum interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNFα), amylase, endotoxin, and albumin were examined. The morphology and pathology of the pancreas, liver, lung, kidney and heart after ANP were observed. Finally, TNFα mRNA in the liver, lung, kidney and heart after ANP were observed by reverse transcriptase-polymerase chain reactions, and the efficiency of somatostatin and growth hormone were also observed in this experiment.Results ANP led to remarkable elevation of the inflammatory mediators which were positively correlated with the development of ANP and MODS. Somatostatin and growth hormone inhibited inflammatory mediators and TNFα mRNA overexpressions, reduced the risk of MODS, corrected hypoalbuminemia, reversed negative nitrogen balance, and controlled the reduction of cell groups with functions and reasonably intervened SIRS caused by ANP.Conclusion TNFα mRNA plays an important role in ANP progression. The amelioration of ANP by combination treatment with somatostatin and growth hormone leads to the reduction of complications and marked increase in survival.

Efficacy of Huoxue Qianyang Qutan Recipe on essential hypertension:A randomized,double-blind,placebo-controlled trial

Background:Hypertension,a prevalent disease,is a significant risk factor for coronary heart disease.Huoxue Qianyang Qutan Recipe (HQQR),a traditional Chinese herbal remedy,has been used for treating hypertension over several years.Objective:This study assesses HQQR’s efficacy for controlling blood pressure among patients with hypertension related to blood stasis,yang hyperactivity and phlegm.Design,setting,participants and interventions:A randomized controlled trial was conducted at the Yueyang Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai University of Traditional Chinese Medicine,China,from July 2020 to June 2022.Major components of HQQR were identified using thin-layer chromatography and high-performance liquid chromatography.Participants aged18–80 years,exhibiting traditional Chinese medicine syndromes of blood stasis,yang hyperactivity or phlegm,along with grades 1 or 2 hypertension,were randomly categorized into two groups.The intervention group was given HQQR granules alongside conventional hypertension treatment,while the control group was given placebo granules in addition to conventional treatment for 12 weeks.Main outcome measures:The primary outcome was clinic blood pressure,whereas secondary outcomes included metabolic indices (e.g.,homeostasis model assessment of insulin resistance[HOMA-IR],total cholesterol[TC],low-density lipoprotein cholesterol and triglyceride),target organ damage indices (left ventricular mass index and urinary albumin creatinine ratio[UACR]) and inflammation indices(interleukin-6[IL-6]and high-sensitivity C-reactive protein[hs-CRP]).Results:HQQR’s primary components were identified as salvianolic acid B,emodin and ferulic acid.Of the 216 participants (108 in each group),compared to the control,the intervention group exhibited significant improvements (P<0.001) in clinic systolic blood pressure ([136.24±7.63]vs[130.06±8.50]mmHg),clinic diastolic blood pressure ([84.34±8.72]vs[80.46±6.05]mmHg),home systolic blood pressure([131.64±8.74]vs[122.36±8.45]mmHg) and home diastolic blood pressure ([78.47±9.53]vs[71.79±6.82]mm Hg).HQQR demonstrated a reduction in ambulatory blood pressure (24-hour systolic blood pressure:[133.75±10.49]vs[132.46±8.84]mmHg and 24-hour diastolic blood pressure:[84.12±8.01]vs[82.11±7.45]mmHg) and an improvement in HOMA-IR ([4.09±1.72]vs[3.98±1.44]),TC ([4.66±1.47]vs[3.75±1.81]mmol/L) and UACR (75.94[5.12,401.12]vs 45.61[4.26,234.26]).Moreover,HQQR demonstrated a decrease in hs-CRP (1.46[0.10,10.53]vs 0.57[0.12,3.99]mg/L) and IL-6 (6.69[2.00,29.74]vs 5.27[2.00,9.73]pg/mL),with no reported side effects (P<0.001).Conclusion:This study highlights the therapeutic potential of HQQR use in ameliorating blood pressure,glycolipid metabolism,and inflammation in patients with hypertension.

Association factors of target organ damage： analysis of 17 682 elderly hypertensive patients in China

Background Hypertensive target organ damage （TOD） is the main reason for mortality or disability in elderly hypertensive patients. The studies on TOD of hypertension in Asia, especially in Chinese elderly hypertensive patients, are very limited. The aim of this study was to evaluate the prevalence and correlative factors of TOD in older Chinese hypertensive inpatients. Methods This is a retrospective survey and data were collected from the computerized medical files of hypertensive inpatients from January of 1993 to December of 2008. The analysis was done on 17 682 inpatients, aged 60 years or older, with a diagnosis of essential hypertension （EH）. The evidence of hypertensive TOD and associated factors with TOD were collected. Results The prevalence of any hypertensive target organ involvement among these subjects was high. In multivariable Logistic regressions adjusted for potentially confounding factors, older age, male gender, diabetes, EH grade 3, systolic blood pressure （SBP）, and low-density lipoprotein cholesterol （LDL-C）, were independently associated with coronary artery disease. Age, duration of EH, EH grade 3, SBP, pulse pressure （PP）, and homocysteine （Hcy） were independently associated with cerebrovascular disease. Age, diabetes, duration of EH, EH grade 3, SBP, PP and estimated glomerular filtration rate （eGFR） were independently associated with chronic kidney disease. Male gender, EH grade 3 and SBP were independently associated with aortic dissection. Conclusions The prevalence of hypertensive TOD is high in older Chinese hypertensive inpatients. Various cardiovascular risk factors are associated with hypertensive TOD. The level of SBP and severe hypertension （grade 3 hypertension） are common independent risk factors of TOD.

Relationships of Inflammatory Factors and Risk Factors with Different Target Organ Damage in Essential Hypertension Patients

Background： Atherosclerosis （AS） is an inflammatory disease. Inflammation was considered to play a role in the whole process of AS. This study aimed to analyze the relationships of inflammatory factors and risk factors with different target organ damages （TOD） in essential hypertension （EH） patients and to explore its clinical significance. Methods： A total of 294 EH patients were selected and divided into four groups according to their conditions of TOD. Forty-eight healthy subjects were selected as control. The clinical biochemical parameters, serum amyloid A, serum tryptase, and lipoprotein-associated phospholipase A2 （Lp-PLA2） in each group were detected, and the related risk factors were also statistically analyzed. Results： Fihrinogen （Fbg） was the most significant independent risk factor in acute coronary syndrome （ACS） group （odds ratio [OR]： 22.242, 95% confidence interval [CI]： 6.458-76.609, P 〈 0.001） with the largest absolute value of the standardized partial regression coefficient B＇ （b＇： 1.079）. Lp-PLA2 was the most significant independent risk factor in stroke group （OR： 13.699, 95% CI： 5.236-35.837, P 〈 0.001） with b＂ 0.708. Uric acid （UA） was the most significant independent risk factor in renal damage group （OR： 15.307, 95% CI：4.022 58.250, P〈0.001）with b＇= 1.026. Conclusions： Fbg, Lp-PLA2, and UA are the strongest independent risk factors toward the occurrence of ACS, ischemic stroke, and renal damage in EH patients, thus exhibiting the greatest impacts on the occurrence ofACS, ischemic stroke, and renal damage in EH patients, respectively.

Effects of enteral nutrition with different energy supplies on metabolic changes and organ damage in burned rats

Background:Enteral nutrition(EN)is an important treatment for burn patients.However,severe gastrointestinal damage caused by major burns often leads to EN intolerance.Trophic EN solves this problem basically,but how to transition from trophic EN to standard EN smoothly is still a challenge in burn clinical nutrition.The aim of this study is to investigate the effects of EN with different energy supplies on metabolic changes,organ damage and prognosis in burned rats.Methods:Different feeding regimens were designed based on the continuous monitoring of resting energy expenditure in rats.Thirty-two Sprague-Dawley rats were randomly divided into a normal control group,burn+50%REE group,burn+75%REE group and burn+100%REE group.At the end of a nutritional treatment cycle(14th day),nuclear magnetic resonance spectroscopy,blood biochemistry analysis and quantification of subscab bacteria were performed to explore the differences in metabolic changes,degrees of organ damage and prognoses between the groups.Results:Sixteen metabolites involving seven metabolic pathways were identified from the different energy supply groups.After burn injury,resting energy consumption and body weight loss increased obviously.Meanwhile,weight loss was inversely related to energy supply.The greatest changes in the degree of organ damage,the level of plasma proteins,lipids and endotoxins,as well as the quantification of subscab bacteria were observed in the 50%REE group,followed by the 75 and 100%groups.Conclusions:Achieving an early balance between energy supply and expenditure is conducive to mitigating metabolic disorders and improving prognosis after burn injury.

Effect of a normal protein diet on oxidative stress and organ damage in malnourished rats

BACKGROUND： We investigated the effects of three weeks of renutrition with a normal protein diet on oxidant/antioxidant status in malnourished rats using biochemistry and histology. METHODS： Eighteen young Wistar rats were divided into three groups： control group was fed on a normal protein diet; malnourished group was fed on low protein diet and renourished group was fed on low protein diet followed by a normal protein diet. Serum albumin was evaluated. Malondialdehyde, protein carbonyl, superoxide dismutase and catalase levels were determined in the intestine, muscle and liver. Intestinal and hepatic damage were assessed by histological examination. RESULTS： Protein malnutrition resulted in a significant decrease of body weight, albumin level, villus length, intraepithelial lymphocytes counts （IELC） and superoxide dismutase level （liver and muscle）. However, catalase activity increased significantly in muscle and gut but there was no difference in liver. In all organs, malondialdehyde and protein carbonyl content of malnourished group showed a significant increase. Interestingly, a normal protein diet for three weeks resulted in a return to normal levels of superoxide dismutase, albumin, malondialdehyde and protein carbonyl in all organs. Catalase activity decreased in the muscle and gut and exhibited no significant difference in the liver. The renutrition diet enhanced also the recovery of intestinal epithelium by increasing villus length. Hepatic damage of rats fed normal protein diet was markedly reduced （macrovesicular steatosis decreased by 45%）. CONCLUSION： The normal protein diet could improve the oxidant/antioxidant imbalance and organ damage induced by protein malnutrition.

Nanomaterials disrupting cell-cell junctions towards various diseases

As the continuous development of the industrial revolution,nanomaterials with excellent characteristics have been widely applied in various fields,greatly increasing the probability of human exposure to nanomaterials and the concerns about the potential nanotoxicity.Existing studies have shown that the toxicity of nanomaterials may be closely related to oxidative stress,inflammatory response,phagocytosis dysfunction,DNA damage,etc.Based on our focus,nanomaterials may cross the human barrier through various channels and disrupt various cell-cell junctions,while the integrity of cellular barrier is a necessary for the normal physiological function of various organs.However,until now,there is still a lack of systematic discussion in this field.This review illustrates the importance of cell-cell junctions in maintaining various organ functions and highlights the mechanism of various nanomaterials disrupt cell-cell junctions,as well as the possible damage to various organs,such as brain,eye,lung,breast,intestine,placenta,testis,heart,liver,kidney,skin,etc.Awareness of the potential negative effects of nanomaterials will help scientists deeply understand the limitations of nanotechnology,inspiring them to develop safer and more efficient nanomaterials for future personalized nanomedicine.

Association between the rate of the morning surge in blood pressure and cardiovascular events and stroke

Background The exaggerated surge in morning blood pressure （BP） that many patients experience upon awakening may be closely related to target organ damage and may be a predictor of cardiovascular complications. However, no previous studies have evaluated the rate of this surge independently of the evening period. It remains unclear whether the rate of increase experienced during the surge is a significant or independent determinant of cardiovascular events. Methods We randomly selected 340 ambulatory BP monitoring （ABPM） patients. All subjects without type 2 diabetes mellitus were divided into two groups： hypertensive group （n=170） and normotensive group （n=170）. We analyzed ambulatory blood pressure recordings using a double logistic curve-fitting procedure to determine whether the magnitude of the surge in BP and heart rate （HR） in the morning is related to the level of BP in hypertensive individuals. We evaluated the association between the rate of the morning surge in systolic BP （SBP） and the incidence of myocardial infarction and stroke in normotensive and hypertensive subjects. Results Comparisons between hypertensive and normotensive subjects showed that the rates of the morning surges in SBP, mean BP （MBP）, and diastolic BP （DBP） were greater in the hypertensive group （P 〈0.05） than in the normotensive group. The rate of morning surge in BP was found to be correlated with the daytime SBP （r=0.236, P 〈0.01）, the difference between the day and night plateau （r=0.249, P 〈0.01）, and the night SBP （r---0.160, P 〈0.05）, respectively. After controlling for age, sex, and mean systolic pressure within 24 hours （24 h SBP）, the rate of morning surge in SBP was closely correlated with daytime SBP （r=0.463, P 〈0.001）, night SBP （r=-0.173, P 〈0.05）, and the difference between the day and night plateau （r=0.267, P 〈0.001）. Logistic regression analysis revealed that the rate of morning surge in SBP was an independent determinant of myocardial infarction （OR=1.266, 95% C1=1.153-1.389, P 〈0.001） and stroke （OR=1.367, 95% C/=1.174-1.591, P 〈0.001）. Conclusions The rate of the morning surge in BP is greater in hypertensive subjects than in normotensive subjects. Daytime SBP may be the best predictor of the rate of morning surge in SBP. The rate of the morning surge in BP is associated with cardiovascular and stroke events.