Acute kidney injury spectrum in patients with chronic liver disease:Where do we stand?

Acute kidney injury (AKI) is a common complication of liver cirrhosis and is of the utmost clinical and prognostic relevance. Patients with cirrhosis, especially decompensated cirrhosis, are more prone to develop AKI than those without cirrhosis. The hepatorenal syndrome type of AKI (HRS–AKI), a spectrum of disorders in prerenal chronic liver disease, and acute tubular necrosis (ATN) are the two most common causes of AKI in patients with chronic liver disease and cirrhosis. Differentiating these conditions is essential due to the differences in treatment. Prerenal AKI, a more benign disorder, responds well to plasma volume expansion, while ATN requires more specific renal support and is associated with substantial mortality. HRS–AKI is a facet of these two conditions, which are characterized by a dysregulation of the immune response. Recently, there has been progress in better defining this clinical entity, and studies have begun to address optimal care. The present review synopsizes the current diagnostic criteria, pathophysiology, and treatment modalities of HRS–AKI and as well as AKI in other chronic liver diseases (non-HRS–AKI) so that early recognition of HRS–AKI and the appropriate management can be established.

Expanding the horizons of targeted protein degradation:A non-small molecule perspective

Targeted protein degradation(TPD)represented by proteolysis targeting chimeras(PROTACs)marks a significant stride in drug discovery.A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond degradation.Non-small-molecule-based approaches play an irreplaceable role in this field.A wide variety of agents spanning a broad chemical spectrum,including peptides,nucleic acids,antibodies,and even vaccines,which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing paradigms.Herein we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs,including three major trajectories,to provide insights for the design strategies based on novel paradigms.

Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease

AIM:To clarify whether nonalcoholic fatty liver disease(NAFLD)increases the risk of cardiovascular disease.METHODS:We carried out a prospective observational study with a total of 1637 apparently healthy Japanese men and women who were recruited from a health check-up program.NAFLD was diagnosed by abdominal ultrasonography.The metabolic syndrome(MS)was defined according to the modified National Cholesterol Education Program(NCEP)ATP Ⅲ criteria.Five years after the baseline evaluations,the incidence of cardiovascular disease was assessed by a self-administered questionnaire.RESULTS:Among 1221 participants available for outcome analyses,the incidence of cardiovascular disease was higher in 231 subjects with NAFLD at baseline(5 coronary heart disease,6 ischemic stroke,and 1 cerebral hemorrhage)than 990 subjects without NAFLD(3 coronary heart disease,6 ischemic stroke,and 1 cerebral hemorrhage).Multivariate analyses indicated that NAFLD was a predictor of cardiovascular disease independent of conventional risk factors(odds ratio 4.12,95% CI,1.58 to 10.75,P = 0.004).MS was alsoindependently associated with cardiovascular events.But simultaneous inclusion of NAFLD and MS in a multivariate model revealed that NAFLD but not MS retained a statistically significant correlation with cardiovascular disease.CONCLUSION:Although both of them were predictors of cardiovascular disease,NAFLD but not MS retained a statistically significant correlation with cardiovascular disease in a multivariate model.NAFLD is a strong predictor of cardiovascular disease and may play a central role in the cardiovascular risk of MS.

Lansoprazole ameliorates intestinal mucosal damage induced by ischemia-reperfusion in rats

AIM: To investigate the protective effect of lansoprazoleon ischemia and reperfusion (I/R)-induced rat intestinalmucosal injury in vivo.METHODS: Intestinal damage was induced by clampingboth the superior mesenteric artery and the celiac trunkfor 30 rain followed by reperfusion in male Sprague-Dawleyrats. lansoprazole was given to rats intraperitoneally 1 hbefore vascular clamping.RESULTS: Both the intraluminal hemoglobin and proteinlevels, as indices of mucosal damage, significantlyincreased in I/R-groups comparion with those of sham-operation groups. These increases in intraluminal hemoglobinand protein levels were significantly inhibited by the treatmentwith lansoprazole at a dose of 1 mg/kg. Small intestineexposed to I/R resulted in mucosal inflammation that wascharacterized by significant increases in thiobarbituric acid-reactive substances (TBARS), tissue-associatedmyeloperoxidase activity (MPO), and mucosal content of ratcytokine-induced neutrophil chemoattractant-1 (CINC-1).These increases in TBARS, MPO activities and CINC-1 contentin the intestinal mucosa after I/R were all inhibited bypretreatment with lansoprazole at a dose of 1 mg/kg.Furthermore, the CINC-1 mRNA expression was increasedduring intestinal I/R, and this increase in mRNA expressionwas inhibited by treatment with lansoprazole.CONCLUSION: Lansoprazole inhibits lipid peroxidation andreduces development of intestinal mucosal inflammationinduced by I/R in rats, suggesting that lansoprazole mayhave a therapeutic potential for I/R injury.

Hematopoietic cell transplantation for Crohn’s disease;is it time?

AIM： To review all studies in the literature that have assessed Hematopoietic cell transplantation （HCT） and Crohn＇s disease （CD） with the ultimate aims of determining if this is a viable treatment option for those with CD. A secondary aim was to review the above literature and determine if the studies shed further light on the mechanisms involved in the pathogenesis of CD. METHODS： An extensive Medline search was performed on all articles from 1970 to 2005 using the keywords; bone marrow transplant, stem cell, hematopoietic cell, Crohn＇s disease and inflammatory bowel disease. RESULTS： We identified one case in which a patient developed CD following an allogeneic HCT from a sibling suffering with CD. Evidence for transfer of the genetic predisposition to develop CD was also identified with report of a patient that developed severe CD following an allogeneic HCT. Following HCT it was found that the donor （that had no signs or symptoms of CD） and the recipient had several haplotype mismatches in HLA class 111 genes in the IBD3 locus including a polymorphism of NOD2/CARD15 that has been associated with CD. Thirty three published cases of patients with CD who underwent either autologous or allogeneic HCT were identified. At the time of publication 29 of these 33 patients were considered to be in remission. The median follow-up time was seven years, and twenty months for allogeneic and autologous HCT respectively. For patients who underwent HCT primarily for treatment of their CD there have been no mortalities related to transplant complications. CONCLUSION： Overall these preliminary data suggest that both allogeneic and autologous HCT may be effective in inducing remission in refractory CD. This supports the hypothesis that the hematolymphatic cells play a key role in CD and that resetting of the immune system may be a critical approach in the management or cure of CD.

Pseudomembranous colitis presenting as acute colonic obstruction without diarrhea in a patient with gastric Burkitt lymphoma

Pseudomembranous colitis (PMC) usually manifests asfever and diarrhea in hospitalized patients treated withsystemic antibiotics. We described a case of PMC withintestinal obstruction but without diarrhea. A 60-yearold man was hospitalized for chemotherapy for the treatment of Burkitt lymphoma of the stomach. The patient became febrile and complained of crampy abdominal pain during the post-chemotherapy nadir. Plain abdominal radiography showed some intestinal gas and niveau. Because stool cytotoxin assay for clostridium difficile was positive and colon fiberscopic examination showed a pseudomembrane at the left side of the colon,and a diagnosis of PMC was made. Treatment with intracolonic vancomycin administration by colonoscopy and nasoileus tube was successful. Physicians should take into account the possibility of bowel obstruction due to PMC occurring in patients undergoing chemotherapy and perform emergency colonoscopy examination of suspected cases.

Rosuvastatin reduces rat intestinal ischemia-reperfusion injury associated with the preservation of endothelial nitric oxide synthase protein

AIM： To investigate the protective effect of rosuvastatin on ischemia-reperfusion （I-R）-induced small intestinal injury and inflammation in rats, and to determine the effect of this agent on the expression of endothelial nitric oxide synthase （eNOS） protein. METHODS： Intestinal damage was induced in male Sprague-Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion for 60 min. Rosuvastatin dissolved in physiological saline was administered intraperitoneally 60 min before ischemia. The severity of the intestinal mucosal injury and inflammation were evaluated by several biochemical markers, as well as by histological findings. The protein levels of eNOS were determined by Western blot. RESULTS： The levels of both intraluminal hemoglobin and protein, as indices of mucosal damage, were significantly increased in the I-R group compared with those in the sham-operated group. These increases, however, were significantly inhibited by treatment with rosuvastatin in a dose-dependent manner. The protective effects of rosuvastatin were also confirmed by histological findings. Exposure of the small intestine to I-R resulted in mucosal inflammation characterized by significant increases in thiobarbituric acid-reactive substances, tissueassociated myeloperoxidase activity, and the mucosal contents of rat cytokine-induced neutrophil chemoattracrant-1 （CINC-1） and tumor necrosis factor-α（TNF-α）. These increases in inflammatory parameters after I-R were significantly inhibited by pretreatment with rosuvo astatin at a dose of 10 mg/kg. Furthermore, mRNA expression of CINC-1 and TNF-α was increased after I-R, and this increase was also inhibited by rosuvastatin. The mucosal protein levels of eNOS decreased during I-R, but were preserved in rats treated with rosuvastatin. CONCLUSION： Rosuvastatin inhibits rat intestinal injury and inflammation induced by I-R, and its protection is associated with the preservation of eNOS protein.

Targeting autophagy and beyond:Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

AbstracBteclin-1 is the firstly-identified mammalian protein of the autophagy machinery,which functions as a molecular scaffold for the assembly of PI3KC3(class II phosphatidylinositol 3 kinase)complex,thus controlling autophagy induction and other cellular trafficking events.Notably,there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes,including tumor suppression and progression as well as resistance to cancer therapeutics and CSC(cancer stem-like cell)maintenance.More importantly,Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers.In this review,we provide a comprehensive survey of the structure,functions,and regulations of Beclin-1,and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology.Moreover,we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy,providing novel insights into a promising strategy for regulating Beclin-1 to improvecancer therapeutics in thefuture.

Establishing a Calculation Method for Estimating the Normal Circumference of the Proximal Interphalangeal Finger Joints

Objective: To estimate the normal circumference of the interphalangeal (IP) thumb joint and the proximal IP (PIP) joints from the index finger to the little finger using individual physical parameters such as body height and body weight. Methods: The maximum size on the ring gauge was recorded which caused resistance when the IP joint of the thumb or PIP joints of the index to small fingers were passed through the gauge. RG was defined as the ring gauge number with the same diameter as the circumference of the IP thumb joint and PIP finger joints from the index finger to the little finger. There were 300 healthy subjects and 600 hands. Univariate and multivariate analyses were used to analyze the relationships between RG and the parameters of age, sex, height, weight, and dominant hand, and regression equations were derived. Results: Age, sex and body weight were all statistically significant predictive factors of RG in all fingers. R2, the coefficient of determination in the regression equation, was almost 0.7 for all fingers, indicating that a moderate or strong correlation was observed between RG and the regression equation. Conclusions: The circumference of the IP thumb joint and PIP finger joints from the index finger to the little finger can be estimated in healthy individuals using a calculation formula that takes age, sex, body height and body weight into account.

Efficacy of MRP8/14 as a Marker of Disease Activity in Rheumatoid Arthritis

Objective: Early and accurate evaluation of the presence and activity of synovitis is extremely important in the diagnosis and treatment of rheumatoid arthritis. Myeloid related protein 8/14 (MRP8/14), also known as calprotectin or S100A8/A9 is considered as a sensitive marker for local inflammatory activity in rheumatoid arthritis. The aim of this study is to demonstrate the efficacy of MRP8/14 as a marker of disease activity in RA. Methods: Thirty-one patients with diagnosis of RA who received treatment without biological drugs at our institution were included in this study. Serum MRP8/14, CRP and MMP-3 were tested in all patients. Disease activity was evaluated using DAS28-CRP and SDAI. Ultrasonography was performed on the wrists and MCP joints of both hands using semi-quantitative scale of power Doppler signal. The sum of scales in joints was calculated as the PD score. The correlation of MRP8/14 with serum biomarkers, disease activity and ultrasonography examination was investigated. Result: Serum MRP8/14 was strongly correlated with CRP (r = 0.63) and MMP-3 (r = 0.69). A correlation was observed between serum MRP8/14 and DAS28-CRP (r = 0.53) and SDAI (r = 0.66). No significant correlation was found between PD scores and MRP8/14. Conclusion: This study demonstrated that MRP8/14 is correlated with evaluated disease activity and markers of serum inflammatory response in patients not using biological drugs. MRP8/14 is considered an effective new method for objective evaluation of synovitis in RA.

Supplying the trip to antibody production-nutrients,signaling,and the programming of cellular metabolism in the mature B lineage

The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody(Ab)secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection.With this backdrop,it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise,persist,and meet the challenge of secreting vast amounts of these glycoproteins.Whereas plasmablasts and plasma cells(PCs)are the primary sources of secreted Abs,the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates.At each step,cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients.Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription,translation,and metabolism.This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion.Salient findings of this group and others,sometimes exhibiting differences,will be summarized with regard to the journey to a distinctive metabolic program in PCs.

Current health resources required for the management of ankylosing spondylitis in developing areas of China

To the Editor:Ankylosing spondylitis(AS)is a chronic inflammatory disease that causes bony fusion of spine and sacroiliac joints,resulting in restricted spinal movement and deformity.In China,the prevalence of AS is about 0.29%with a male to female ratio of approximately 3:1,and most cases occur in the adolescent period.[1]The misdiagnosis rate of AS patients in China is>50%.

The involvement of interleukin-22 in the expression of pancreatic beta cell regenerative Reg genes

Background:In Type 1 diabetes,the insulin-producingβ-cells within the pancreatic islets of Langerhans are destroyed.We showed previously that immunotherapy with Bacillus Calmette-Guerin(BCG)or complete Freund’s adjuvant(CFA)of non-obese diabetic(NOD)mice can prevent disease process and pancreaticβ-cell loss.This was associated with increased islet Regenerating(Reg)genes expression,and elevated IL-22-producing Th17 T-cells in the pancreas.Results:We hypothesized that IL-22 was responsible for the increased Reg gene expression in the pancreas.We therefore quantified the Reg1,Reg2,and Reg3δ(INGAP)mRNA expression in isolated pre-diabetic NOD islets treated with IL-22.We measured IL-22,and IL-22 receptor(R)-αmRNA expression in the pancreas and spleen of pre-diabetic and diabetic NOD mice.Our results showed:1)Reg1 and Reg2 mRNA abundance to be significantly increased in IL-22-treated islets in vitro;2)IL-22 mRNA expression in the pre-diabetic mouse pancreas increased with time following CFA treatment;3)a reduced expression of IL-22Rαfollowing CFA treatment;4)a down-regulation in Reg1 and Reg2 mRNA expression in the pancreas of pre-diabetic mice injected with an IL-22 neutralizing antibody;and 5)an increased isletβ-cell DNA synthesis in vitro in the presence of IL-22.Conclusions:We conclude that IL-22 may contribute to the regeneration ofβ-cells by up-regulating Regenerating Reg1 and Reg2 genes in the islets.

A Tibetan adolescent girl suffered frostbite on the journey of pilgrimage:A case report

Frostbite in Southwestern China has been overlooked due to its low incidence,relatively mild temperature and lack of literature published before.However,it needs to be further studied for religious diversity and distinct geomorphology.In this article,we reported an 18-year-old Tibetan girl who suffered from blizzard attack during pilgrimage.Her feet and several fingers showed mummified gangrene upon physical examination with poor movement.She was diagnosed with 3rd to 4th degree of frostbite.The girl was given oral ibuprofen,debridement and other regular treatment daily,but she was eventually amputated due to insufficient thrombolytic management in primary hospital,delayed informing consent in the referral hospital and ethnic conflict between religion and guidelines.This case enriched the experience of managing complex frostbite in Tibetan population and alarms that efforts should be integrated to protect pilgrims and mountaineers in the Tibetan region.

Frostbite in Southwest China:A Single-Center Retrospective Analysis

Objective:The current study aimed to profile the demographics,hematological index,and extrinsic factors of patients treated for frostbite in a single center in Southwest China.Methods:We collected the clinical data of patients with frostbite admitted to a regional hospital from January 1st,2009 to January 1st,2019.The baseline information was summarized,and the causes and hematological indexes of frostbite were analyzed.Results:The study cohort comprised 27 patients.The median patient age was 22 years(range 14-81 years).All frostbite injuries occurred between September 22nd and April 27th.Half of the patients were Tibetans.Cold injuries in Tibetan patients were associated with pilgrimage(70%,9/13)and grazing(15%,2/13),while the leading causes of frostbite in Han residents of the Southwest China basin were mandatory fieldwork without protection(36%,5/14)and loss of consciousness(36%,5/14).The hematological examination findings did not significantly differ between amputees and those who did not undergo amputation.Several hematological indexes significantly differed between patients with good outcomes versus those with poor outcomes.Conclusion:To avoid severe frostbite damage,routine mandatory activities like pilgrimage should be conducted under proper protection in extreme weather.Hematological indexes such as the red blood cell count,hematocrit,and hemoglobin level should be monitored closely by first-line medical personnel during hospitalization,as these indexes might indicate the outcome of frostbite.Further research is needed to improve the management of patients with frostbite in Southwest China.