Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies.

Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation's delicate balance, spanning innate and adaptive immunity. Viral factors' disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation's impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Novel gene-based therapeutic approaches for the management of hepatic complications in diabetes: Reviewing recent advances.

Diabetes mellitus is a chronic metabolic disorder marked by hyperglycemia and systemic complications, including hepatic dysfunction, significantly contributing to disease progression and morbidity. This article reviews recent advances in gene-based therapeutic strategies targeting hepatic complications in diabetes, offering a promising approach for precision medicine by addressing underlying molecular mechanisms. Traditional treatments for hepatic complications in diabetes often manage symptoms rather than molecular causes, showing limited efficacy. Gene-based therapies are poised to correct dysfunctional pathways and restore hepatic function. Fundamental gene therapy approaches include gene silencing via small interfering RNAs (siRNAs) to target hepatic glucose production, lipid metabolism, and inflammation. Viral vectors can restore insulin sensitivity and reduce oxidative stress in diabetic livers. Genome editing, especially CRISPR-Cas9, allows the precise modification of disease-associated genes, offering immense potential for hepatic complication treatment. Strategies using CRISPR-Cas9 to enhance insulin receptor expression and modulate aberrant lipid regulatory genes are explored. Safety challenges in gene-based therapies, such as off-target effects and immune responses, are discussed. Advances in nanoparticle-based delivery systems and targeted gene editing techniques offer solutions to enhance specificity and minimize adverse effects. In conclusion, gene-based therapeutic approaches are a transformative direction in managing hepatic complications in diabetes. Further research is needed to optimize efficacy, safety, and long-term outcomes. Nevertheless, these innovative strategies promise to improve the lives of individuals with diabetes by addressing hepatic dysfunction's genetic root causes.

The role and mechanism of action of microbiota-derived short-chain fatty acids in neutrophils: From the activation to becoming potential biomarkers.

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, have emerged as critical mediators in the communication between the human microbiota and its host. As the first responder to the inflammatory site, neutrophils play an important role in protecting the host against bacterial infections. Recent investigations revealed that SCFAs generated from microbiota influence various neutrophil activities, including activation, migration, and generation of mediators of inflammatory processes. SCFAs have also been demonstrated to exhibit potential therapeutic benefits in a variety of disorders related to neutrophil dysfunction, including inflammatory bowel disease, viral infectious disorders, and cancer. This study aims to examine the molecular processes behind the complicated link between SCFAs and neutrophils, as well as their influence on neutrophil-driven inflammatory disorders. In addition, we will also provide an in-depth review of current research on the diagnostic and therapeutic value of SCFAs as possible biomarkers for neutrophil-related diseases.

Blood Cell Parameters Combined with Inflammatory Markers in the Early Diagnosis of Pulmonary Embolism.

Venous thrombosis is a semi-solid formation of blood components that coalesce in the venous system, and the pathological process of its formation is called venous thrombosis. The deep veins of the lower extremities are a common site of prevalence, and the clinical diagnosis of lower extremity deep vein thrombosis can occur independently or as a complication of other diseases. There is a clear link between inflammation and coagulation/anticoagulation, with inflammatory mechanisms upregulating pro-inflammatory factors, downregulating natural anticoagulant substances, and inhibiting fibrinolytic activity; systemic inflammation is a strong pro-thrombotic stimulus; and in vivo, natural anticoagulant substances not only prevent thrombosis, but also deter inflammatory processes. The interconnection between inflammation and coagulation plays an important role in venous thrombosis. In this study, we analyzed the relationship between inflammatory markers CRP and Fg, FVIII:C and FIX:C by measuring plasma CRP concentration, Fg level, FVIII:C and FIX:C levels in patients with DVT diagnosed by ultrasound, and explored the role and mechanism of inflammatory response and coagulation factor abnormalities and the interaction between them in the development of DVT. In this paper, human blood DNA was extracted by phenol-chloroform-isoamyl alcohol extraction, and CRP 1059G/C gene polymorphism was detected by polymerase chain reaction-restriction enzyme segment length polymorphism (PCR-RFLP) nucleotide typing technique, and the genotypes of each subject were distinguished according to the bands seen by gel electrophoresis, and the frequency of each genotype was counted. Plasma CRP concentrations were measured by immunoturbidimetric assay, FVIII:C and FIX:C levels were measured by phase I assay, and plasma Fg levels were measured by coagulation assay in 59 cases (38 males and 21 females, aged 21-82 years, mean 49.67±11.12 years) and 26 controls (17 males and 9 females, aged 32-67 years, mean 50.13±8.96 years). The above indexes were compared between the two groups, and the correlation between CRP and FVIII:C, FIX:C and Fg was analyzed. Polymerase chain reaction-restriction enzyme segment length polymorphism nucleotide typing technique was used to detect the relationship between CRP 1059G/C gene polymorphism and DVT, to further search for risk factors of venous thrombosis, thus providing new ideas for the future prevention and treatment of this disease in clinical practice.

Comparative study on electrocardiograms and serological examinations of acute pulmonary embolism and acute non-ST elevation myocardial infarction.

BACKGROUND: The aim of this study was to investigate the value of electrocardiograms (ECGs) and serological examinations in the differential diagnosis of acute pulmonary embolism (APE) and acute non-ST elevation myocardial infarction (NSTEMI) in order to reduce the rate of clinical misdiagnosis. METHODS: The clinical data of 37 patients with APE and 103 patients with NSTEMI admitted to our hospital were retrospectively analyzed. The differences in the clinical manifestations, ECGs, myocardial zymograms, D-dimers, and troponin (cTn) of the two groups were compared. RESULTS: In the patients with APE, the main symptom-found in 25 cases (67.56%)-was dyspnea, while in the patients with NSTEMI, the main symptom-found in 52 cases (50.49%)-was chest tightness. The incidences of sinus tachycardia and SI QIII TIII in the group of patients with APE were higher than in the group of patients with NSTEMI, and the difference was statistically significant (p < .05). There was no statistical significance in the difference of aspartate aminotransferase and lactate dehydrogenase (LDH) in the two groups (p > .05), although there was a statistically significant difference of creatine kinase (CK) and the creatine kinase isoenzyme-MB (CK-MB) in the two groups (p < .05). The levels of D-dimers and cTn were increased in both groups, but the level of D-dimers in the group of patients with APE was higher than that in the group of patients with NSTEMI. CONCLUSION: With the occurrence of clinical manifestations like dyspnea, chest tightness, chest pain, and palpitation of unknown causes, the possibility of APE and NSTEMI should be considered.

Efficacy of High Specific Volume Polysaccharide - A New Type of Dietary Fiber - On Molecular Mechanism of Intestinal Water Metabolism in Rats With Constipation.

BACKGROUND The aim of this study was to evaluate the effects of a new type of dietary fiber - high specific volume polysaccharide (HSVP) - on fecal properties, serum vasoactive intestinal peptide (VIP) concentration, intestinal flora count, and expression of the VIP-cAMP-PKA-AQP3 signaling pathway. MATERIAL AND METHODS Compound diphenoxylate was used in 48 healthy Wistar rats to establish a constipation model. Rats were divided into a normal control group, a constipation model group, an HSVP low-dose group, an HSVP medium-dose group, an HSVP high-dose group, and a fructose control group. We used colony count method, ELISA, WB, and RT-PCR to determine fecal moisture content, fecal hardness, fecal passage time, serum VIP concentration, number of intestinal bacteria, and VIP-cAMP-PKA-AQP3 signal pathway protein expression. RESULTS The constipation model was established successfully. HSVP (the medium dose was 10% and the high dose was 15%) improved fecal moisture content, reduced hardness, shortened fecal emptying time, increased intestinal bacteria, reduced serum VIP concentration, downregulated cAMP and PKAm RNA transcription, reduced protein expression, and reduced intestinal AQP3 expression. CONCLUSIONS HSVP improved constipation, increased the number of intestinal bacteria, and elevated expression of the VIP-cAMP-PKA-AQP3 signaling pathway. The mechanism of HSVP in regulating intestinal water metabolism in constipated rats may occur through the VIP-cAMP-PKA-AQP3 signaling pathway, and be closely related to changes in intestinal bacteria. The important role of the brain-gut-microbiome axis in the pathogenesis of constipation has been confirmed in this study.

Current Status of Functional Studies on Circular RNAs in Bladder Cancer and their Potential Role as Diagnostic and Prognostic Biomarkers: A Review.

d_abstr_R Worldwide, bladder cancer represents the ninth most common malignancy and is the 13th cause of cancer-associated death. Although surgery combined with chemotherapy and radiotherapy has improved patient outcomes, the prognosis remains poor for most patients with muscle-invasive bladder cancer. The exact mechanisms and critical regulators of bladder cancer remain unknown. Circular RNAs (circRNAs) are a distinct type of endogenous non-coding RNA. Recent studies have shown that circRNAs participate in many processes, including proliferation, invasion, migration, and apoptosis in multiple types of malignancy, including bladder cancer. Some circRNAs are dysregulated in bladder cancer and play essential roles in cancer progression. Importantly, some circRNAs may serve as diagnostic and prognostic biomarkers for bladder cancer. This review aims to summarize the findings from recent studies that have focused on the roles of human circRNAs in bladder cancer and discusses the clinical roles for circRNAs, including their potential roles as diagnostic or prognostic biomarkers.

High Level Antibody Response to Pandemic Influenza H1N1/09 Virus Is Associated With Interferon-Induced Transmembrane Protein-3 rs12252-CC in Young Adults.

Background: The C allele of the interferon-induced transmembrane protein-3 (IFITM3) SNP rs12252, a common allele in South East Asia and China, is strongly associated with severe influenza infection. However, despite the high occurrence of rs12252-CC genotype in Chinese population (~25%), severe influenza infection is rare. The aim of study is to determine whether rs12252-CC individuals have pre-existing antibody responses to previous seasonal influenza infections. Cohort and Method: A total 99 young healthy volunteers (18-20 years) were recruited and received an influenza seasonal Vaccination [A/Switzerland/9715293/2013(H3N2), A/California/7/2009 (pdm09H1N1) and B/Jeep/3073/2013-like virus (Flu-B)]. Plasma and gDNA was isolated from each volunteer before, and 14, 28, 180, 360, and 540 days after vaccination. Additionally, 68 elderlies (>65 years) were also recruited as a control group to compare the levels of antibodies at baseline between the young adults and the elderly. For each sample IFITM3 rs12252 genotype was determined and antibody levels in response to pdmH1N1, H3N2 and Influenza B infection were measured for each time point. Results: We found a significantly higher level of pre-existing antibodies to pandemic influenza H1N1/09 virus (pdm09H1N1) but not to H3N2 or FluB in CC donors in comparison with CT/TT donors prior to vaccination. No impact of IFITM3 genotype in boosting influenza specific antibodies in young adults within 1 year after receiving seasonal influenza vaccination was observed. In addition, there was no difference in pdm09H1N1 specific antibody levels observed in the elderly cohort between volunteers carrying different IFITM3 genotypes. Higher levels of antibodies to pdmH1N1 were observed in elderly CC carriers when compared to the young CC carriers, but this trend was not replicated in TT carriers. Conclusion:IFITM3-rs12252 CC carriers exhibit a high level of pre-existing immunity to pdm09H1N1 compared to TT carriers in the young cohort. This suggests that compensatory mechanisms exist which might contribute to viral control in patients carrying the rs12252-CC genotype who do not become sick after flu infection. However, such a potential compensatory effect appears to be lost overtime, as evidenced in the elderly cohort. If this compensatory mechanism is lost, it may make the CC carrying elderly more susceptible to severe influenza infection.

Resveratrol supplement inhibited the NF-κB inflammation pathway through activating AMPKα-SIRT1 pathway in mice with fatty liver.

Nonalcoholic fatty liver disease (NAFLD) is characterized by high levels of nonesterified fatty acids (NEFA), inflammation, and hepatic steatosis. Inflammation plays a crucial role in the development of fatty liver. Resveratrol (RSV) supplement could improve inflammatory response and hepatic steatosis, whereas the underlying mechanism was not well understood. In this study, mice fed with high-fat diet (HFD) exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6, and IL-1ß. Hepatic NF-κB inflammatory pathway was over-induced in HFD mice. In vitro, NEFA treatment further increased NF-κB pathway activation in mice hepatocytes, which then promoted the synthesis of inflammatory cytokines. Interestingly, RSV treatment significantly inhibited overactivation of NF-κB pathway and improved hepatic steatosis. Furthermore, RSV further increased the AMP-activated protein kinaseα (AMPKα) phosphorylation and sirtuin1 (SIRT1) protein levels to inhibit overactivation of NF-κB pathway induced by HFD or high levels of NEFA. AMPKα or SIRT1 inhibition significantly decreased the improvement effect of RSV on the NF-κB pathway induced by high levels of NEFA. Taken together, these findings indicate that RSV supplement decreases the inflammatory level and improves hepatic steatosis through activating AMPKα-SIRT1 pathway. Therefore, these data suggested an important clinical application of RSV in preventing NAFLD in humans.

Upregulation of cyclooxygenase-2 is associated with activation of the alternative nuclear factor kappa B signaling pathway in colonic adenocarcinoma.

Cyclooxygenase-2 expression by malignant tumors, including colonic adenocarcinoma, is associated with increased tumor aggression and poor prognosis. Nuclear factor kappa B is a key regulator of cyclooxygenase-2 and is regulated by two pathways, the 'canonical' and the 'alternative' pathway. The alternative pathway is triggered by members of the tumor necrosis factor cytokine family, including RelB and p52. This present study was undertaken to evaluate cyclooxygenase-2 and the alternative nuclear factor-kappa B signaling pathway in colonic adenocarcinoma. Formalin-fixed, paraffin-embedded tissue samples diagnosed with colonic adenocarcinoma and a human colonic adenocarcinoma cell line, LS174, were studied. The expression of cyclooxygenase-2, RelB and p52 were determined using immunohistochemistry, immunofluorescence, and Western blots. Quantitative analysis of mRNA by real-time reverse transcriptase polymerase chain reaction and chromatin immunoprecipitation were performed on the tissue and cell samples. To investigate nuclear factor kappa B gene regulation of the cyclooxygenase-2 gene, dual luciferase assays were performed, and LS174 cells were transfected with RelB or p100/p52 short interfering RNA. Upregulation of cyclooxygenase-2 was associated with activation of the alternative nuclear factor kappa B signaling pathway components RelB, and p52, in colonic adenocarcinoma cells in tissues and the cell line, LS174. Chromatin immunoprecipitation assay determined that cyclooxygenase-2 gene was associated with both RelB and p52. A luciferase reporter assay showed that the nuclear factor kappa B enhancer of cyclooxygenase-2 was sufficient to regulate the transcriptional activity of a heterologous promoter in LS174 cells. RNA interference-mediated knockdown of RelB or p52 resulted in significant inhibition of cyclooxygenase-2 at both mRNA and protein levels in LS174 cells. These findings support a potential role for inhibition of components of the alternative nuclear factor kappa B signaling pathway, RelB-p52-cyclooxygenase-2, as a possible therapeutic target in the treatment of adenocarcinoma of the colon. Further studies on the role of this pathway in this and other malignancies are recommended.

Efficacy and Safety of High Specific Volume Polysaccharide-A New Type of Dietary Fiber for Treatment of Functional Constipation and IBS-C.

We investigated the efficacy and safety of a new type of dietary fiber (high specific volume polysaccharide) for use in treating constipation of different etiologies. Functional constipation patients and irritable bowel syndrome-constipation (IBS-C) patients were administrated high specific volume polysaccharide (HSVP) three times daily for a period of 2 wk to relieve their symptoms. Scores on a stool form scale, and patient reports of straining during a bowel movement, having sensations of an incomplete bowel movement or a blocked anorectum, and abnormal defecation intervals were recorded, graded, and scored by a functional constipation sample group. Similarly, a cohort of IBS-C patients reported their occurrence of abdominal discomfort or pain, abnormal stool formation, defecation frequency, and straining during a bowel movement. Additionally, both groups reported any adverse reactions associated with taking HSVP. All patients in both groups returned for follow-up visits, and no adverse reactions to treatment with HSVP were reported. In the functional constipation group, HSVP was effective for treating symptoms of constipation in 81.46% and 93.17% of patients after 7 and 14 d of dosing, respectively (both p<0.05). In the IBS-C group, symptoms of constipation were relieved in 71.67% and 88.34% of patients after 7 and 14 d of dosing, respectively (both p<0.05). High specific volume polysaccharide was shown be effective for treatment of functional constipation and IBS-C, without causing significant adverse events.

Association of TAP1 and TAP2 polymorphisms with the outcome of persistent HBV infection in a northeast Han Chinese population.

OBJECTIVE: Transporter associated with antigen processing (TAP) plays a central role in a cellular immune response against HBV. Polymorphisms exist at the coding region of TAP and alter its structure and function. The aim of this study was to evaluate the potential relationship between polymorphisms of TAP and different outcomes of persistent HBV infection in a Han population in northeastern China. MATERIAL AND METHODS: 189 HBV spontaneously recovered (SR) subjects, 571 HBV-infected patients including 180 chronic hepatitis B (CHB), 196 liver cirrhosis (LC) and 195 hepatocellular carcinoma (HCC) individuals were included in this study. TAP1-333 Ile/Val and -637 Asp/Gly, TAP2-651 Arg/Cys and -687 Stop/Gln were genotyped in all the samples by using a PCR-RFLP method. RESULTS: The frequency of TAP1-637-Gly (allele G) was significantly higher in persistently HBV-infected individuals (CHB and LC) than that of SR subjects (OR = 1.58, 95% CI 1.12-2.45, p = 0.024; OR = 1.78, 95% CI 1.27-2.68, p = 0.002) by a logistic regression analysis. In addition, the statistically significant difference in the distribution of TAP2-651-Cys (allele T) was observed between HCC cases and SR controls (OR = 2.30, 95% CI 1.51-3.72, p < 0.001), and TAP2-687-Gln (allele C) in CHB patients was more common than that in SR subjects (OR = 1.41, 95% CI 1.13-1.97, p = 0.021). The data also revealed that haplotype 687 Gln-651 Cys-637 Gly-333 Ile was strongly associated with persistent HBV infection (CHB, LC and HCC) (p < 0.001, < 0.05 and < 0.001, respectively). CONCLUSION: These results suggested that TAP variants were likely to play a substantial role in different outcomes of persistent HBV infection in the studied population.

Association of TNF-α promoter polymorphisms with the outcome of persistent HBV infection in a northeast Chinese Han population.

Tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis and clinical outcome of chronic hepatitis B virus (HBV) infection. The objective of this study was to evaluate the relationship between functional polymorphisms of TNF-α and different outcomes of persistent HBV infection in a northeast Chinese Han population. Here 189 HBV spontaneously recovered subjects (SR), 571 HBV-infected patients including 180 chronic hepatitis B (CHB), 196 liver cirrhosis (LC), and 195 hepatocellular carcinoma (HCC) individuals were enrolled in this study. All the samples were genotyped for TNF-α -857C/T and -863C/A using the polymerase chain reaction-restriction fragment length polymorphism method. The frequency of -857CC genotype was significantly higher in CHB and LC individuals compared with that of SR subjects (P= 0.03, OR = 1.57, 95% CI 1.04-2.39 and P= 0.03, OR = 1.57, 95% CI 1.04-2.35, respectively). A significant difference in the distribution of the allele -857C was observed for both CHB vs. SR (P= 0.01, OR = 1.52, 95% CI 1.08-2.13) and LC vs. SR (P= 0.02, OR = 1.47, 95% CI 1.06-2.04) cohorts. In addition, the frequency of -863AA genotype was significantly higher in CHB and LC patients than that of SR subjects (P= 0.01, OR = 3.90, 95% CI 1.35-11.23 and P= 0.01, OR = 3.83, 95% CI 1.34-10.96, respectively), and allele -863A frequency was significantly more common in CHB, LC, and HCC cohorts than that of SR controls (P= 0.004, OR = 1.72, 95% CI 1.19-2.50; P= 0.001, OR = 1.81, 95% CI 1.26-2.61 and P= 0.001, OR = 1.90, 95% CI 1.33-2.73, respectively). Our data also revealed that haplotype CA was strongly associated with persistent HBV infection. These results suggest an association between the TNF-α promoter variants and different outcomes of persistent HBV infection in the studied population.

[Adefovir dipivoxil treatment of hepatic cirrhosis complicated with hepatitis B virus associated glomerulonephritis].

OBJECTIVE: To investigate the efficacy and safety of adefovir dipivoxil (ADV) in treating hepatic cirrhosis complicated with hepatitis B virus associated glomerulonephritis. METHODS: Six hepatic cirrhosis (Child-Pugh A grade, liver function compensated) patients complicated with hepatitis B virus associated glomerulonephritis diagnosed by renal biopsy, real time PCR and urinary protein tests were treated with ADV for one year in addition to a routine treatment. The dosage of ADV was 100mg daily. RESULTS: After 3 and 6 months treatment the negative conversion rates of HBV-DNA were 33.3% and 83.3%; the negative conversion rates of HBeAg were 16.7% and 66.7%; the positive conversion rates of HBeAb were both 16.7%; the recovery rates of ALT were 83.3% and 100.0%; and the recovery rates of TBil were 66.7% and 83.3% respectively. Protein in the urine of two patients was decreased to 0.3 g/d and in three patients it was 50% of the original values. After 1 year treatment the disease subsided fully in 3 and partially in 2 patients. CONCLUSION: Treating hepatic cirrhosis complicated with hepatitis B virus associated glomerulonephritis using adefovir dipivoxil is effective and safe.

[Relationship between expression of cyclin D1, Ki-67 and bcl-2 and biologic behavior in CD117-positive gastrointestinal stromal tumors].

OBJECTIVE: To investigate the clinicopathologic features of gastrointestinal stromal tumors (GISTs) and to identify reliable prognostic parameters. METHODS: Fifty-nine GISTs were studied by immunostaining of CD117, CD34, SMA, desmin, S-100, bcl-2, and Ki-67. Histopathologic evaluations included tumor size, necrosis, histological growth patterns, mitotic activities and tumor lymphocytic infiltrate. The patients were clinically followed for 2 to 9 years. Univariate, multivariate and correlative statistical evaluations were used to analyze the data. RESULTS: Among the 59 patients, 40 were alive and 15 died of their tumors at follow-up, the remaining 4 patients died of other causes. Pathological parameters that correlated with prognosis included tumor sizes of more than 5 cm, tumor tissue necrosis, mitotic cell count equal or higher than 5 per 50 high power field, Ki-67 labeling index (LI) equal or higher than 5% and intense bcl-2 immunostaining. Multivariate analysis showed that the mitotic count and Ki-67 LI were independent prognostic indicators. There was a correlation between mitotic count and Ki-67 LI. CONCLUSIONS: Mitotic count and Ki-67 LI are the best predictors for a poor outcome of GIST after surgical treatment. Ki-67 immunostaining may substitute mitotic count as a useful prognostic parameter.