Implication of acute tubular injury in minimal change nephrotic syndrome.

While acute tubular injury (ATI) is known to occur in a significant number of minimal change disease (MCD) nephrotic syndrome cases with acute kidney injury (AKI), the clinical significance is not certain, and AKI may also occur without ATI. This study aimed to evaluate whether the severity of AKI defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria correlated with the presence or severity of ATI in a series of adult patients with MCD. We also looked at whether time to remission of nephrotic syndrome (NS) with treatment correlated with the presence of ATI in those with and without AKI. We excluded patients with secondary MCD. Of 61 patients, 20 had AKI (33%). ATI was significantly more likely to occur in those with AKI than in those without AKI (60 vs. 24%). Overall, the severity of AKI did not clearly correspond with the severity of ATI. Remission rates at 4 weeks were lowest (25%) in those with both AKI and ATI, while they were highest (100%) in those with neither AKI nor ATI. Patients with AKI but no ATI and those with no AKI but having ATI were intermediate in remission rates and similar to each other (60 and 62%, respectively). The time to remission in the group of those without AKI was significantly longer in those with ATI than in those without (p = 0.0027), but the numerical difference in remission did not reach statistical significance in the smaller group of AKI patients. Patients with ATI were older and more often male than those without ATI. It appears that having ATI may predict a slower remission rate in MCD though the reason for this is unclear. The different demographics of those with ATI may also play a role.

Adherence to risk-reducing salpingo-oophorectomy guidelines among gynecologic oncologists compared to general gynecologists.

BACKGROUND: Risk-reducing bilateral salpingo-oophorectomy reduces mortality from high-grade serous carcinoma in patients with hereditary breast and ovarian cancer associated gene mutations. Ideal surgical management includes 5 steps outlined in 2005 by the Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists. In addition, it is recommended that pathologic examination include serial sectioning of specimens. In practice, risk-reducing salpingo-oophorectomy is performed by both gynecologic oncologists and general gynecologists. To ensure optimal detection of occult malignancy, standardized adherence to outlined guidelines is necessary. OBJECTIVE: This study aimed to evaluate the adherence to optimal surgical and pathologic examination guidelines and to compare the rate of occult malignancy at the time of surgery between 2 provider types. STUDY DESIGN: Institutional review board exemption was obtained. A retrospective review of patients undergoing risk-reducing bilateral salpingo-oophorectomy without hysterectomy from October 1, 2015, to December 31, 2020, at 3 sites within a healthcare system was conducted. The inclusion criteria included age ≥18 years and a documented indication for surgery being a mutation in BRCA1 or BRCA2 or a strong family history of breast and/or ovarian cancer. Compliance with 5 surgical steps and pathologic specimen preparation was based on medical record documentation. Multivariable logistic regression was used to determine differences in adherence between provider groups and surgical and pathologic examination guidelines. A P value of <.025 was considered statistically significant for the 2 primary outcomes after Bonferroni correction was applied to adjust for multiple comparisons. RESULTS: A total of 185 patients were included. Among the 96 cases performed by gynecologic oncologists, 69 (72%) performed all 5 steps of surgery, 22 (23%) performed 4 steps, 5 (5%) performed 3 steps, and none performed 1 or 2 steps. Among the 89 cases performed by general gynecologists, 4 (5%) performed all 5 steps, 33 (37%) performed 4 steps, 38 (43%) performed 3 steps, 13 (15%) performed 2 steps, and 1 (1%) performed 1 step. Gynecologic oncologists were more likely to document adherence to all 5 recommended surgical steps in their surgical dictation (odds ratio, 54.3; 95% confidence interval, 18.1-162.7; P<.0001). Among the 96 cases documented by gynecologic oncologists, 41 (43%) had serial sectioning of all specimens performed, compared with 23 of 89 cases (26%) performed by general gynecologists. No difference in adherence to pathologic guidelines was identified between the 2 provider groups (P=.0489; note: P value of >.025). Overall, 5 patients (2.70%) had occult malignancy diagnosed at the time of risk-reducing surgery, with all surgeries performed by general gynecologists. CONCLUSION: Our results demonstrated greater compliance with surgical guidelines for risk-reducing bilateral salpingo-oophorectomy in gynecologic oncologists than in general gynecologists. No considerable difference was determined between the 2 provider types in adherence to pathologic guidelines. Our findings demonstrated a need for institution-wide protocol education and implementation of standardized nomenclature to ensure provider adherence to evidence-based guidelines.

Acupuncture Reduces Severity of Hot Flashes in Breast Cancer: A Randomized Single-Blind Trial.

This study evaluated the effectiveness of traditional Chinese medicine-based therapeutic acupuncture (TA) in reducing the severity of hot flashes (HFs) in breast cancer patients and compared the effectiveness of TA to "sham" placebo acupuncture (SA). Subjects experiencing more than 10 episodes of HF/week were randomly assigned to TA or SA. The response was assessed by the Menopause-specific Quality of Life (MenQoL) scale, scoring the subject's perception of the severity of HFs. HFs were scored at baseline, after treatment, and 1-month follow-up. A total of 54 subjects enrolled (28 TA and 26 SA). Seven women withdrew from the study. A hot flash diary documented the number of HFs a subject experienced. Analysis included 47 subjects (27 TA and 20 SA). A statistically significant response in HF scores was noted in the TA group compared with the SA group (P = .0064.) On average HF scores dropped by 1.89 with TA, and only 0.16 with SA. At follow-up, TA subjects had a sustained response. TA is effective in reducing the intensity and severity of HF. With SA, no relative response/change in HF scores was noted. Larger studies and longer follow-up to assess durability of response to TA are needed.

Associations of self-efficacy, social support and coping strategies with health-related quality of life after radical cystectomy for bladder cancer: A cross-sectional study.

OBJECTIVES: Investigating associations between self-efficacy, social support and quality of life (HRQoL) and mediating effects of coping among bladder cancer (BC) patients treated with radical cystectomy (RC). METHODS: A cross-sectional study was conducted from January 2012 to December 2014 with 99 BC patients. An online survey assessed patient characteristics, HRQoL, coping strategies, self-efficacy and social support. A stepwise multiple linear regression model was used. RESULTS: Self-efficacy and social support were significantly associated with HRQoL. Complete mediation effects of adaptive/maladaptive coping strategies emerged for the associations between self-efficacy and social support with functional well-being (B = 0.247, 95% CI 0.119-0.374, p < 0.001; B = -0.414, 95% CI -0.526 to -0.302, p < 0.001) and total Functional Assessment of Cancer Therapy-Bladder (FACT-BI) (B = 0.779, 95% CI 0.351-1.207, p < 0.001; B = -1.969, 95% CI -2.344 to -1.594, p < 0.001). Maladaptive coping mediated the associations of self-efficacy and social support with physical well-being (B = -0.667, 95% CI -0.752 to -0.516, p < 0.001) and disease-specific symptoms (B = -0.413, 95% CI -0.521 to -0.304, p < 0.001). A partial mediation effect of adaptive coping was found for the association between self-efficacy and social well-being (B = 0.145, 95% CI 0.016-0.273, p < 0.05). Social support was significantly associated with emotional (B = 0.067, 95% CI 0.027-0.108, p < 0.001) and social well-being (B = 0.200, 95% CI 0.146-0.255, p < 0.001). CONCLUSION: Interventions should tackle self-efficacy, social support and coping strategies to improve BC patients' HRQoL.

Preoperative Stress Test and Postoperative MI in Patients Requiring Lower Extremity Bypass for Critical Limb Ischemia.

BACKGROUND: Patients with critical limb ischemia (CLI) often require lower extremity bypass surgery for limb salvage. A myocardial infarction (MI) is a major postoperative risk. Our objective is to assess the utility of preoperative stress test in determining patient outcomes. METHODS: This is a retrospective study utilizing the national Vascular Quality Initiative database. We collected data from 2013-2018 on all patients undergoing lower extremity bypass for CLI and assessed whether or not they had a preoperative stress test. Rates of an MI were then compared between groups of patients who either did not receive a stress test, had a normal stress test or a positive stress test. An MI was distinguished as troponin only and electrocardiogram (EKG)/clinical. Our secondary end point was in-hospital mortality. Univariate and multivariate analysis with the stress test as a covariate was used to determine significance. RESULTS: During this time period, 29,937 bypasses were performed on 27,219 patients. The average age was 67.5 years (±11.09), 66.3% were men, and 17.3% were African American. Risk factors included hypertension (89.5%), diabetes (55.9%), congestive heart failure (20%), coronary artery disease (32.5%), coronary artery bypass graft (22.2%), and percutaneous coronary intervention (21%). 19,108 patients (64.1%) did not undergo the stress test before bypass, 6,830 (22.9%) had a normal stress test, and 2,898 (9.7%) had a positive stress test. Overall rate of an MI was 4%, with 2% being troponin only and 2% EKG/clinical. The positive stress test had a higher rate of troponin only (2.85%) as well as EKG/clinical (3.37%) MI. For every 10 year increase in age, the odds of having a postoperative MI increased by 27% (P < 0.0001). Overall in-hospital mortality was 1.4%. Patients with positive stress tests had a 2.6% mortality compared with normal/not performed at 1.3%. Of the patients who died, 21.5% had an EKG/clinical MI. Of those patients, 50% did not have a stress test, 12% had normal stress tests, and 23% had positive stress tests. When comparing rates of patients who died or had an MI, there was no difference between patients who had no or a normal stress test (7.29%) versus those who had a positive stress test (7.58%), (P = 0.11). CONCLUSIONS: A positive stress test before lower extremity bypass is a significant predictor of a postoperative MI. However, mortality increase was minimal in patients with a positive stress test. Therefore, the stress test result should not delay care for patients needing urgent revascularization.

Risk Factors for Postoperative Hypotension and Hypertension following Carotid Endarterectomy.

BACKGROUND: Patients undergoing carotid endarterectomy (CEA) often experience postoperative hemodynamic changes that require intravenous medications for hypo- and hypertension. Prior studies have found these changes to be associated with increased risks of 30-day mortality, stroke, myocardial infarction (MI), and length of stay (LOS). Our aim is to investigate preoperative risk factors associated with the need for postoperative intravenous medications for blood pressure control. METHODS: A retrospective review of an internally maintained prospective database of patients undergoing carotid interventions between January 2014 and March 2019 was performed. Demographic data, clinical history, and perioperative data were recorded. Carotid artery stents and reinterventions were excluded. Our primary end points were the need to intervene with intravenous medication for either postoperative hypotension [systolic blood pressure (SBP) <100 mm Hg] or postoperative hypertension (SBP >160 mm Hg). RESULTS: A total of 221 patients were included in the study after excluding those with a prior ipsilateral CEA or carotid artery stent. The mean age was 72.3 (±8.9) years, 157 (71%) patients were male, and 78 (35.3%) were Caucasian. Following CEA, 151 (68.3%) patients were normotensive, while 33 (14.9%) and 37 (16.7%) required medication for hypotension and hypertension, respectively. A univariate logistic regression identified 5 variables as being associated with postoperative blood pressure including race, history of MI, prior percutaneous transluminal coronary angioplasty (PTCA), statin use, and angiotensin-converting enzyme-inhibitor/angiotensin-receptor blocker (ARB) use. A stepwise regression selection found race, prior MI, and statin use to be associated with our primary end points. The hypertensive group was more likely to have a history of MI compared to the hypotensive and normotensive groups (40.5% vs. 27.3% vs. 18.5%, P = 0.02), PTCA (43.2% vs. 39.4% vs. 23.8%, P = 0.03), and statin use (94.6% vs. 93.9% vs. 78.8%, P = 0.01). Mean LOS was also the highest for the hypertensive group, followed by hypotensive and normotensive patients [2.0 (±1.6) vs. 1.8 (±2.4) vs. 1.3 (±0.8), P = 0.002]. Multivariable logistic regression demonstrated that non-Caucasian patients [odds ratio (OR) 2.72, 95% confidence interval (CI) 1.26-5.86, P = 0.01] and those with a history of MI (OR 2.98, 95% CI 1.33-6.67) were more likely to have postoperative hypertension compared to patients who were Caucasian or had no history of MI. CONCLUSIONS: Postoperative hypertension is associated with non-Caucasian race and a history of MI. Given the potential implications for adverse perioperative outcomes including MI, mortality, and LOS, it is important to continue to elucidate potential risk factors in order to further tailor the perioperative management of patients undergoing CEA.

Involving Patients in the Development and Evaluation of an Educational and Training Experiential Intervention (ETEI) to Improve Muscle Invasive Bladder Cancer Treatment Decision-making and Post-operative Self-care: a Mixed Methods Approach.

This study aims to describe the acceptability and feasibility of an educational and training experiential intervention (ETEI) we developed to enhance muscle invasive bladder cancer (MIBC) patients with treatment decision-making and post-operative self-care. Twenty-five patients were randomized to a control group (N = 8) or ETEI group (N = 17). ETEI group participated in a nurse-led session on MIBC education. The control group received diet and nutrition education. Study questionnaires were completed at baseline and at 1-month post-intervention. Our results showed acceptable recruitment (58%) and retention rates (68%). The ETEI group reported increased knowledge (82% vs. 50%), improved decisional support (64% vs. 50%), improved communication (73% vs. 50%), and increased confidence in treatment decisions (73% vs. 50%) compared to the control group. Patients in the control group reported improved diet (50% v. 27%) as well as maintaining a healthy lifestyle (67% vs. 45%) compared to the ETEI group. Patients in the ETEI group reported a significant decrease in cancer worries and increases in self-efficacy beliefs over time compared to the control group. The ETEI was feasible, acceptable, and showed a potential for inducing desired changes in cancer worries and efficacy beliefs.

Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury.

OBJECTIVE: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression. DESIGN AND RESULTS: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn-/- mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K-pAkt1/2/3 pathway to upregulate collagen-I. CONCLUSIONS: During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.

Bee's honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway.

PURPOSE: We aim to examine whether honey ameliorates hepatic injury in non-alcoholic steatohepatitis (NASH) animal and cell line steatosis models. METHODS: NASH was induced in female Sprague-Dawley rat by 8-week feeding with a high-fat diet. During the experiment, 5 g/kg honey was intragastrically fed daily. Rat normal hepatocyte BRL-3A cell was treated with sodium palmitate (SP) to induce steatosis in the absence or presence of honey pre-treatment or specific siRNA/overexpress plasmid of thioredoxin-interacting protein (TXNIP) or antagonist/agonist of Nod-like receptor protein 3 (NLRP3). RESULTS: Honey significantly improved the high-fat-diet-induced hepatic injury, steatosis, fibrosis, oxidative stress, and inflammation in rats. Honey also inhibited the overexpression of TXNIP and the activation of NLRP3 inflammasome. These effects were replicated in BRL-3A cell line which showed that the down-regulation of TXNIP or inhibition of NLRP3 contributed to the suppression of NLRP3 inflammasome activation, inflammation, and re-balanced lipid metabolism. In contrast, overexpression of TXNIP or agonism of NLRP3 exacerbated the cellular damage induced by SP. CONCLUSION: Suppression of the TXNIP-NLRP3 inflammasome pathway may partly contribute to the amelioration of hepatic injury during the progression of NASH by honey. Targeting hepatic TXNIP-NLRP3 inflammasome pathway is a potential therapeutic way for the prevention and treatment of NASH.

High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD).

Growing clinical and experimental evidence suggests that sterile inflammation contributes to alcoholic liver disease (ALD). High mobility group box-1 (HMGB1) is highly induced during liver injury; however, a link between this alarmin and ALD has not been established. Thus, the aim of this work was to determine whether HMGB1 contributes to the pathogenesis of ALD. Liver biopsies from patients with ALD showed a robust increase in HMGB1 expression and translocation, which correlated with disease stage, compared with healthy explants. Similar findings were observed in chronic ethanol-fed wild-type (WT) mice. Using primary cell culture, we validated the ability of hepatocytes from ethanol-fed mice to secrete a large amount of HMGB1. Secretion was time- and dose-dependent and responsive to prooxidants and antioxidants. Selective ablation of Hmgb1 in hepatocytes protected mice from alcohol-induced liver injury due to increased carnitine palmitoyltransferase-1, phosphorylated 5'AMP-activated protein kinase-α, and phosphorylated peroxisome proliferator-activated receptor-α expression along with elevated LDL plus VLDL export. Native and post-translationally modified HMGB1 were detected in humans and mice with ALD. In liver and serum from control mice and in serum from healthy volunteers, the lysine residues within the peptides containing nuclear localization signals (NLSs) 1 and 2 were non-acetylated, and all cysteine residues were reduced. However, in livers from ethanol-fed mice, in addition to all thiol/non-acetylated isoforms of HMGB1, we observed acetylated NLS1 and NLS2, a unique phosphorylation site in serine 35, and an increase in oxidation of HMGB1 to the disulfide isoform. In serum from ethanol-fed mice and from patients with ALD, there was disulfide-bonded hyperacetylated HMGB1, disulfide-bonded non-acetylated HMGB1, and HMGB1 phosphorylated in serine 35. Hepatocytes appeared to be a major source of these HMGB1 isoforms. Thus, hepatocyte HMGB1 participates in the pathogenesis of ALD and undergoes post-translational modifications (PTMs) that could condition its toxic effects.

Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice.

UNLABELLED: Although osteopontin (OPN) is induced in alcoholic patients, its role in the pathophysiology of alcoholic liver disease (ALD) remains unclear. Increased translocation of lipopolysaccharide (LPS) from the gut is key for the onset of ALD because it promotes macrophage infiltration and activation, tumor necrosis factor-α (TNFα) production, and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Wild-type (WT), OPN knockout (Opn(-/-)), and transgenic mice overexpressing OPN in hepatocytes (Opn(HEP) Tg) were fed either the control or the ethanol Lieber-DeCarli diet. Ethanol increased hepatic, plasma, biliary, and fecal OPN more in Opn(HEP) Tg than in WT mice. Steatosis was less in ethanol-treated Opn(HEP) Tg mice as shown by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining, and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower alanine aminotransferase (ALT) activity, hepatocyte ballooning degeneration, LPS levels, the inflammation score, and the number of macrophages and TNFα(+) cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed binding affinity for LPS which prevented macrophage activation, reactive oxygen, and nitrogen species generation and TNFα production. Treatment with milk OPN (m-OPN) blocked LPS translocation in vivo and protected from early alcohol-induced liver injury. CONCLUSION: Natural induction plus forced overexpression of OPN in the liver or treatment with m-OPN protect from early alcohol-induced liver injury by blocking the gut-derived LPS and TNFα effects in the liver.

Osteopontin induces ductular reaction contributing to liver fibrosis.

OBJECTIVE: In human chronic liver disease, there is association between ductular reaction (DR) and fibrosis; yet, the mechanism triggering its onset and its role in scar formation remains unknown. Since we previously showed that osteopontin (OPN) is highly induced during drug-induced liver fibrosis, we hypothesised that OPN could drive oval cells (OC) expansion and DR and signal to hepatic stellate cells (HSC) to promote scarring. RESULTS: In vivo studies demonstrated increased OPN expression in biliary epithelial cells (BEC) and in OC in thioacetamide (TAA)-treated mice. OPN ablation protected mice from TAA and bile duct ligation-induced liver injury, DR and scarring. This was associated with greater hepatocyte proliferation, lower OC expansion and DR along with less fibrosis, suggesting that OPN could activate the OC compartment to differentiate into BEC, which could then signal to HSC to enhance scarring. Since TAA-treated wild-type mice and cirrhotic patients showed TGF-ß(+) BEC, which were lacking in TAA-treated Opn(-/-) mice and in healthy human explants, this suggested that OPN could regulate TGF-ß, a profibrogenic factor. In vitro experiments confirmed that recombinant OPN (rOPN) decreases hepatocyte proliferation and increases OC and BEC proliferation. To evaluate how BEC regulate collagen-I production in HSC, co-cultures were established. Co-cultured BEC upregulated OPN and TGF-ß expression and enhanced collagen-I synthesis by HSC. Lastly, recombinant TGF-ß (rTGFß) and rOPN promoted BEC proliferation and neutralisation of OPN and TGF-ß reduced collagen-I expression in co-cultured HSC. CONCLUSIONS: OPN emerges as a key matricellular protein driving DR and contributing to scarring and liver fibrosis via TGF-ß.

Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways.

PURPOSE: To investigate the protective mechanisms of an 85 % pure extract of (-) epigallocatechin gallate (EGCG) in the development of fibrosis, oxidative stress and inflammation in a recently developed dietary-induced animal model of non-alcoholic fatty liver disease (NAFLD). METHODS: Female Sprague-Dawley rats were fed with either normal rat diet or high-fat diet for 8 weeks to develop NAFLD. For both treatments, rats were treated with or without EGCG (50 mg/kg, i.p. injection, 3 times per week). At the end, blood and liver tissue samples were obtained for histology, molecular, and biochemical analyses. RESULTS: Non-alcoholic fatty liver disease (NAFLD) rats showed significant amount of fatty infiltration, necrosis, fibrosis, and inflammation. This was accompanied by a significant expressional increase in markers for fibrosis, oxidative stress, and inflammation. TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways were also activated. Treatment with EGCG improved hepatic histology (decreased number of fatty score, necrosis, and inflammatory foci), reduced liver injury (from ~0.5 to ~0.3 of ALT/AST ratio), attenuated hepatic changes including fibrosis (reduction in Sirius Red and synaptophysin-positive stain) with down-regulation in the expressions of key pathological oxidative (e.g. nitrotyrosine formation) and pro-inflammatory markers (e.g. iNOS, COX-2, and TNF-α). EGCG treatment also counteracted the activity of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Treatment with EGCG did not affect the healthy rats. CONCLUSIONS: Epigallocatechin gallate (EGCG) reduced the severity of liver injury in an experimental model of NAFLD associated with lower concentration of pro-fibrogenic, oxidative stress, and pro-inflammatory mediators partly through modulating the activities of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Therefore, green tea polyphenols and EGCG are useful supplements in the prevention of NAFLD.

Factors associated with immune responses to SARS-CoV-2 vaccination in individuals with autoimmune diseases.

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 patients with autoimmune diseases, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted patients with multiple sclerosis (MS) were associated with higher CD8 T cell responses. By contrast, patients taking mycophenolate mofetil (MMF) exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low anti-spike IgG response included B cell depletion within the last year, fingolimod, and combination treatment with MMF and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of preexisting anti-type I IFN antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.

Osteopontin delays resolution of liver fibrosis.

To date, considerable progress has been made both in the mechanisms driving liver fibrosis and in the prevention of disease progression. Resolution of liver fibrosis is an emerging field in hepatology; yet, the mediators involved remain elusive. Earlier work from our laboratory demonstrated that the matricellular cytokine osteopontin (OPN) is pro-fibrogenic by promoting hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition in vitro and in vivo and specifically by governing fibrillar collagen-I expression, the key pro-fibrogenic protein. Here we hypothesized that OPN could also delay the resolution of liver fibrosis by sustaining collagen-I synthesis or by preventing its degradation. To demonstrate this, wild-type (WT) and OPN-knockout (Opn(-/-)) mice were administered thioacetamide (TAA) in the drinking water for 4 months. Half of the mice were killed at 4 months to assess the extent of fibrosis at the peak of injury, and the rest of the mice were killed 2 months after TAA withdrawal to determine the rate of fibrosis resolution. Following TAA cessation, livers from Opn(-/-) mice showed no centrilobular and parenchymal necrosis along with faster ECM remodeling than WT mice. The latter was quantified by less fibrillar collagen-I immunostaining. Western blot analysis demonstrated a significant decrease in fibrillar collagen-I and in tissue inhibitor of metalloproteinase-1 (TIMP-1) in Opn(-/-) mice undergoing fibrosis resolution compared with WT mice. In conclusion, these results suggest that OPN delays liver fibrosis resolution due to sustained fibrillar collagen-I deposition; hence, inhibiting OPN could be an effective therapeutic strategy for resolving liver fibrosis.

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice.

General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knock-out mice (Gcn2(-/-)) showed increased susceptibility to both acute or chronic liver damage induced by CCl(4), as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl(4) treatment increased deposition of interstitial collagen type I more in Gcn2(-/-) mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl(4)-treated Gcn2(-/-) mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.

CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.

Alcoholic (ALD) and non-alcoholic fatty liver diseases (NAFLD) are clinical conditions leading to hepatocellular injury and inflammation resulting from alcohol consumption, high fat diet, obesity and diabetes, among others. Oxidant stress is a major contributing factor to the pathogenesis of ALD and NAFLD. Multiple studies have shown that generation of reactive oxygen species (ROS) is key for the progression of fatty liver to steatohepatitis. Cytochrome P450 2E1 (CYP2E1) plays a critical role in ROS generation and CYP2E1 is also induced by alcohol itself. This review summarizes the role of CYP2E1 in ALD and NAFLD.

Milk osteopontin, a nutritional approach to prevent alcohol-induced liver injury.

Alcohol consumption is a leading cause of liver disease worldwide; thus, there is an urgent need to develop novel therapeutic interventions. Key events for the onset and progression of alcoholic liver disease result in part from the gut-to-liver interaction. Osteopontin is a cytokine present at high concentration in human milk, umbilical cord, and infants' plasma with beneficial potential. We hypothesized that dietary administration of milk osteopontin could prevent alcohol-induced liver injury perhaps by maintaining gut integrity and averting hepatic inflammation and steatosis. Wild-type mice were fed either the control or the ethanol Lieber-DeCarli diets alone or in combination with milk osteopontin for 3 wk, and parameters of gut and liver damage were measured. Milk osteopontin protected the stomach and the gut by increasing gland height, crypt cell plus enterocyte proliferation, and mucin content in addition to lowering macrophages, plasmacytes, lymphocytes, and neutrophils in the mucosa and submucosa in alcohol-fed mice. Milk osteopontin targeted the gut-liver axis, preserving the expression of tight-junction proteins in alcohol-fed mice thus maintaining intestinal integrity and permeability. There was protection from liver injury since transaminases, the activity scores, triglyceride levels, neutrophil infiltration, 3-nitrotyrosine residues, lipid peroxidation end products, translocation of gram-negative bacteria, lipopolysaccharide levels, and tumor necrosis factor-α were lower in cotreated than in ethanol-fed mice. Furthermore, milk osteopontin diminished ethanol-mediated liver injury in OPN knockout mice. Milk osteopontin could be a simple effective nutritional therapeutic strategy to prevent alcohol hepatotoxicity due, among others, to gut protective, anti-inflammatory, and anti-steatotic actions.

Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.

UNLABELLED: Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the L-citrulline/nitric oxide (NO·) cycles regulating protein catabolism, ammonia levels, and NO· generation. Because a proteomics analysis identified ASS and nitric oxide synthase-2 (NOS2) as coinduced in rat hepatocytes by chronic ethanol consumption, which also occurred in alcoholic liver disease (ALD) and in cirrhosis patients, we hypothesized that ASS could play a role in ethanol binge and chronic ethanol-induced liver damage. To investigate the contribution of ASS to the pathophysiology of ALD, wildtype (WT) and Ass(+/-) mice (Ass(-/-) are lethal due to hyperammonemia) were exposed to an ethanol binge or to chronic ethanol drinking. Compared with WT, Ass(+/-) mice given an ethanol binge exhibited decreased steatosis, lower NOS2 induction, and less 3-nitrotyrosine (3-NT) protein residues, indicating that reducing nitrosative stress by way of the L-citrulline/NO· pathway plays a significant role in preventing liver damage. However, chronic ethanol-treated Ass(+/-) mice displayed enhanced liver injury compared with WT mice. This was due to hyperammonemia, lower phosphorylated AMP-activated protein kinase alpha (pAMPKα) to total AMPKα ratio, decreased sirtuin-1 (Sirt-1) and peroxisomal proliferator-activated receptor coactivator-1α (Pgc1α) messenger RNAs (mRNAs), lower fatty acid ß-oxidation due to down-regulation of carnitine palmitoyl transferase-II (CPT-II), decreased antioxidant defense, and elevated lipid peroxidation end-products in spite of comparable nitrosative stress but likely reduced NOS3. CONCLUSION: Partial Ass ablation protects only in acute ethanol-induced liver injury by decreasing nitrosative stress but not in a more chronic scenario where oxidative stress and impaired fatty acid ß-oxidation are key events.

Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin α(V)ß(3) engagement and PI3K/pAkt/NFκB signaling.

UNLABELLED: A key feature in the pathogenesis of liver fibrosis is fibrillar Collagen-I deposition; yet, mediators that could be key therapeutic targets remain elusive. We hypothesized that osteopontin (OPN), an extracellular matrix (ECM) cytokine expressed in hepatic stellate cells (HSCs), could drive fibrogenesis by modulating the HSC pro-fibrogenic phenotype and Collagen-I expression. Recombinant OPN (rOPN) up-regulated Collagen-I protein in primary HSCs in a transforming growth factor beta (TGFß)-independent fashion, whereas it down-regulated matrix metalloprotease-13 (MMP13), thus favoring scarring. rOPN activated primary HSCs, confirmed by increased α-smooth muscle actin (αSMA) expression and enhanced their invasive and wound-healing potential. HSCs isolated from wild-type (WT) mice were more profibrogenic than those from OPN knockout (Opn(-/-)) mice and infection of primary HSCs with an Ad-OPN increased Collagen-I, indicating correlation between both proteins. OPN induction of Collagen-I occurred via integrin α(v)ß(3) engagement and activation of the phosphoinositide 3-kinase/phosphorylated Akt/nuclear factor kappa B (PI3K/pAkt/NFκB)-signaling pathway, whereas cluster of differentiation 44 (CD44) binding and mammalian target of rapamycin/70-kDa ribosomal protein S6 kinase (mTOR/p70S6K) were not involved. Neutralization of integrin α(v) ß(3) prevented the OPN-mediated activation of the PI3K/pAkt/NFκB-signaling cascade and Collagen-I up-regulation. Likewise, inhibition of PI3K and NFκB blocked the OPN-mediated Collagen-I increase. Hepatitis C Virus (HCV) cirrhotic patients showed coinduction of Collagen-I and cleaved OPN compared to healthy individuals. Acute and chronic liver injury by CCl(4) injection or thioacetamide (TAA) treatment elevated OPN expression. Reactive oxygen species up-regulated OPN in vitro and in vivo and antioxidants prevented this effect. Transgenic mice overexpressing OPN in hepatocytes (Opn(HEP) Tg) mice developed spontaneous liver fibrosis compared to WT mice. Last, chronic CCl(4) injection and TAA treatment caused more liver fibrosis to WT than to Opn(-/-) mice and the reverse occurred in Opn(HEP) Tg mice. CONCLUSION: OPN emerges as a key cytokine within the ECM protein network driving the increase in Collagen-I protein contributing to scarring and liver fibrosis.