miR-141/200c contributes to ethanol-mediated hepatic glycogen metabolism.

OBJECTIVE: Hepatic glucose metabolism is profoundly perturbed by excessive alcohol intake. miR-141/200c expression is significantly induced by chronic ethanol feeding. This study aimed at identifying the role of miR-141/200c in glucose homeostasis during chronic ethanol exposure. METHODS: WT and miR-141/200c KO mice were fed a control or an ethanol diet for 30 days, followed by a single binge of maltose dextrin or ethanol, respectively. Untargeted metabolomics analysis of hepatic primary metabolites was performed along with analyses for liver histology, gene expression, intracellular signaling pathways, and physiological relevance. Primary hepatocytes were used for mechanistic studies. RESULTS: miR-141/200c deficiency rewires hepatic glucose metabolism during chronic ethanol feeding, increasing the abundance of glucose intermediates including G6P, an allosteric activator for GS. miR-141/200c deficiency replenished glycogen depletion during chronic ethanol feeding accompanied by reduced GS phosphorylation in parallel with increased expression of PP1 glycogen targeting subunits. Moreover, miR-141/200c deficiency prevented ethanol-mediated increases in AMPK and CaMKK2 activity. Ethanol treatment reduced glycogen content in WT-hepatocytes, which was reversed by dorsomorphin, a selective AMPK inhibitor, while KO-hepatocytes displayed higher glycogen content than WT-hepatocytes in response to ethanol treatment. Furthermore, treatment of hepatocytes with A23187, a calcium ionophore activating CaMKK2, lowered glycogen content in WT-hepatocytes. Notably, the suppressive effect of A23187 on glycogen deposition was reversed by dorsomorphin, demonstrating that the glycogen depletion by A23187 is mediated by AMPK. KO-hepatocytes exhibited higher glycogen content than WT-hepatocytes in response to A23187. Finally, miR-141/200c deficiency led to improved glucose tolerance and insulin sensitivity during chronic ethanol feeding. CONCLUSIONS: miR-141/200c deficiency replenishes ethanol-mediated hepatic glycogen depletion through the regulation of GS activity and calcium signaling coupled with the AMPK pathway, improving glucose homeostasis and insulin sensitivity. These results underscore miR-141/200c as a potential therapeutic target for the management of alcohol intoxication.

Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity.

Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signaling, and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high-fat diet-fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation, and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH and fibrosis in mice fed a NASH-promoting diet. Thus, mitochondria- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and progression to NASH and fibrosis in obesity.

Hunting for Pearls: A Qualitative Analysis of the Reflections of Students Creating Psychiatric Podcasts.

Purpose: This paper aims to explore medical student experiences of creating a peer-to-peer psychiatry educational podcast. Methods: During psychiatry placement, ten year-4 University of Bristol medical students created peer-educational multi-episode podcasts on psychiatric topics. Following completion, they submitted reflective essays on their experiences. Qualitative thematic analysis of these essays was completed by two independent authors. Following data familiarisation, authors independently generated codes that were collated into relevant themes. Upon reaching thematic saturation, findings were collated, and member checking was carried out to confirm the validity of findings. Results: Themes included effective preparation, choosing content, podcast production, enhancing learning, the weight of responsibility and creating educational support networks. All students found podcast creation to be beneficial for personal learning. Conclusion: Exploration of students' experiences creating podcasts can support clearer guidance for medical podcast production, providing opportunities for educators to optimise podcast creation efficiency and educational effectiveness.

Cognitive Therapy-as-Usual versus Cognitive Therapy plus the Memory Support Intervention for adults with depression: 12-month outcomes and opportunities for improved efficacy in a secondary analysis of a randomized controlled trial.

OBJECTIVE: Patient memory for treatment is emerging as an important transdiagnostic mechanism of treatment outcomes. However, patient memory for treatment is limited. The Memory Support Intervention was developed to improve patient memory for treatment and thereby strengthen treatment outcomes. In this secondary analysis, the primary, preregistered aim was to test the 12-month follow-up outcomes of the Memory Support Intervention when used with cognitive therapy (CT + MS) for major depressive disorder, relative to CT-as-usual. The secondary, exploratory aim was to investigate opportunities to improve efficacy of the Memory Support Intervention. METHOD: Adults (N = 178) with major depressive disorder were randomized to CT-as-usual or CT + MS. Therapist use of memory support and patient memory for treatment, depression symptoms, and overall functioning were measured in blind assessments. RESULTS: Findings did not support differences between treatment conditions at 12-month follow-up. Therapists used memory support strategies with a narrow subset of treatment contents, and similarly, patients recalled a narrow subset of treatment contents. CONCLUSIONS: The findings highlight ways to strengthen the efficacy of the Memory Support Intervention, such as applying memory support strategies across a wider variety of treatment contents, which in turn, may boost patient recall and outcomes.

Giant Klebsiella pneumoniae pyogenic liver abscess in the left liver lobe presenting with dyspepsia and vaginal discharge.

Pyogenic liver abscess (PLA) commonly occurs in the right liver lobe, causing the typical symptoms of fever and right upper quadrant pain. Less than one-third of cases occur in the left lobe. We describe an unusual presentation of a giant left-sided PLA that was compressing the stomach and surrounding venous vasculature, causing the respective symptoms of gastro-oesophageal reflux and vaginal discharge from secondary pelvic congestion syndrome. CT revealed a solitary 14 cm×10 cm×10 cm multiloculated lesion, replacing most of the left liver lobe. It was successfully treated with intravenous antibiotics and percutaneous drainage, resulting in complete resolution at 1-year follow-up. This case explores the predisposing risk factor of diabetes in PLA and its association with Klebsiella pneumoniae, which was the offending pathogen in our patient. We also discuss the phenomenon of secondary pelvic venous congestion syndrome and compare similar cases of left-sided PLA, highlighting the different modes of presentation and treatment options.

Jumonji domain-containing protein-3 (JMJD3) promotes myeloid fibroblast activation and macrophage polarization in kidney fibrosis.

BACKGROUND AND PURPOSE: Renal fibrosis is a common feature of chronic kidney disease. Myeloid fibroblasts and macrophages contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying myeloid fibroblast activation and macrophage polarization are not fully understood. In this study, we examined the role of Jumonji domain-containing protein-3 (JMJD3) in myeloid fibroblast activation, macrophage polarization, and renal fibrosis development in a preclinical model of obstructive nephropathy. EXPERIMENTAL APPROACH: To examine the role of JMJD3 in renal fibrosis, we generated mice with global or myeloid cell-specific deletion of JMJD3, and we treated wild-type mice with vehicle or GSK-J4 (selective JMJD3 inhibitor). Mice were subjected to unilateral ureteral obstructive injury to induce renal fibrosis. KEY RESULTS: JMJD3 expression was significantly increased in the kidneys during the development of renal fibrosis, which was associated with an increase in H3K27 dimethylation. Mice with either global or myeloid JMJD3 deficiency exhibited significantly reduced total collagen deposition and extracellular matrix protein production, myeloid fibroblast activation and M2 macrophage polarization in the obstructed kidney. Moreover, IFN regulatory factor 4, a mediator of M2 macrophage polarization, was significantly induced in the obstructed kidneys, which was abolished by JMJD3 deficiency. Furthermore, pharmacological inhibition of JMJD3 with GSK-J4 attenuated kidney fibrosis, reduced myeloid fibroblast activation and suppressed M2 macrophage polarization in the obstructed kidney. CONCLUSION AND IMPLICATIONS: Our study identifies JMJD3 as a critical regulator of myeloid fibroblast activation, macrophage polarization, and renal fibrosis development. Therefore, JMJD3 may represent a promising therapeutic target for chronic kidney disease.

SerpinA3N deficiency attenuates steatosis and enhances insulin signaling in male mice.

Aberrant hepatic lipid metabolism is the major cause of non-alcoholic fatty liver disease (NAFLD) and is associated with insulin resistance and type 2 diabetes. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) is highly expressed in the liver; however, its functional role in regulating NAFLD and associated metabolic disorders are not known. Male wildtype and hepatocyte Serpina3N knockout (HKO) mice were fed a control diet, methionine- and choline-deficient diet or high-fat high-sucrose diet to induce NAFLD and markers of lipid metabolism and glucose homeostasis were assessed. SerpinA3N protein was markedly induced in mice with fatty livers. Hepatic deletion of SerpinA3N attenuated steatosis which correlated with altered lipid metabolism genes, increased fatty acid oxidation activity and enhanced insulin signaling in mice with NAFLD. Additionally, SerpinA3N HKO mice had reduced epididymal white adipose tissue mass, leptin, and insulin levels, improved glucose tolerance, and enhanced insulin sensitivity which was associated with elevated insulin-like growth factor binding protein-1 (IGFBP1) and activation of the leptin receptor (LEPR)-STAT3 signaling pathway. Our findings provide a novel insight into the functional role of SerpinA3N in regulating NAFLD and glucose homeostasis.

[Impact of the COVID-19 pandemic on breast cancer management: Experience of a French Comprehensive Cancer Center]. / Impact de la pandémie de COVID-19 sur la prise en charge du cancer du sein : retour d'expérience d'un centre de lutte contre le cancer.

INTRODUCTION: The COVID-19 pandemic had a profound impact on health-care systems and reduced access to care. This study assays the mid-term effects of the COVID-19 pandemic on breast cancer management over a 2-year-period in a single French Comprehensive Cancer Center. METHODS: We performed, in a French comprehensive cancer center, an observational study including all patients with newly diagnosed breast cancer between 2019 and 2021. We collected the number of first consultations for breast cancer, the number of breast and axillary surgeries, pTNM and ypTNM cancer staging, the therapeutic sequence (surgery or neoadjuvant chemotherapy as a primary treatment), patients' age and their place of residence. RESULTS: In total, 14,772 patients had a first consultation for breast cancer. Among these 9058 breast and axillary surgeries were performed, 1798 patients had neoadjuvant chemotherapy as a primary treatment. During the first COVID-19 lockdown ( March17, 2020-May 10, 2020), we observed a reduction in the number of first consultations for breast cancer and breast cancer surgeries giving respectively a 42.3% and 27% rate of change. Subsequently, we observed a resumption of consultations and surgeries with a slight increase in early 2021 compared to 2019. In addition, we did not find any difference in terms of therapeutic sequence, pTNM and ypTNM stages, age at diagnosis or place of residence between the reference year 2019 and the years 2020 and 2021. CONCLUSION: Our study shows a decrease in activity during the first lockdown of 2020, then a resumption of activity. These reassuring results only concern patients with breast cancer, and are specific to our institution, whose oncology activity was preserved during the COVID-19 pandemic.

Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis.

The TGF-ß/Smad3 signaling pathway is an important process in the pathogenesis of kidney fibrosis. However, the molecular mechanisms are not completely elucidated. The current study examined the functional role of S100A4 in regulating TGF-ß/Smad3 signaling in fibroblast activation and kidney fibrosis development. S100A4 was upregulated in the kidney in a murine model of renal fibrosis induced by folic acid nephropathy. Further, S100A4 was predominant in the tubulointerstitial cells of the kidney. Pharmacological inhibition of S100A4 with niclosamide significantly attenuated fibroblast activation, decreased collagen content, and reduced extracellular matrix protein expression in folic acid nephropathy. Overexpression of S100A4 in cultured renal fibroblasts significantly facilitated TGF-ß1-induced activation of fibroblasts by increasing the expression of α-SMA, collagen-1 and fibronectin. In contrast, S100A4 knockdown prevented TGF-ß1-induced activation of fibroblast and transcriptional activity of Smad3. Mechanistically, S100A4 interacts with Smad3 to stabilize the Smad3/Smad4 complex and promotes their translocation to the nucleus. In conclusion, S100A4 facilitates TGF-ß signaling via interaction with Smad3 and promotes kidney fibrosis development. Manipulating S100A4 may provide a beneficial therapeutic strategy for chronic kidney disease.

Can integrating the Memory Support Intervention into cognitive therapy improve depression outcome? A randomized controlled trial.

We investigated if improving a patient's memory for the content of their treatment, via the Memory Support Intervention, improves illness course and functional outcomes. The platform for investigating this question was major depressive disorder (MDD) and cognitive therapy (CT). Adults diagnosed with MDD (N = 178) were randomly allocated to CT + Memory Support (n = 91) or CT-as-usual (n = 87). Both treatments were comprised of 20-26, 50-min sessions over 16 weeks. Blind assessments were conducted before and immediately following treatment (post-treatment) and 6 months later (6FU). Patient memory for treatment, assessed with a free recall task, was higher in CT + Memory Support for past session recall at post-treatment. Both treatment arms were associated with reductions in depressive symptoms and functional impairment except: CT + Memory Support exhibited lower depression severity at 6FU (b = -3.09, p = 0.050, d = -0.27), and greater reduction in unhealthy days from baseline to 6FU (b = -4.21, p = 0.010, d = -1.07), compared to CT-as-usual. While differences in illness course and functional outcomes between the two treatment arms were limited, it is possible that future analyses of the type of memory supports and longer follow-up may yield more encouraging outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01790919. Registered October 6, 2016.

Risk of preeclampsia in patients with symptomatic COVID-19 infection.

OBJECTIVES: Recent studies suggest an association between COVID-19 infection during pregnancy and preeclampsia. Nonetheless, these studies are subject to numerous biases. We compared the onset of preeclampsia in a group with symptomatic COVID-19 during pregnancy to that in a group whose non-exposure to the virus was certain, in a center where pregnancy management was identical in both groups. STUDY DESIGN: This was a single-center study comparing exposed and unexposed patients. The exposed group included pregnant women with symptomatic COVID-19 infection (diagnosed by RT-PCR or CT scan), who gave birth between March and December, 2020. The unexposed group included pregnant women who gave birth between March and December, 2019. Only cases of preeclampsia that occurred after COVID-19 infection were considered. A multivariate analysis was performed to study the existence of an association between COVID-19 and preeclampsia. A sensitivity analysis was performed among nulliparous patients. RESULTS: The frequency of preeclampsia was 3.2% (3/93) in the exposed group, versus 2.2% (4/186) in the unexposed group (P = 0.58). Among the nulliparous patients, the frequency of preeclampsia was 4.9% (2/41) in the exposed group versus 0.9% (1/106) in the unexposed group (P = 0.13). The association between COVID-19 and preeclampsia was not significant after multivariate analysis (OR 3.12, 95% CI 0.39-24.6). CONCLUSION: Symptomatic COVID-19 infection during pregnancy does not appear to increase the risk of preeclampsia strongly, although the size of our sample prevents us from reaching a conclusion about a low or moderate risk. It therefore does not appear necessary to reinforce preeclampsia screening in patients with symptomatic COVID-19 infection during pregnancy.

MicroRNA-200c coordinates HNF1 homeobox B and apolipoprotein O functions to modulate lipid homeostasis in alcoholic fatty liver disease.

Hepatic steatosis is an initial manifestation of alcoholic liver disease. An imbalance of hepatic lipid processes including fatty acid uptake, esterification, oxidation, and triglyceride secretion leads to alcoholic fatty liver (AFL). However, the precise molecular mechanisms underlying the pathogenesis of AFL remain elusive. Here, we show that mice deficient in microRNAs (miRs)-141 and -200c display resistance to the development of AFL. We found that miR-200c directly targets HNF1 homeobox B (Hnf1b), a transcriptional activator for microsomal triglyceride transfer protein (Mttp), as well as apolipoprotein O (ApoO), an integral component of the mitochondrial contact site and cristae organizing system complex. We show that expression of these miRs is significantly induced by chronic ethanol exposure, which is accompanied by reduced HNF1B and APOO levels. Furthermore, miR-141/200c deficiency normalizes ethanol-mediated impairment of triglyceride secretion, which can be attributed to the restored levels of HNF1B and MTTP, as well as phosphatidylcholine abundance. Moreover, we demonstrate that miR-141/200c deficiency restores ethanol-mediated inhibition of APOO expression and mitochondrial dysfunction, improving mitochondrial antioxidant defense capacity and fatty acid oxidation. Taken together, these results suggest that miR-200c contributes to the modulation of lipid homeostasis in AFL disease by cooperatively regulating Hnf1b and ApoO functions.

Phosphoinositide 3 Kinase γ Plays a Critical Role in Acute Kidney Injury.

Inflammatory cells contribute to the pathogenesis of renal ischemia-reperfusion injury (IRI). However, the signaling mechanisms underlying the infiltration of inflammatory cells into the kidney are not well understood. In this study, we examined the effects of phosphoinositide 3 kinase γ (PI3Kγ) on inflammatory cells infiltration into the kidney in response to ischemia-reperfusion injury. Compared with wild-type mice, PI3Kγ knockout mice displayed less IRI in the kidney with fewer tubular apoptotic cell. Furthermore, PI3Kγ deficiency decreased the number of infiltrated neutrophils, macrophages, and T cells in the kidney, which was accompanied by a decrease in the expression of pro-inflammatory cytokines in the kidney. Moreover, wild-type mice treated with AS-605240, a selective PI3Kγ inhibitor, displayed less tubular damage, accumulated fewer inflammatory cells, and expressed less proinflammatory molecules in the kidney following IRI. These results demonstrate that PI3Kγ has a critical role in the pathogenesis of kidney damage in IRI, indicating that PI3Kγ inhibition may serve as a potential therapeutic strategy for the prevention of ischemia-reperfusion-induced kidney injury.

Myeloid PTEN deficiency aggravates renal inflammation and fibrosis in angiotensin II-induced hypertension.

Hypertension is a major cause of chronic kidney disease. However, the pathogenesis of hypertensive kidney disease is not fully understood. Recently, we have shown that CXCL16/phosphoinositide-3 kinase γ (PI3Kγ) plays an important role in the development of renal inflammation and fibrosis in angiotensin II (AngII) induced hypertensive nephropathy. In the present study, we examined the role of phosphatase and tensin homolog (PTEN), a major regulator of PI3K signaling, in the pathogenesis of renal inflammation and fibrosis in an experimental model of hypertension induced by AngII. We generated myeloid PTEN conditional knockout mice by crossing PTENflox/flox mice with LysM-driven Cre mice. Littermate LysM-Cre-/- PTENflox/flox mice were used as a control. Both myeloid PTEN knockout mice and their littermate control mice exhibited similar blood pressure at baseline. AngII treatment resulted in an increase in blood pressure that was comparable between myeloid PTEN knockout mice and littermate control mice. Compared with littermate control mice, myeloid PTEN knockout mice developed more severe kidney dysfunction, proteinuria, and fibrosis following AngII treatment. Furthermore, myeloid PTEN deficiency exacerbated total collagen deposition and extracellular matrix protein production and enhanced myeloid fibroblast accumulation and myofibroblast formation in the kidney following AngII treatment. Finally, myeloid PTEN deficiency markedly augmented infiltration of F4/80+ macrophages and CD3+ T cells into the kidneys of AngII-treated mice. Taken together, these results indicate that PTEN plays a crucial role in the pathogenesis of renal inflammation and fibrosis through the regulation of infiltration of myeloid fibroblasts, macrophages, and T lymphocytes into the kidney.

MiR-200c-3p targets SESN1 and represses the IL-6/AKT loop to prevent cholangiocyte activation and cholestatic liver fibrosis.

Cholestasis causes ductular reaction in the liver where the reactive cholangiocytes not only proliferate but also gain a neuroendocrine-like phenotype, leading to inflammatory cell infiltration and extracellular matrix deposition and contributing to the development and progression of cholestatic liver fibrosis. This study aims to elucidate the role of miR-200c in cholestasis-induced biliary liver fibrosis and cholangiocyte activation. We found that miR-200c was extremely abundant in cholangiocytes but was reduced by cholestasis in a bile duct ligation (BDL) mouse model; miR-200c was also decreased by bile acids in vitro. Phenotypically, loss of miR-200c exacerbated cholestatic liver injury, including periductular fibrosis, intrahepatic inflammation, and biliary hyperplasia in both the BDL model and the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) model. We identified sestrin 1 (SESN1) as a target of miR-200c. Sesn1-/--BDL mice showed mitigation of cholestatic liver injury. On a molecular level, the pro-proliferative IL-6/AKT feedback loop was activated in Mir200c-/- livers but was inhibited in Sesn1-/- livers upon cholestasis in mice. Furthermore, rescuing expression of miR-200c by the adeno-associated virus serotype 8 ameliorated BDL-induced liver injury in Mir200c-/- mice. Taken together, this study demonstrates that miR-200c restrains the proliferative and neuroendocrine-like activation of cholangiocytes by targeting SESN1 and inhibiting the IL-6/AKT feedback loop to protect against cholestatic liver fibrosis. Our findings provide mechanistic insights regarding biliary liver fibrosis, which may help to reveal novel therapeutic targets for the treatment of cholestatic liver injury and liver fibrosis.

Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance.

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance. Conversely, reductions in skeletal muscle NOX4 in aging and obesity contribute to the development of insulin resistance. NOX4 deletion in skeletal muscle compromised exercise capacity and antioxidant defense and promoted oxidative stress and insulin resistance in aging and obesity. The abrogated adaptive mechanisms, oxidative stress, and insulin resistance could be corrected by deleting the H2O2-detoxifying enzyme GPX-1 or by treating mice with an agonist of NFE2L2, the master regulator of antioxidant defense. These findings causally link NOX4-derived ROS in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity.

STAT6 Deficiency Attenuates Myeloid Fibroblast Activation and Macrophage Polarization in Experimental Folic Acid Nephropathy.

Renal fibrosis is a pathologic feature of chronic kidney disease, which can lead to end-stage kidney disease. Myeloid fibroblasts play a central role in the pathogenesis of renal fibrosis. However, the molecular mechanisms pertaining to myeloid fibroblast activation remain to be elucidated. In the present study, we examine the role of signal transducer and activator of transcription 6 (STAT6) in myeloid fibroblast activation, macrophage polarization, and renal fibrosis development in a mouse model of folic acid nephropathy. STAT6 is activated in the kidney with folic acid nephropathy. Compared with folic-acid-treated wild-type mice, STAT6 knockout mice had markedly reduced myeloid fibroblasts and myofibroblasts in the kidney with folic acid nephropathy. Furthermore, STAT6 knockout mice exhibited significantly less CD206 and PDGFR-ß dual-positive fibroblast accumulation and M2 macrophage polarization in the kidney with folic acid nephropathy. Consistent with these findings, STAT6 knockout mice produced less extracellular matrix protein, exhibited less severe interstitial fibrosis, and preserved kidney function in folic acid nephropathy. Taken together, these results have shown that STAT6 plays a critical role in myeloid fibroblasts activation, M2 macrophage polarization, extracellular matrix protein production, and renal fibrosis development in folic acid nephropathy. Therefore, targeting STAT6 may provide a novel therapeutic strategy for fibrotic kidney disease.

Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis.

A hallmark of chronic kidney disease is renal fibrosis, which can result in progressive loss of kidney function. Currently, there is no effective therapy for renal fibrosis. Therefore, there is an urgent need to identify potential drug targets for renal fibrosis. In this study, we examined the effect of a selective STAT6 inhibitor, AS1517499, on myeloid fibroblast activation, macrophage polarization, and development of renal fibrosis in two experimental murine models. To investigate the effect of STAT6 inhibition on myeloid fibroblast activation, macrophage polarization, and kidney fibrosis, wild-type mice were subjected to unilateral ureteral obstruction or folic acid administration and treated with AS1517499. Mice treated with vehicle were used as control. At the end of experiments, kidneys were harvested for analysis of myeloid fibroblast activation, macrophage polarization, and renal fibrosis and function. Unilateral ureteral obstruction or folic acid administration induced STAT6 activation in interstitial cells of the kidney, which was significantly abolished by AS1517499 treatment. Mice treated with AS1517499 accumulated fewer myeloid fibroblasts and myofibroblasts in the kidney with ureteral obstruction or folic acid nephropathy compared with vehicle-treated mice. Moreover, AS1517499 significantly suppressed M2 macrophage polarization in the injured kidney. Furthermore, AS1517499 markedly reduced the expression levels of extracellular matrix proteins, and development of kidney fibrosis and dysfunction. These findings suggest that AS1517499 inhibits STAT6 activation, suppresses myeloid fibroblast activation, reduces M2 macrophage polarization, attenuates extracellular matrix protein production, and preserves kidney function. Therefore, targeting STAT6 with AS1517499 is a novel therapeutic approach for chronic kidney disease.

A Potential Role for SerpinA3N in Acetaminophen-Induced Hepatotoxicity.

Acetaminophen (APAP) is a commonly used pain and fever reliever but is also the most frequent cause of drug-induced liver injury. The mechanism pertaining acetaminophen toxicity has been well documented, whereas mechanisms of hepatotoxicity are not well established. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N), a serine protease inhibitor, is synthesized in the liver but the role of SerpinA3N in relation to APAP-induced liver injury is not known. Wild-type and hepatocyte-specific SerpinA3N knockout (HKO) mice were injected intraperitoneally with a single dose of PBS or APAP (400 mg/kg) for 12 hours, and markers of liver injury, cell death, and inflammation were assessed. SerpinA3N expression was highly induced in mice with APAP overdose. SerpinA3N HKO mice had diminished liver injury and necrosis as shown by lower alanine aminotransferase and interleukin-6 levels, accompanied by suppressed inflammatory cytokines and reduced neutrophil infiltration. The reduced oxidative stress was associated with enhanced antioxidant enzyme capabilities. Taken together, hepatocyte SerpinA3N deficiency reduced APAP-induced liver injury by ameliorating inflammation and modulating the 5' AMP-activated protein kinase-unc-51-like autophagy activating kinase 1 signaling pathway. Our study provides novel insights into a potential role for SerpinA3N in APAP-induced liver injury. SIGNIFICANCE STATEMENT: Our studies indicate that serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) may have a pathophysiological role in modulating acetaminophen (APAP)-induced liver injury. More specifically, mice with hepatic deletion of SerpinA3N suppressed inflammation and liver injury to reduce APAP-induced hepatotoxicity. Controlling the inflammatory response offers possible approaches for novel therapeutics; therefore, understanding the pathophysiological role of SerpinA3N in inducing liver injury may add to the development of more efficacious treatments.