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Homeostasis of body fluid is a key component for maintaining health. An imbalance of body sodium and water causes various pathological states, such as dehydration, volume overload, hypertension, cardiovascular and renal diseases, and metabolic disorders. Conventional concepts regarding physiology and pathophysiology of body sodium and water balance have been established by several assumptions. These assumptions are that the kidneys are the master regulator of body sodium and water content, and that sodium moves inside the body in parallel with water. However, recent clinical and basic studies have proposed alternative concepts. These concepts are that body sodium and water balance are regulated by various organs and multiple factors, such as physical activity and the environment, and that sodium accumulates locally in tissues independently of the blood status and/or water. Various concerns remain unclear, and the regulatory mechanism of body sodium, fluid, and blood pressure needs to be readdressed. In the present review article, we discuss novel concepts regarding the regulation of body sodium, water, and blood pressure with a particular focus on the systemic water conservation system and fluid loss-triggered elevation in blood pressure.

We have previously reported that monoclonal antibodies against the (pro)renin receptor [(P)RR] can reduce the Wnt/β-catenin-dependent development of pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer. Antibodies against two (P)RR regions (residues 47-60 and 200-213) located in the extracellular domain (ECD) reduced the proliferation of human PDAC cells in vitro. Although these regions probably participate in the activation of Wnt/β-catenin signaling, their functional significance remains unclear. Moreover, the (P)RR ECD is predicted to possess an intrinsically disordered region (IDR), which allows multiple protein interactions because of its conformational flexibility. In this study, we investigated the significance of the two regions and the IDR by in silico 3D structural analysis using the AlphaFold2 program and evolutionary sequence conservation profile. The model showed that ECD adopted a folded domain (residues 17-269) and had an IDR (residues 270-296). The two regions mapped onto the structural model formed a continuous surface patch comprising evolutionarily conserved hydrophobic residues. The homodimeric structure predicted by AlphaFold2 showed that full-length (P)RR comprising the ECD, single-span transmembrane, and cytoplasmic domains formed a twofold symmetric dimer via the ECD, which explains the experimentally proven homodimerization. The dimer model possessed two hand-shaped grooves with residues 47-60 and 200-213 in their palms and the IDR as their fingers. Based on these findings, we propose that the IDR-containing hydrophobic grooves act as a binding site for (P)RR and perform multiple functions, including Wnt signaling activation. Antibodies against the (pro)renin receptor residues 47-60 and 200-213 can inhibit pancreatic ductal adenocarcinoma (PDAC) cell proliferation by suppressing Wnt signaling. This study provides 3D structural insights into receptor binding and one-to-many interactions, which underpin the functional versatility of this receptor.

Pulmonary endarterectomy (PEA) is one of the most effective treatments for chronic thromboembolic pulmonary hypertension (CTEPH). Right heart catheterization (RHC) is the gold standard assessment for pulmonary circulatory dynamics. However, computed tomography (CT) is less invasive than RHC and can elucidate some of the morphological changes caused by thromboembolism. We hypothesized that CT could facilitate the evaluation of heterogeneous pulmonary perfusion. This study investigated whether CT imaging features reflect the disease severity and changes in pulmonary circulatory dynamics in patients with CTEPH before and after PEA.This retrospective study included 58 patients with CTEPH who underwent PEA. Pre-PEA and post-PEA CT images were assessed for heterogeneity using CT texture analysis (CTTA). The CT parameters were compared with the results of the RHC and other clinical indices and analyzed with receiver operating characteristic curves analysis for patients with and without residual pulmonary hypertension (PH) (post-PEA mean pulmonary artery pressure ≥ 25 mmHg).CT measurements reflecting heterogeneity were significantly correlated with mean pulmonary artery pressure. Kurtosis, skewness, and uniformity were significantly lower, and entropy was significantly higher in patients with residual PH than patients without residual PH. Area under the curve values of pre-PEA and post-PEA entropy between patients with and without residual PH were 0.71 (95% confidence interval 0.57-0.84) and 0.75 (0.63-0.88), respectively.Heterogeneity of lung density might reflect pulmonary circulatory dynamics, and CTTA for heterogeneity could be a less invasive technique for evaluation of changes in pulmonary circulatory dynamics in patients with CTEPH undergoing PEA.

We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.

Background Galactose-deficient immunoglobulin A1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathological role of Gd-IgA1-containing immune complexes (ICs) and the mechanism of deposition in the mesangial region remain unclear. Methods To examine the deposition of Gd-IgA1-containing ICs in the mesangial region through glomerular endothelial cell injury, we evaluated the alteration of renal microvascular endothelial glycocalyx in nude mice injected with Gd-IgA1-IgG ICs. Human renal glomerular endothelial cells (HRGECs) were used to assess the potential capacity of Gd-IgA1-IgG ICs to activate endothelial cells. Results Nude mice injected with Gd-IgA1-containing ICs showed podocyte and endothelial cell injuries, with IgA, IgG and C3 depositions in glomerular capillaries and the mesangium. Moreover, albuminuria and hematuria were induced. Real-time glycocalyx imaging showed that renal microvascular glycocalyx was decreased immediately after injection of Gd-IgA1-containing ICs and then mesangial IgA deposition was increased. After coculture of Gd-IgA1-containing ICs with HRGECs, messenger RNA expression levels of endothelial adhesion molecules and proinflammatory mediators were upregulated significantly. Conclusion Gd-IgA1-IgG ICs had a high affinity for glomerular endothelial cells, which resulted in glomerular filtration barrier dysfunction mediated by glycocalyx loss. Furthermore, Gd-IgA1-IgG ICs accelerated the production of adhesion factors and proinflammatory cytokines in glomerular endothelial cells. The glomerular endothelial cell injury induced by Gd-IgA1-containing ICs may enhance the permeability of Igs in the mesangial region and subsequent inflammatory responses in the pathogenesis of IgAN.

——The concept of local formation of angiotensin II in the kidney has changed over the last 10–15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as mega-lin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/nepri-lysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. Significance Statement——Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.

Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define metabolic differences between steady-state and stress conditions in HSCs and elucidate their regulatory mechanisms. Through quantitative13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of adenosine triphosphate (ATP) levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression ofPfkfb3induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss ofPfkfb3suppressed them. This study reveals the flexible and multilayered regulation of HSC metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells.Key PointsCombined isotope tracing, mathematical modeling, and single cell ATP analysis enable high-resolution evaluation of blood cell metabolism.Under stress, HSCs quickly accelerate glycolysis to meet ATP demands and maintain hematopoiesis via context-dependent PFKFB3 activation.

Metabolic Syndrome (MetS) affects more than 30% of the US population and unmanaged can lead to cardiovascular disease and type II diabetes mellitus. MetS is a cluster of conditions, which include elevated arterial pressure, poor glucose tolerance with or without insulin resistance, and abdominal obesity. Existing literature has demonstrated high cholesterol diet’s (HCD) potential to develop MetS cluster factor conditions like dyslipidemia. Our lab has previously shown that angiotensin receptor blockers (ARBs), a common therapy to treat hypertension by disrupting the renin-angiotensin-aldosterone system (RAAS), attenuate cluster factor conditions of MetS. However, the efficacy of ARBs during the consumption of a HCD remains unclear. Otsuka Long Evan Tokushima Fatty (OLETF) rats (a MetS model) were fed an HCD and at presentation of elevated arterial pressure, they were treated with ARB (10 mg olmesartan/kg/d x 3 wks) by oral gavage. Blood pressure was monitored in real-time with surgically implanted radio telemeters. ARB reduced systolic blood pressure by 15±1mmHg (11%; p This work was supported by the National Institutes of Health NCMHD 9T37MD001480 and National Institutes of Health, National Center on Minority Health and Health Disparities. E.E.J was supported by NIH GRISE BIO-STeP. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiovascular disease (CVD) is the leading cause of death among individuals with Type II diabetes (T2D) with approximately 30 million people afflicted within the United States. Diabetic cardiomyopathy is defined as cardiovascular dysfunction induced by diabetic complications such as sustained hyperglycemia and insulin resistance. During insulin resistance the heart undergoes a metabolic shift in which fatty acids (FA) accounts for about 99% of the ATP production. Some major consequences of a metabolic shift with impaired glucose tolerance can cause an increase in reactive oxygen species (ROS), lipotoxicity, mitochondrial dysfunction, ultimately leading to cardiovascular dysfunction. We have previously shown thyroid hormones (THs) increase GLUT4 translocation in cardiac tissue, indicating the potential to improve the impaired glucose metabolism in the heart. THs have also been shown to improve oxidative injury and increase antioxidant defense systems yet contradicting data exists demonstrating THs induce oxidative stress. Thus, the effects of THs on redox biology and oxidative stress are incongruent and warrant further investigation. Insulin resistant, Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the effects of exogenous thyroxine (T4) on oxidative damage and antioxidant defense in cardiac tissue. Rats were assigned to four groups: 1) lean, Long Evans Tokushima Otsuka (LETO; n=6), 2) LETO + T4 (8 μg/100g BM/d × 5 wks; n=7), 3) untreated OLETF (n=6), and 4) OLETF + T4 (n=7). T4 increased NADPH oxidase (NOX) NOX2 mRNA in both treated LETO (2.04 ± 0.6) and OLETF (2.02 ± 0.6) compared to LETO control (1 ± 0.2). T4 further increased NOX4 mRNA in OLETF by 78% compared to untreated OLETF. In addition, T4 increased Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) protein expression in OLETF by 45% compared to untreated OLETF. These data suggest that the potential for an oxidizing environment in the insulin resistant OLETF rat is increased and T4 has the cardioprotective potential to increase Nrf2-mediated antioxidant defense mechanisms. APS Porter Fellowship and American Heart Association grant # 946746. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

We previously reported that silencing of the PRR gene, which encodes the (pro)renin receptor [(P)RR], significantly reduced Wnt/β-catenin–dependent development of pancreatic ductal adenocarcinoma (PDAC). Here, we examined the effects of a panel of blocking mAbs directed against the (P)RR extracellular domain on proliferation of the human PDAC cell lines PK-1 and PANC-1 in vitro and in vivo. We observed that four rat anti-(P)RR mAbs induced accumulation of cells in the G0–G1-phase of the cell cycle and significantly reduced proliferation in vitro concomitant with an attenuation of Wnt/β-catenin signaling. Systemic administration of the anti-(P)RR mAbs to nude mice bearing subcutaneous PK-1 xenografts significantly decreased tumor expression of active β-catenin and the proliferation marker Ki-67, and reduced tumor growth. In contrast, treatment with the handle region peptide of (pro)renin did not inhibit tumor growth in vitro or in vivo, indicating that the effects of the anti-(P)RR mAbs were independent of the renin–angiotensin system. These data indicate that mAbs against human (P)RR can suppress PDAC cell proliferation by hindering activation of the Wnt/β-catenin signaling pathway. Thus, mAb-mediated (P)RR blockade could be an attractive therapeutic strategy for PDAC.

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Hypertension is the most prevalent comorbidity in cancer patients. Consequently, many cancer patients are prescribed antihypertensive drugs before cancer diagnosis or during cancer treatment. However, whether antihypertensive drugs affect the incidence, treatment efficacy, or prognosis of cancer remains unanswered. For instance, renin–angiotensin and β-adrenergic signaling may be involved not only in blood pressure elevation but also in cell proliferation, angiogenesis, and tissue invasion. Therefore, the inhibition of these pathways may have beneficial effects on cancer prevention or treatment. In this article, we reviewed several studies regarding antihypertensive drugs and cancer. In particular, we focused on the results of clinical trials to evaluate whether the use of antihypertensive drugs affects future cancer risk and prognosis. Unfortunately, the results are somewhat inconsistent, and evidence demonstrating the effect of antihypertensive drugs remains limited. We indicate that the heterogeneity in the study designs makes it difficult to clarify the causal relationship between antihypertensive drugs and cancer. We also propose that additional experimental studies, including research with induced pluripotent cells derived from cancer patients, single-cell analyses of cancer cell clusters, and clinical studies using artificial intelligence electronic health record systems, might be helpful to reveal the precise association between antihypertensive drugs and cancer risk.

BACKGROUND Results of preceding studies on the relationship between blood pressure (BP) and cancers have been confounded due to individuals taking antihypertensive medications or shared risk factors. We assessed whether medication-naïve high BP is a risk factor for incident cancers. METHODS This retrospective observational study included 1,388,331 individuals without a prior history of cancer and not taking antihypertensive medications enrolled in the JMDC Claims Database between 2005 and 2018. The primary outcome was 16 cancers. RESULTS The median [interquartile range] age was 45 [40–52] years and 56.2% were men. Mean systolic BP (SBP) and diastolic BP (DBP) were 117.7 ± 15.8 and 72.8 ± 11.6 mm Hg. Multivariate Cox regression analysis demonstrated that SBP per 1-SD was associated with a higher incidence of thyroid (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.03–1.16), esophageal (HR: 1.15, 95% CI: 1.07–1.24), colorectal (HR: 1.04, 95% CI: 1.01–1.07), liver (HR: 1.11, 95% CI: 1.03–1.20), and kidney (HR: 1.22, 95% CI: 1.14–1.31) cancers, but with a lower incidence of stomach cancer (HR: 0.94, 95% CI: 0.91–0.98). These associations remained significant after adjustment for multiple testing. DBP was associated with higher incidences of thyroid, esophageal, colorectal, kidney, and corpus uteri cancers, but with a lower incidence of stomach cancer. The associations between SBP and incidences of thyroid, esophageal, colorectal, liver, and kidney cancers were confirmed in the Korean National Health Insurance Service database. CONCLUSIONS Medication-naïve BP was associated with higher incidences of thyroid, esophageal, colorectal, liver, and kidney cancers. Uncovering the underlying mechanisms for our results may help identify novel therapeutic approach for hypertension and cancer.

Whether blood pressure (BP) classification using the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline can identify patients at high risk for proteinuria remains unknown. We examined the association of BP classification using the 2017 ACC/AHA guideline with the subsequent risk for the development of proteinuria. This is an observational cohort study using the JMDC Claims Database. We analyzed 914,786 participants with negative proteinuria assessed using urine dipstick tests at the initial health check-ups, not taking BP-lowering medications, and who underwent repeated urine dipstick tests within 4 years. Based on the 2017 ACC/AHA guideline, each participant was categorized as having normal BP (n = 487,020), elevated BP (n = 134,798), stage 1 hypertension (n = 197,618), or stage 2 hypertension (n = 95,350). The primary outcome was incident proteinuria. We investigated the association of BP based on the 2017 ACC/AHA guideline category with incident proteinuria using multivariable analyses. We used restricted cubic spline functions to identify the relation between systolic BP (SBP) and the risk for proteinuria. The median age was 45 years, and 59.4% were men. Multivariable analysis demonstrated that stage 1 hypertension (relative risk 1.14, 95% confidence interval 1.11 to 1.17), and stage 2 hypertension (relative risk 1.48, 95% confidence interval 1.43 to 1.52) were associated with a higher incidence of proteinuria than normal BP. The restricted cubic spline demonstrated that the risk for proteinuria increased linearly with SBP after SBP exceeded 120 mm Hg. Not only stage 2 hypertension but also stage 1 hypertension was associated with a greater risk for proteinuria, suggesting the importance of establishing the management strategy for stage 1 hypertension.

This study aimed to investigate whether phosphate contributes to the pathogenesis of chronic kidney disease (CKD) in dolphins. Renal necropsy tissue of an aged captive dolphin was analyzed and in vitro experiments using cultured immortalized dolphin proximal tubular (DolKT-1) cells were performed. An older dolphin in captivity died of myocarditis, but its renal function was within the normal range until shortly before death. In renal necropsy tissue, obvious glomerular and tubulointerstitial changes were not observed except for renal infarction resulting from myocarditis. However, a computed tomography scan showed medullary calcification in reniculi. Micro area X-ray diffractometry and infrared absorption spectrometry showed that the calcified areas were primarily composed of hydroxyapatite. In vitro experiments showed that treatment with both phosphate and calciprotein particles (CPPs) resulted in cell viability loss and lactate dehydrogenase release in DolKT-1 cells. However, treatment with magnesium markedly attenuated this cellular injury induced by phosphate, but not by CPPs. Magnesium dose-dependently decreased CPP formation. These data support the hypothesis that continuous exposure to high phosphate contributes to the progression of CKD in captive-aged dolphins. Our data also suggest that phosphate-induced renal injury is mediated by CPP formation in dolphins, and it is attenuated by magnesium administration., イルカの腎老化メカニズムを解明 --高齢化社会を迎える飼育イルカの健康維持に向けて--. 京都大学プレスリリース. 2023-04-24.

Antimicrobial resistance (AMR) in Salmonella in poultry poses a serious human health threat as it has zoonotic importance. Poultry is often linked with outbreaks of Salmonella-associated foodborne illness. Since antimicrobials are heavily used in poultry in Bangladesh, multidrug-resistant (MDR) Salmonella is quite frequently found there. MDR Salmonella is challenging to treat with antimicrobials and often causes a severe economic loss in the poultry sector. By horizontal gene transfer and/or evolutionary mutations, antimicrobials primarily exert selection pressure that contributes to antimicrobials resistance. In addition, resistance patterns can vary with variations in time and space. Without having prior knowledge of resistance patterns, no effective drugs could be prescribed. Therefore, it is crucial to have updated knowledge on the status of AMR in Salmonella in Bangladesh for effective treatment and management of the flocks against salmonellosis. There are several review articles on AMR in Salmonella in poultry in Bangladesh; they lack the whole scenario of the country and particularly do not have enough data on the poultry environment. Considering this scenario, in this review, we have focused on AMR in Salmonella in poultry in Bangladesh (2011–2021), with particular emphasis on data from the poultry and farm environments on a divisional zone basis.

Although oral cytology using Papanicolaou stain is useful for the early detection of oral premalignant lesions and squamous cell carcinoma (SCC) in people, little work has been conducted on this topic in veterinary medicine. This paper describes the features of oral cytology using Papanicolaou stain and immunocytochemistry on liquid-based cytology slides in a case of oral SCC in an Indo-Pacific bottlenose dolphin (Tursiops aduncus). In this case, dysplastic cells with koilocyte-like changes and SCC cells were identified using the Papanicolaou stain. These cells were positive for p53 using an immunocytochemistry analysis. A cytologic diagnosis of SCC was made. We believe that the early detection of premalignant oral lesions and SCC in dolphins can be significantly improved with cytology using liquid-based cytology, Papanicolaou staining, and immunocytochemistry.

This study aimed to evaluate the effects of jaw-opening exercises with and without pain on temporomandibular disorders (TMDs), specifically in relation to pain intensity and range-of-mouth opening in patients with TMDs. Participants were randomly assigned to either the jaw-opening exercise with pain (JE w/pain) or the jaw-opening exercise without pain (JE w/o pain) groups, and each exercise was performed for eight weeks. TMDs pain intensity was assessed using a 100-mm visual analog scale (VAS), and the range-of-mouth opening was evaluated at the baseline (T0), 2 weeks (T1), 4 weeks (T2), and 8 weeks (T3). Of the 61 participants, 57 (JE w/pain group, n = 30; JE w/o pain group, n = 27) were included in the analysis. The range-of-mouth opening and TMDs pain intensity improved from T1 to T3 in both groups. The JE w/pain group showed significant differences at T3 compared to T1 (pain-free unassisted mouth opening, p = 0.006; jaw-opening pain, p = 0.014; chewing pain, p = 0.018). In addition, the JE w/pain group showed significantly greater changes in the maximum unassisted mouth opening at T2 and T3 than the JE w/o pain group (T2, p < 0.001; T3, p = 0.003). Thus, jaw-opening exercises, until the occurrence of pain, may be effective in patients with TMDs.

In mammals, primordial germ cells (PGCs) enter meiosis and differentiate into primary oocytes in embryonic ovaries. Previously, we demonstrated that meiotic gene induction and meiotic initiation were impaired in female germline cells of conditional knockout (CKO) mice lacking the Smarcb1 (Snf5) gene, which encodes a core subunit of the switching defective/sucrose non-fermenting (SWI/SNF) complex. In this study, we classified meiotic genes expressed at lower levels in Snf5 CKO females into two groups based on promoter accessibility. The promoters of 74% of these genes showed lower accessibility in mutant mice, whereas those of the remaining genes were opened without the SWI/SNF complex. Notably, the former genes included Meiosin, which encodes a transcriptional regulator essential for meiotic gene activation. The promoters of the former and the latter genes were mainly modified with H3K27me3/bivalent and H3K4me3 histone marks, respectively. A subset of the former genes was precociously activated in female PGCs deficient in polycomb repressive complexes (PRCs). Our results point to a mechanism through which the SWI/SNF complex coordinates meiotic gene activation via the remodeling of PRC-repressed genes, including Meiosin, in female germline cells.

Metabolic syndrome (MetS) is a rapidly increasing health concern during midlife and is an emerging risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD). While angiotensin receptor blockers (ARB) are widely used for MetS-associated hypertension and kidney disease, its therapeutic potential in the brain during MetS are not well-described. Here, we tested whether treatment with ARB could alleviate the brain pathology and inflammation associated with MetS using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Here, we report that chronic ARB treatment with olmesartan (10 mg/kg/day by oral gavage for 6 weeks) partially but significantly ameliorated accumulation of oxidized and ubiquitinated proteins, astrogliosis and transformation to neurotoxic astrocytes in the brain of old OLETF rats, which otherwise exhibit the progression of these pathological hallmarks associated with MetS. Additionally, olmesartan treatment restored claudin-5 and ZO-1, markers of the structural integrity of the blood-brain barrier as well as synaptic protein PSD-95, which were otherwise decreased in old OLETF rats, particularly in the hippocampus, a critical region in cognition, memory and AD. These data demonstrate that the progression of MetS in OLETF rats is associated with deterioration of various aspects of neuronal integrity that may manifest neurodegenerative conditions and that overactivation of angiotensin receptor directly or indirectly contributes to these detriments. Thus, olmesartan treatment may slow or delay the onset of degenerative process in the brain and subsequent neurological disorders associated with MetS.

Background: Immune checkpoint inhibitors (ICIs) are becoming widely used for novel cancer treatments. Immune-related adverse events, including cardiac toxicity, are frequently observed following immune checkpoint inhibitor (ICI) use. However, little is known regarding the association between ICIs initiation and hypertension in cancer patients. Methods: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. The risk of hypertension associated with ICI initiation in randomized controlled trials (RCTs) was evaluated. Hypertension was categorized according to the Common Terminology Criteria for Adverse Events. The odds ratios of grades I to V and grades III to V hypertension were calculated using a random-effects meta-analysis. Results: Thirty-two RCTs (n=19 810 cancer patients) were included. At a median follow-up of 36 months, the median overall survival was 15 months in the ICI group. ICI initiation was not significantly associated with hypertension (grades I–V: odds ratio, 1.12 [95% CI, 0.96–1.30]; grades III–V: odds ratio, 0.95 [95% CI, 0.78–1.16]). Additionally, no significant differences in hypertension risk were evident in ICI combination therapies with various drugs, including anti-VEGF (vascular endothelial growth factor) agents. In a subgroup analysis based on clinical setting (placebo RCT versus nonplacebo RCT), there were discrepancies between the results obtained with different methodologies, with patients in the nonplacebo RCTs having higher grades I–V hypertension (I 2 =88.6%, P for heterogeneity=0.003). Conclusions: ICI initiation was not associated with short-term risk of hypertension in cancer patients, and the association was similar regardless of concomitant treatment with other anticancer drugs.

PURPOSE Despite the growing recognition of the importance of hypertension in patients with cancer, little is known about whether high blood pressure (BP) among patients with cancer is associated with incident heart failure (HF) and other cardiovascular disease (CVD) events and what BP levels are linked to these events. We examined the association of BP classification on the basis of the 2017 American College of Cardiology/American Heart Association BP guideline with the risk of HF and CVD events in patients with cancer. METHODS We studied 33,991 patients with a history of breast, colorectal, or stomach cancer (median age, 53 years; 34.1% men). Patients receiving treatment with BP-lowering medications or having a history of CVD including HF were excluded. Using BP measurements at baseline, 33,991 participants were categorized as having normal BP (n = 17,444), elevated BP (n = 4,733), stage 1 hypertension (n = 7,502), or stage 2 hypertension (n = 4,312). The primary outcome was HF. RESULTS Over a mean follow-up of 2.6 ± 2.2 years, 779 HF events were recorded. After multivariable adjustment, the hazard ratios (HRs) for HF were 1.15 (95% CI, 0.93 to 1.44) for elevated BP, 1.24 (95% CI, 1.03 to 1.49) for stage 1 hypertension, and 1.99 (95% CI, 1.63 to 2.43) for stage 2 hypertension. A stepwise increase in risk with BP categories was also observed in other CVD events. This association was observed even in patients undergoing active cancer treatment. The relationship between hypertension and the risk of developing HF in patients with cancer was confirmed in the Korean National Health Insurance Service database. CONCLUSION Medication-naïve stage 1 and 2 hypertension was associated with a greater risk of HF and other CVD events in patients with cancer. Our results suggest the importance of multidisciplinary collaboration (eg, oncologists and cardiologists) to establish the optimal management strategy for hypertension in patients with cancer.

Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1-7), which mediates mechanisms counterregulatory to AT1 signaling. Elevated plasma Ang 1-7 is associated with decreased plasma triacylglycerol (TAG), cholesterol, glucose, and insulin; however, the benefits of RAS modulation to prevent non-alcoholic fatty liver disease (NAFLD) are not fully investigated. To better address the relationships among chronic ARB treatment, plasma Ang 1-7, and hepatic steatosis, three groups of 10-week-old-rats were studied: (1) untreated lean Long Evans Tokushima Otsuka (LETO), (2) untreated Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF+ARB (ARB; 10mg olmesartan/kg/d×6 weeks). Following overnight fasting, rats underwent an acute glucose load to better understand the dynamic metabolic responses during hepatic steatosis and early MetS. Tissues were collected at baseline (pre-load; T0) and 1 and 2h post-glucose load. AT1 blockade increased plasma Ang 1-7 and decreased liver lipids, which was associated with decreased fatty acid transporter 5 (FATP5) and fatty acid synthase (FASN) expression. AT1 blockade decreased liver glucose and increased glucokinase (GCK) expression. These results demonstrate that during MetS, overactivation of AT1 promotes hepatic lipid deposition that is stimulated by an acute glucose load and lipogenesis genes, suggesting that the chronic hyperglycemia associated with MetS contributes to fatty liver pathologies via an AT1-mediated mechanism.

Purpose Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS. Methods Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose). Results Compared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB. Conclusions Chronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors., IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.

Context Although diabetes mellitus (DM) was reported to be associated with incident colorectal cancer (CRC), the detailed association between fasting plasma glucose (FPG) and incident CRC has not been fully understood. Objective We assessed whether hyperglycemia is associated with a higher risk for CRC. Design Analyses were conducted using the JMDC Claims Database [n = 1 441 311; median age (interquartile range), 46 (40-54) years; 56.6% men). None of the participants were taking antidiabetic medication or had a history of CRC, colorectal polyps, or inflammatory bowel disease. Participants were categorized as normal FPG (FPG level < 100 mg/dL; 1 125 647 individuals), normal-high FPG (FPG level = 100-109 mg/dL; 210 365 individuals), impaired fasting glucose (IFG; FPG level = 110-125 mg/dL; 74 836 individuals), and DM (FPG level ≥ 126 mg/dL; 30 463 individuals). Results Over a mean follow-up of 1137 ± 824 days, 5566 CRC events occurred. After multivariable adjustment, the hazard ratios for CRC events were 1.10 (95% CI 1.03-1.18) for normal-high FPG, 1.24 (95% CI 1.13-1.37) for IFG, and 1.36 (95% CI 1.19-1.55) for DM vs normal FPG. We confirmed this association in sensitivity analyses excluding those with a follow-up of< 365 days and obese participants. Conclusion The risk of CRC increased with elevated FPG category. FPG measurements would help to identify people at high-risk for future CRC.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to

The asymmetric transfer hydrogenation of α,β-unsaturated aldehyde with Hantzsch ester catalyzed by polymer-supported chiral pyrrolidine organocatalyst was achieved. The effects of the pyrrolidine s...

Tumor spread through air spaces (STAS) in non-small-cell lung cancer (NSCLC) is known to influence a poor patient outcome, even in patients presenting with early-stage disease. However, the pre-operative diagnosis of STAS remains challenging. With the progress of radiomics-based analyses several attempts have been made to predict STAS based on radiological findings. In the present study, patients with NSCLC which is located peripherally and tumors ≤ 2 cm in size on computed tomography (CT) that were potential candidates for sublobar resection were enrolled in this study. The radiologic features of the targeted tumors on thin-section CT were extracted using the PyRadiomics v3.0 software package, and a predictive model for STAS was built using the t-test and XGBoost. Thirty-five out of 226 patients had a STAS histology. The predictive model of STAS indicated an area under the receiver-operator characteristic curve (AUC) of 0.77. There was no significant difference in the overall survival (OS) for lobectomy between the predicted-STAS (+) and (−) groups (p = 0.19), but an unfavorable OS for sublobar resection was indicated in the predicted-STAS (+) group (p

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors were developed for treatment of renal anemia. Patients applicable for HIF-PHD inhibitor treatment experience complications such as chronic kidney disease, whereby water and electrolyte homeostasis is disrupted. The effects of hypoxia-inducible factor stabilization on salt accumulation in the setting of reduced renal function remain unclear. In the present study, we investigated the effect of a HIF-PHD inhibitor, molidustat, on salt distribution and excretion in rats with subtotal nephrectomy-induced chronic kidney disease. Male Wistar rats were subjected to 5/6 nephrectomy. After confirming blood pressure elevation (>150 mmHg, at 4 weeks after surgery), rats were treated with molidustat. After 1 week of treatment, molidustat did not significantly improve blood cell volume or blood pressure. Distribution of sodium, potassium, and water in skin, carcass, and bone samples was not affected by molidustat. Furthermore, molidustat had no significant effect on urinary sodium excretion or concentration in response to acute oral salt loading (1 g/kg). In conclusion, molidustat did not affect distribution or excretion of salt in rats subjected to a model of nephron loss.

Classical dendritic cells (cDCs) are essential for immune responses and differentiate from hematopoietic stem cells via intermediate progenitors, such as monocyte−DC progenitors (MDPs) and common DC progenitors (CDPs). Upon infection, cDCs are activated and rapidly express host defense-related genes, such as those encoding cytokines and chemokines. Chromatin structures, including nuclear compartments and topologically associating domains (TADs), have been implicated in gene regulation. However, the extent and dynamics of their reorganization during cDC development and activation remain unknown. In this study, we comprehensively determined higher-order chromatin structures by Hi-C in DC progenitors and cDC subpopulations. During cDC differentiation, chromatin activation was initially induced at the MDP stage. Subsequently, a shift from inactive to active nuclear compartments occurred at the cDC gene loci in CDPs, which was followed by increased intra-TAD interactions and loop formation. Mechanistically, the transcription factor IRF8, indispensable for cDC differentiation, mediated chromatin activation and changes into the active compartments in DC progenitors, thereby possibly leading to cDC-specific gene induction. Using an infection model, we found that the chromatin structures of host defense-related gene loci were preestablished in unstimulated cDCs, indicating that the formation of higher-order chromatin structures prior to infection may contribute to the rapid responses to pathogens. Overall, these results suggest that chromatin structure reorganization is closely related to the establishment of cDC-specific gene expression and immune functions. This study advances the fundamental understanding of chromatin reorganization in cDC differentiation and activation.