Recurrence of rectal cancer on the pelvic sidewall after lateral lymph node dissection.

PURPOSE: Although lateral lymph node dissection has been performed to prevent lateral pelvic recurrence in locally advanced lower rectal cancer, the incidence of lateral pelvic recurrence after this procedure has not been investigated. Therefore, this study aimed to investigate the long-term outcomes of patients who underwent lateral pelvic lymph node dissection, with a particular focus on recurrence patterns. METHODS: This was a retrospective study conducted at a single high-volume cancer center in Japan. A total of 493 consecutive patients with stage II-III rectal cancer who underwent lateral lymph node dissection between January 2005 and August 2022 were included. The primary outcome measures included patterns of recurrence, overall survival, and relapse-free survival. Patterns of recurrence were categorized as lateral or central pelvic. RESULTS: Among patients who underwent lateral lymph node dissection, 18.1% had pathologically positive lateral lymph node metastasis. Lateral pelvic recurrence occurred in 5.5% of patients after surgery. Multivariate analysis identified age > 75 years, lateral lymph node metastasis, and adjuvant chemotherapy as independent risk factors for lateral pelvic recurrence. Evaluation of the recurrence rate by dissection area revealed approximately 1% of recurrences in each area after dissection. CONCLUSION: We demonstrated the prognostic outcome and limitations of lateral lymph node dissection for patients with advanced lower rectal cancer, focusing on the incidence of recurrence in the lateral area after the dissection. Our study emphasizes the clinical importance of lateral lymph node dissection, which is an essential technique that surgeons should acquire.

Hazard function analysis of prognosis after recurrent colorectal cancer.

BACKGROUND AND OBJECTIVES: Mean survival time (MST) is used as the indicator of prognosis in patients with a colorectal cancer (CRC) recurrence. The present study aimed to visualize the changes in death risk after a CRC recurrence using hazard function analysis (HFA) to provide an alternative prognostic indicator to MST. METHODS: The medical records of 725 consecutive patients with a recurrence following R0 radical surgery for CRC were retrospectively reviewed. RESULTS: The five-year, post-recurrence survival rate was 37.8%, and the MST was 3.5 years while the risk of death peaked at 2.9 years post-recurrence. Seven variables were found to predict short-term survival, including the number of metastatic organs ≥ 2, non-surgical treatment for the recurrence, and a short interval before recurrence. In patients with a recurrence in one organ, the MST was four years, the peak time of death predicted by HFA was 2.9 years, and the five-year survival rate was 45.8%. In patients with a surgical resection of the recurrence, the MST was 8 years, the peak time of death was 3.3 years, and the five-year survival rate was 62%. CONCLUSIONS: The present study established a novel method of assessing changes in mortality risk over time using HFA in patients with a CRC recurrence.

Modified neoadjuvant rectal score as a novel prognostic model for rectal cancer patients who underwent chemoradiotherapy.

BACKGROUND: The neoadjuvant rectal score (NAR score) has recently been proposed as a better prognostic model than the conventional TNM classification for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy. We recently developed an apoptosis-detection technique for assessing the viability of residual tumors in resected specimens after chemoradiotherapy. This study aimed to establish an improved prognostic classification by combining the NAR score and the assessment of the apoptosis of residual cancer cells. METHODS: We retrospectively enrolled 319 rectal cancer patients who underwent chemoradiotherapy followed by radical surgery. The recurrence-free survival and overall survival of the four models were compared: TNM stage, NAR score, modified TNM stage by re-staging according to cancer cell viability, and modified NAR score also by re-staging. RESULTS: Downstaging of the ypT stage was observed in 15.5% of cases, whereas only 4.5% showed downstaging of ypN stage. C-index was highest for the modified NAR score (0.715), followed by the modified TNM, TNM, and NAR score. Similarly, Akaike's information criterion was smallest in the modified NAR score (926.2), followed by modified TNM, TNM, and NAR score, suggesting that the modified NAR score was the best among these four models. The overall survival results were similar: C-index was the highest (0.767) and Akaike's information criterion was the smallest (383.9) for the modified NAR score among the four models tested. CONCLUSION: We established a novel prognostic model, for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy, using a combination of apoptosis-detecting immunohistochemistry and neoadjuvant rectal scores.

Clinicopathological characteristics of Lynch-like syndrome.

BACKGROUND: Lynch-like syndrome (LLS) has recently been proposed as a third type of microsatellite instability (MSI) tumor after Lynch syndrome (LS) and sporadic MSI colorectal cancer (CRC) without either a germline variant of mismatch repair (MMR) genes or hypermethylation of the MLH1 gene. The present study aimed to clarify and compare the clinicopathological characteristics of LLS with those of the other MSI CRC subtypes. METHODS: In total, 2634 consecutive patients with CRC who underwent surgical resection and subsequently received universal tumor screening (UTS), including MSI analysis were enrolled between January 2008 and November 2019. Genetic testing was performed in patients suspected of having Lynch syndrome. RESULTS: UTS of the cohort found 146 patients with MSI CRC (5.5%). Of these, excluding sporadic MSI CRC, 30 (1.1%) had a diagnosis of LS, and 19 (0.7%) had no germline pathogenic variants of the MMR gene. The CRC type in the latter group was identified as LLS. LLS occurred significantly more often in young patients, was left-sided, involved a KRAS variant and BRAF wild-type, and had a higher concordance rate with the Revised Bethesda Guidelines than sporadic MSI CRC. No significant differences were observed in terms of the clinicopathological factors between LLS and LS-associated MSI CRC; however, LLS had a lower frequency of LS-related neoplasms compared with LS. CONCLUSIONS: Distinguishing clinically between LS and LLS was challenging, but the incidence of neoplasms was higher in LS than in LLS, suggesting the need for different screening and surveillance methods for the two subtypes.

Glomerular deposition of galactose-deficient IgA1-containing immune complexes via glomerular endothelial cell injuries.

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.

Tolvaptan induces body fluid loss and subsequent water conservation in normal rats.

We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V2 receptor antagonist, on water conservation. We evaluated the water conservation system in rats that consumed a control diet or a diet containing 0.1% tolvaptan. Tolvaptan increased urine volume on day 1, but this renal water loss then gradually decreased. Body water and osmolyte content were decreased by tolvaptan on day 1 but had normalized by day 7. Tolvaptan induced fluid loss on day 1, and the following restoration of body fluid on day 7 was associated with an increase in urea transporter A1-associated renal urea recycling. Tolvaptan did not affect hepato-muscular ureagenesis on day 1 and day 7, or cardiovascular energy expenditure during treatment. Thus, tolvaptan-induced fluid loss leads to activation of the water conservation system via renal urea recycling.

A novel Lynch syndrome pedigree bearing germ-line MSH2 missense mutation c.1808A>T (Asp603Val).

We report the first pedigree of Lynch syndrome bearing a germ-line MSH2 missense mutation c.1808A>T (Asp603Val). Until now, this missense mutation, in exon 12 of MSH2, was identified as a variant of unknown significance in the International Society for Gastrointestinal Hereditary Tumours database. In vitro induction mutagenesis experiments indicated that the MSH2 mutant protein (Asp603Val) is easily degraded in embryonic stem cells, albeit there is no clinical information concerning this mutant. Our pedigree includes four patients with Lynch syndrome-associated malignancies and clinically matches the Amsterdam II criteria. The proband, a female, first had an endometrial cancer at the age of 49 and then mantle cell lymphoma, colonic and gastric adenocarcinomas and neuroendocrine carcinoma, successively. Her mother also had Lynch syndrome-associated malignancies, including colonic, uterine and gastric cancers, and her elder son had rectal cancer. In the germline of the proband and her son, an MSH2 missense mutation c.1808A>T was discovered. Immunohistochemical analyses indicated that the expression of the MSH2 protein was decreased in the tumors, such as gastric cancer and neuroendocrine carcinoma, due to the missense mutation c.1808A>T. This study showed that the MSH2 missense mutation c.1808A>T (Asp603Val) is a likely pathogenic mutation and is responsible for typical Lynch syndrome-associated malignancies, including neuroendocrine carcinoma.

Glucose Increases Hepatic Mitochondrial Antioxidant Enzyme Activities in Insulin Resistant Rats Following Chronic Angiotensin Receptor Blockade.

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world's population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1ß) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.

Guidewire-assisted over-the-scope clip delivery method into the distal intestine: a case series.

BACKGROUND: The Over-the-scope clip (OTSC) has been recently introduced for multiple purposes, including refractory bleeding, perforation, fistula, and anastomotic dehiscence of the gastrointestinal tract. However, no easy access techniques for delivering OTSCs to distant sites have been described. Therefore, we have developed a simple and safe guidewire-assisted OTSC delivery (GOD) method for use on the distal intestine. This study aimed to investigate the technical feasibility and safety of the method. MATERIAL AND METHODS: Between June 2018 and April 2019, all eight patients who underwent the GOD method were retrospectively examined. The primary outcome was the successful rate of OTSC delivery to the lesion without complications. The secondary outcomes were GOD procedure time, total procedure time, technical and clinical OTSC success rates, and GOD- and OTSC-associated complications. RESULTS: The rate of successful OTSC delivery was 100%. The median procedure time of GOD was 21 min (range 8-29). The median total procedure time was 38.5 min (range 26-41). The technical and clinical success rates of OTSC were 100% and 75% (6/8), respectively. No GOD- or OTSC-associated complications occurred. CONCLUSIONS: The GOD method is a feasible and safe technique for delivering OTSC toward the small and proximal large intestine.

Long-term outcomes of over-the-scope clip for refractory gastrointestinal diseases.

BACKGROUND: The Over-The-Scope Clip (OTSC) can effectively treat refractory gastrointestinal diseases. However, most reports have focused on short-term effectiveness. We examined clinical outcomes of the deployed clips and long-term characteristics. MATERIAL AND METHODS: Of 47 patients with OTSC treatment, 35 with follow-up periods of ≥3 months were retrospectively examined. The indications were 11 bleedings, 17 perforations, and seven fistulas. The observation period was defined as medium-term (3 to <12 months) or long-term (≥12 months). The primary outcome was the clinical success rate without disease recurrence. The secondary outcomes were the complication rate, survival duration, and clip retention rate. RESULTS: The medium- and long-term clinical success rates were 100% during the observation period (median, 44 months; range, 3-78 months). The complication rate was 2.9% (n = 1). The median survival time was 1,634 days for bleeding, 1,757 days for perforation, and 444 days for fistulas. The overall clip retention rates were 56.4%, 38.1%, 30.9%, and 25.9% after one, six, and 12 months and at the final follow-up, respectively. The average clip retention duration was 244 days in bleeding, 656 days in perforations, and 188 days in fistulas. CONCLUSIONS: Regardless of clip detachment, the OTSC can be effective in long-term.

Wafer paper and ring-mounted polyglycolic acid sheet method for shielding artificial gastric floor.

BACKGROUND: The management of postoperative bleeding, after gastric endoscopic submucosal dissection (ESD), has become particularly important because of the recent increase in antithrombotic use. Endoscopic shielding with polyglycolic acid (PGA) sheets has been shown to be effective. However, shrinkage and early displacement of the sheet remain challenges. This study aimed to determine the efficacy and safety of our developed method, named wafer paper and ring-mounted PGA sheet (WaRP). MATERIAL AND METHODS: Twenty-four patients with antithrombotic uptake who underwent the WaRP method following gastric ESD were retrospectively examined. This involved the delivery of a PGA sheet wrapped in wafer paper with ring-thread, and its fixation on the gastric floor using hemoclips. The primary outcome was the technical success rate of the WaRP, and several secondary outcomes were evaluated. RESULTS: The technical success rate of WaRP was 100%. The procedure lasted a mean of 10.5 min (SD 6.7 min). The prevalence of complete retention at follow-up endoscopy was 83.3% (20/24). There were no WaRP-associated complications, but post-ESD hemorrhage occurred in two patients undergoing hemodialysis (8.3%). CONCLUSIONS: The WaRP method is a simple and reliable means of PGA sheet delivery and placement that reduces the incidence of post-ESD hemorrhage.

Renal NG2-expressing cells have a macrophage-like phenotype and facilitate renal recovery after ischemic injury.

Pericytes play an important role in the recovery process after ischemic injury of many tissues. Brain pericytes in the peri-infarct area express macrophage markers in response to injury stimuli and are involved in neovascularization. In the kidney, nerve/glial antigen 2 (NG2)+ pericytes have been found to accumulate after renal injury. These accumulated NG2+ cells are not involved in scar formation. However, the role of accumulated NG2+ cells in injured kidneys remains unknown. Here, using a reversible ischemia-reperfusion (I/R) model, we found that renal NG2+ cells were increased in injured kidneys and expressed macrophage markers (CD11b or F4/80) on day 3 after reperfusion. Isolated NG2+ cells from I/R kidneys also had phagocytic activity and expressed anti-inflammatory cytokine genes, including mannose receptor and IL-10. These macrophage-like NG2+ cells did not likely differentiate into myofibroblasts because they did not increase α-smooth muscle actin expression. Intravenous transfusion of renal NG2+ cells isolated from donor mice on day 3 after reperfusion into recipient mice on day 1 after I/R surgery revealed that NG2+ cell-injected mice had lower plasma blood urea nitrogen, reduced kidney injury molecule-1 mRNA expression, ameliorated renal damage, and reduced cellular debris accumulation compared with PBS-injected mice on day 5 after reperfusion. In conclusion, these data suggest that renal NG2+ cells have an M2 macrophage-like ability and play a novel role in facilitating the recovery process after renal I/R injury.NEW & NOTEWORTHY Brain pericytes have macrophage-like activities after injury. However, such properties of pericytes in peripheral tissues have not been investigated. Here, we provide evidence that nerve/glial antigen 2-positive cells increase after renal injury. The population of nerve/glial antigen 2-positive cells, which does not increase expression of myofibroblast-associated gene, express macrophage markers and anti-inflammatory cytokine genes, have phagocytic activity, and play a role in renal recovery after kidney injury.

Chronic AT1 blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.

Sodium/glucose cotransporter 2 and renoprotection: From the perspective of energy regulation and water conservation.

Sodium/glucose cotransporter 2 (SGLT2) is a renal low-affinity high-capacity sodium/glucose cotransporter expressed in the apical membrane of the early segment of proximal tubules. SGLT2 reabsorbs filtered glucose in the kidney, and its inhibitors represent a new class of oral medications used for type 2 diabetes mellitus, which act by increasing glucose and sodium excretion in urine, thereby reducing blood glucose levels. However, clinical trials showed marked improvement of renal outcomes, even in nondiabetic kidney diseases, although the underlying mechanism of this renoprotective effect is unclear. We showed that long-term excretion of salt by the kidneys, which predisposes to osmotic diuresis and water loss, induces a systemic body response for water conservation. The energy-intensive nature of water conservation leads to a reprioritization of systemic body energy metabolism. According to current data, use of SGLT2 inhibitors may result in similar reprioritization of energy metabolism to prevent dehydration. In this review article, we discuss the beneficial effects of SGLT2 inhibition from the perspective of energy metabolism and water conservation.

Effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, on sodium dynamics in hypertensive subtotally nephrectomized rats.

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.

A multicentre confirmatory single-arm trial of the safety and efficacy of a transanal drain for prevention of anastomotic leakage after surgery for rectal cancer.

AIM: Recent reports have described the use and efficacy of several types of transanal tube (TAT) for preventing anastomotic leakage by reducing intraluminal pressure. The aim of this study was to evaluate the safety and efficacy of a newly developed TAT for the prevention of anastomotic leakage after low anterior resection (LAR) for rectal cancer. METHOD: A multicentre confirmatory single-arm trial was designed to evaluate the safety and efficacy of a new TAT after LAR for rectal cancer. A total of 115 patients were registered in the trial at several cancer centres and other hospitals. All patients initially received reconstruction with a stapled anastomosis, but 18 then underwent creation of a diverting stoma. Of the remaining 97 patients, the first 96 were included in the protocol-defined primary analysis set. The primary outcome was the incidence of symptomatic leakage and the secondary endpoint was the incidence of complications associated with use of the TAT. The TAT was placed during LAR without creating a covering stoma and the drain was removed 4 or 5 days postoperatively. RESULTS: The rate of symptomatic leakage was 5.2% (95% confidence interval 1.7-11.7), which was significantly lower than the predetermined threshold value of 15.8% (one-sided p-value 0.0013). Only one patient had Grade 3 rectal bleeding that might have been related to use of the TAT. CONCLUSION: This nonrandomized study shows that the TAT appears to be safe and results in lower rates of anastomotic leakage in LAR compared with previous studies.

Luseogliflozin, a SGLT2 Inhibitor, Does Not Affect Glucose Uptake Kinetics in Renal Proximal Tubules of Live Mice.

Proximal tubules (PTs) take up most of the glucose in the glomerular filtrate and return it to peritubular capillary blood. Sodium-glucose cotransporter 2 (SGLT2) at the apical membrane takes up glucose into the cell. Glucose then flows across the cells and is transported to the interstitium via glucose transporter 2 (GLUT2) at the basolateral membrane. However, glucose transport under SGLT2 inhibition remains poorly understood. In this study, we evaluated the dynamics of a fluorescent glucose analog, 2-NBDG, in the PTs of live mice treated with or without the SGLT2 inhibitor, luseogliflozin. We employed real-time multiphoton microscopy, in which insulin enhanced 2-NBDG uptake in skeletal muscle. Influx and efflux of 2-NBDG in PT cells were compared under hypo-, normo-, and hyperglycemic conditions. Luseogliflozin did not exert significant effects on glucose influx parameters under any level of blood glucose. Our results suggest that blood glucose level per se does not alter glucose influx or efflux kinetics in PTs. In conclusion, neither SGLT2 inhibition nor blood glucose level affect glucose uptake kinetics in PTs. The former was because of glucose influx through basolateral GLUT2, which is an established bidirectional transporter.

Cardioprotective Effects of a Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, in Dahl Salt-Sensitive Hypertensive Rats.

We investigated the effects of esaxerenone, a novel, nonsteroidal, and selective mineralocorticoid receptor blocker, on cardiac function in Dahl salt-sensitive (DSS) rats. We provided 6-week-old DSS rats a high-salt diet (HSD, 8% NaCl). Following six weeks of HSD feeding (establishment of cardiac hypertrophy), we divided the animals into the following two groups: HSD or HSD + esaxerenone (0.001%, w/w). In survival study, all HSD-fed animals died by 24 weeks of age, whereas the esaxerenone-treated HSD-fed animals showed significantly improved survival. We used the same protocol with a separate set of animals to evaluate the cardiac function by echocardiography after four weeks of treatment. The results showed that HSD-fed animals developed cardiac dysfunction as evidenced by reduced stroke volume, ejection fraction, and cardiac output. Importantly, esaxerenone treatment decreased the worsening of cardiac dysfunction concomitant with a significantly reduced level of systolic blood pressure. In addition, treatment with esaxerenone in HSD-fed DSS rats caused a reduced level of cardiac remodeling as well as fibrosis. Furthermore, inflammation and oxidative stress were significantly reduced. These data indicate that esaxerenone has the potential to mitigate cardiac dysfunction in salt-induced myocardial injury in rats.

Screening of Promising Chemotherapeutic Candidates from Plants against Human Adult T-Cell Leukemia/Lymphoma (VII): Active Principles from Thuja occidentalis L.

During the screening of novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, we identified that the extracts of Thuja occidentalis (Cupressaceae) showed potent anti-proliferative activity in MT-1 and MT-2 cells. Therefore, we attempted to isolate the active components from this plant. We isolated and identified 32 compounds (1-32; eight lignans, 18 terpenoids, and six flavonoids) from the extracts of the leaves and cones. Their structures were determined by spectroscopic analysis. Several of the isolated compounds inhibited the growth of both cell lines. Lignans showed more potent activity than other classes of compounds. A comparison of the activities of compounds 1-8 revealed that the presence of a trans-lactone (linkage of C-6 to C-7) correlated with increased activity. Diterpenes showed moderate activity, and the presence of a ketone moiety at the C-7 position correlated with increased activity in compounds 12-21. In addition, biflavones showed moderate activity, and the presence of methoxy functions appeared to influence the activity of these compounds. Several lignans were lead compound of anti-cancer reagent (etoposide). In conclusion, not only lignans, but also diterpenes and/or biflavones, may be promising candidates for the treatment of adult T-cell leukemia/lymphoma.

Lipopolysaccharide induces filtrate leakage from renal tubular lumina into the interstitial space via a proximal tubular Toll-like receptor 4-dependent pathway and limits sensitivity to fluid therapy in mice.

Sustained oliguria during fluid resuscitation represents a perplexing problem in patients undergoing therapy for septic acute kidney injury. Here, we tested whether lipopolysaccharide induces filtrate leakage from the proximal tubular lumen into the interstitium, thus disturbing the recovery of urine output during therapy, such as fluid resuscitation, aiming to restore the glomerular filtration rate. Intravital imaging of the tubular flow rate in the proximal tubules in mice showed that lipopolysaccharide did not change the inflow rate of proximal tubule filtrate, reflecting an unchanged glomerular filtration rate, but significantly reduced the outflow rate, resulting in oliguria. Lipopolysaccharide disrupted tight junctions in proximal tubules and induced both paracellular leakage of filtered molecules and interstitial accumulation of extracellular fluid. These changes were diminished by conditional knockout of Toll-like receptor 4 in the proximal tubules. Importantly, these conditional knockout mice showed increased sensitivity to fluid resuscitation and attenuated acute kidney injury. Thus, lipopolysaccharide induced paracellular leakage of filtrate into the interstitium via a Toll-like receptor 4-dependent mechanism in the proximal tubules of endotoxemic mice. Hence, this leakage might diminish the efficacy of fluid resuscitation aiming to maintain renal hemodynamics and glomerular filtration rate.