Carbohydrate-Mediated Pregnancy Gut Microbiota and Neonatal Low Birth Weight.

The effects of gut microbiota on the association between carbohydrate intake during pregnancy and neonatal low birth weight (LBW) were investigated. A prospective cohort study was conducted with 257 singleton-born mother-child pairs in Taiwan, and maternal dietary intake was estimated using a questionnaire, with each macronutrient being classified as low, medium, or high. Maternal fecal samples were collected between 24 and 28 weeks of gestation, and gut microbiota composition and diversity were profiled using 16S rRNA amplicon gene sequencing. Carbohydrates were the major source of total energy (56.61%), followed by fat (27.92%) and protein (15.46%). The rate of infant LBW was 7.8%, which was positively correlated with maternal carbohydrate intake. In the pregnancy gut microbiota, Bacteroides ovatus and Dorea spp. were indirectly and directly negatively associated with fetal growth, respectively; Rosenburia faecis was directly positively associated with neonatal birth weight. Maternal hypertension during pregnancy altered the microbiota features and was associated with poor fetal growth. Microbiota-accessible carbohydrates can modify the composition and function of the pregnancy gut microbiota, thus providing a potential marker to modulate deviations from dietary patterns, particularly in women at risk of hypertension during pregnancy, to prevent neonatal LBW.

Impact of Transgenerational Nutrition on Nonalcoholic Fatty Liver Disease Development: Interplay between Gut Microbiota, Epigenetics and Immunity.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent pediatric liver disorder, primarily attributed to dietary shifts in recent years. NAFLD is characterized by the accumulation of lipid species in hepatocytes, leading to liver inflammation that can progress to steatohepatitis, fibrosis, and cirrhosis. Risk factors contributing to NAFLD encompass genetic variations and metabolic disorders such as obesity, diabetes, and insulin resistance. Moreover, transgenerational influences, resulting in an imbalance of gut microbial composition, epigenetic modifications, and dysregulated hepatic immune responses in offspring, play a pivotal role in pediatric NAFLD development. Maternal nutrition shapes the profile of microbiota-derived metabolites in offspring, exerting significant influence on immune system regulation and the development of metabolic syndrome in offspring. In this review, we summarize recent evidence elucidating the intricate interplay between gut microbiota, epigenetics, and immunity in fetuses exposed to maternal nutrition, and its impact on the onset of NAFLD in offspring. Furthermore, potential therapeutic strategies targeting this network are also discussed.

The impact of diabetes on overactive bladder presentations and associations with health-seeking behavior in China, South Korea, and Taiwan: Results from a cross-sectional, population-based study.

BACKGROUND: This study aimed to explore the impact of diabetes on overactive bladder (OAB) presentations and related predictors of healthcare-seeking behavior among adults aged ≥ 40 years in China, Taiwan, and South Korea. METHODS: An internet-based survey was conducted to assess the prevalence of diabetes, OAB presentations, and self-perceived urinary symptoms by a multi-national sample of 8284 individuals who completed the survey between June 2, 2015 and July 31, 2015. Independent associations with health-seeking behavior for urinary symptoms were estimated with odds ratio (OR) with 95% confidence interval (95% CI) using multivariate logistic regression. RESULTS: Diabetes was reported in 13.6% of participants and OAB was 20.8%. Diabetic participants were older than non-diabetic participants in both sexes. Participants with diabetes reported a higher rate of OAB (43.1%) and increased bothersome symptoms associated with OAB than those without diabetes. Participants with diabetes (OR, 3.07 [2.39-3.96]], urgent incontinence (OR, 2.38 [1.86-3.03]), frequency (OR, 1.86 [1.45-2.38]), and nocturia (OR, 1.14 [1.05-1.24]) were associated with healthcare-seeking behavior. CONCLUSION: The proportion of diabetic participants with OAB was 2.5-fold higher than those without diabetes. Diabetes, urinary frequency, nocturia, and urgent incontinence are predictors of medical treatment-seeking behavior, but the key symptom of OAB-urgency is not a predictor of treatment-seeking behavior. It is important for clinicians to recognize the interplay between diabetes and OAB and to early identify various bothersome urinary symptoms for better health outcomes in daily practice.

A Higher Abundance of Actinomyces spp. in the Gut Is Associated with Spontaneous Preterm Birth.

Preterm birth is a major challenge in pregnancy worldwide. Prematurity is the leading cause of death in infants and may result in severe complications. Nearly half of preterm births are spontaneous, but do not have recognizable causes. This study investigated whether the maternal gut microbiome and associated functional pathways might play a key role in spontaneous preterm birth (sPTB). Two hundred eleven women carrying singleton pregnancies were enrolled in this mother-child cohort study. Fecal samples were freshly collected at 24-28 weeks of gestation before delivery, and the 16S ribosomal RNA gene was sequenced. Microbial diversity and composition, core microbiome, and associated functional pathways were then statistically analyzed. Demographic characteristics were collected using records from the Medical Birth Registry and questionnaires. The result showed that the gut microbiome of mothers with over-weight (BMI ≥ 24) before pregnancy have lower alpha diversity than those with normal BMI before pregnancy. A higher abundance of Actinomyces spp. was filtered out from the Linear discriminant analysis (LDA) effect size (LEfSe), Spearman correlation, and random forest model, and was inversely correlated with gestational age in sPTB. The multivariate regression model showed that the odds ratio of premature delivery was 3.274 [95% confidence interval (CI): 1.349; p = 0.010] in the group with over-weight before pregnancy with a cutoff Hit% > 0.022 for Actinomyces spp. The enrichment of Actinomyces spp. was negatively correlated with glycan biosynthesis and metabolism in sPTB by prediction from the Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) platform. Maternal gut microbiota showing a lower alpha diversity, increased abundance of Actinomyces spp., and dysregulated glycan metabolism may be associated with sPTB risk.

Reprogramming Effects of Postbiotic Butyrate and Propionate on Maternal High-Fructose Diet-Induced Offspring Hypertension.

Maternal nutrition has a key role in the developmental programming of adult disease. Excessive maternal fructose intake contributes to offspring hypertension. Newly discovered evidence supports the idea that early-life gut microbiota are connected to hypertension later in life. Short-chain fatty acids (SCFAs), butyrate, and propionate are microbiota-derived metabolites, also known as postbiotics. The present study aimed to determine whether maternal butyrate or propionate supplementation can protect offspring from hypertension using a maternal high-fructose (HF) diet rat model. Female Sprague Dawley rats were allocated during pregnancy and lactation to (1) regular chow (ND); (2) 60% high-fructose diet (HF); (3) HF diet plus butyrate (HFB, 400 mg/kg/day); and (4) HF diet plus propionate (HFP, 200 mmol/L). Male offspring were sacrificed at 12 weeks of age. The maternal HF diet impaired the offspring's BP, which was prevented by perinatal butyrate or propionate supplementation. Both butyrate and propionate treatments similarly increased plasma concentrations of propionic acid, isobutyric acid, and valeric acid in adult offspring. Butyrate supplementation had a more profound impact on trimethylamine N-oxide metabolism and nitric oxide parameters. Whilst propionate treatment mainly influenced gut microbiota composition, it directly altered the abundance of genera Anaerovorax, Lactobacillus, Macellibacteroides, and Rothia. Our results shed new light on targeting gut microbiota through the use of postbiotics to prevent maternal HF intake-primed hypertension, a finding worthy of clinical translation.

Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection.

Urinary tract infections (UTIs) are the most frequent bacterial infections in the clinical setting. Even without underlying anatomic or functional abnormalities, more than 40% of women experience at least one UTI in their lifetime, of which 30% develop recurrent UTIs (rUTIs) within 6 months. Conventional management with antibiotics for rUTIs may eventually lead to the development of multidrug-resistant uropathogens. Targeting of the pathogenicity of rUTIs, the evolution of uropathogenic Escherichia coli (UPEC), and inadequate host defenses by immune responses should be explored to provide non-antibiotic solutions for the management of rUTIs. The adaptive evolution of UPEC has been observed in several aspects, including colonization, attachment, invasion, and intracellular replication to invade the urothelium and survive intracellularly. Focusing on the antivirulence of UPEC and modulating the immunity of susceptible persons, researchers have provided potential alternative solutions in four categories: antiadhesive treatments (i.e., cranberries and D-mannose), immunomodulation therapies, vaccines, and prophylaxis with topical estrogen therapy and probiotics (e.g., Lactobacillus species). Combination therapies targeting multiple pathogenic mechanisms are expected to be a future trend in UTI management, although some of these treatment options have not been well established in terms of their long-term efficacy. Additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques.

Treating Neurogenic Lower Urinary Tract Dysfunction in Chronic Spinal Cord Injury Patients-When Intravesical Botox Injection or Urethral Botox Injection Are Indicated.

Lower urinary tract symptoms (LUTS), such as urgency, urinary incontinence, and/or difficulty voiding, hamper the quality of life (QoL) of patients with spinal cord injury (SCI). If not managed adequately, urological complications, such as urinary tract infection or renal function deterioration, may further deteriorate the patient's QoL. Botulinum toxin A (BoNT-A) injection within the detrusor muscle or urethral sphincter yields satisfactory therapeutic effects for treating urinary incontinence or facilitating efficient voiding; however, adverse effects inevitably follow its therapeutic efficacy. It is important to weigh the merits and demerits of BoNT-A injection for LUTS and provide an optimal management strategy for SCI patients. This paper summarizes different aspects of the application of BoNT-A injection for lower urinary tract dysfunctions in SCI patients and provides an overview of the benefits and drawbacks of this treatment.

Laparoendoscopic Single-Site Inguinal Herniorrhaphy: Experience of a Single Institute.

Background: Minimally invasive techniques for inguinal herniorrhaphy have focused on developing the laparoendoscopic single-site (LESS) procedure to improve cosmesis. Outcomes of total extraperitoneal (TEP) herniorrhaphy vary considerably because of being performed by different surgeons. We aimed to evaluate the perioperative characteristics and outcomes of patients undergoing the LESS-TEP approach for inguinal herniorrhaphy and to determine its overall safety and effectiveness. Methods: Data of 233 patients who underwent 288 laparoendoscopic single-site total extraperitoneal approach (LESS-TEP) herniorrhaphies at Kaohsiung Chang Gung Memorial Hospital between January 2014 and July 2021 were reviewed retrospectively. We reviewed the experiences and results of LESS-TEP herniorrhaphy performed by a single surgeon (CHC) using homemade glove access and standard laparoscopic instruments with a 50 cm long 30° telescope. Results: Among 233 patients, 178 patients had unilateral hernias and 55 patients had bilateral hernias. About 32% (n = 57) of patients in the unilateral group and 29% (n = 16) of patients in the bilateral group were obese (body mass index ≥ 25). The mean operative time was 66 min for the unilateral group and 100 min for the bilateral group. Postoperative complications occurred in 27 (11%) cases, which were minor morbidities except for one mesh infection. Three (1.2%) cases were converted to open surgery. Comparison of the variables between obese and non-obese patients found no significant differences in operative times or postoperative complications. Conclusion: LESS-TEP herniorrhaphy is a safe and feasible operation with excellent cosmetic results and a low rate of complication, even in obese patients. Further large-scale prospective controlled studies and long-term analyses are needed to confirm these results.

Platelet Lysate Therapy Attenuates Hypoxia Induced Apoptosis in Human Uroepithelial SV-HUC-1 Cells through Regulating the Oxidative Stress and Mitochondrial-Mediated Intrinsic Apoptotic Pathway.

(1) Background: Ischemia/hypoxia plays an important role in interstitial cystitis/bladder pain syndrome (IC/BPS). Platelet-rich plasma (PRP) has been shown to relieve symptoms of IC/BPS by regulating new inflammatory processes and promoting tissue repair. However, the mechanism of action of PRP on the IC/BPS bladder remains unclear. We hypothesize that PRP might protect the urothelium during ischemia/hypoxia by decreasing apoptosis. (2) Methods: SV-HUC-1 cells were cultured under hypoxia for 3 h and treated with or without 2% PLTGold® human platelet lysate (PL). Cell viability assays using trypan blue cell counts were examined. Molecules involved in the mitochondrial-mediated intrinsic apoptosis pathway, HIF1α, and PCNA were assessed by Western blot analysis. The detection of apoptotic cells and CM-H2DCFDA, an indicator of reactive oxygen species (ROS) in cells, was analyzed by flow cytometry. (3) Results: After 3 h of hypoxia, the viability of SV-HUC-1 cells and expression of PCNA were significantly decreased, and the expression of ROS, HIF1α, Bax, cytochrome c, caspase 3, and early apoptosis rate were significantly increased, all of which were attenuated by PL treatment. The addition of the antioxidant N-acetyl-L-cysteine (NAC) suppressed the levels of ROS induced by hypoxia, leading to inhibition of late apoptosis. (4) Conclusions: PL treatment could potentially protect the urothelium from apoptosis during ischemia/hypoxia by a mechanism that modulates the expression of HIF1α, the mitochondria-mediated intrinsic apoptotic pathway, and reduces ROS.

Role of Urological Botulinum Toxin-A Injection for Overactive Bladder and Voiding Dysfunction in Patients with Parkinson's Disease or Post-Stroke.

Botulinum toxin A (BoNT-A) paralyzes muscle by blocking acetylcholine release at the synaptic junction. BoNT-A has shown its therapeutic effects in neurological disorders such as Parkinson's disease (PD) and post-stroke spasticity. A high proportion of patients with PD and post-stroke develop neurogenic detrusor overactivity (nDO) and then develop urinary incontinence and overactive bladder (OAB) symptoms. This study aimed to disclose the safety and efficacy of BoNT-A injection in treating bladder and voiding dysfunction in PD and post-stroke patients by reviewing the current evidence. At present, intradetrusor injection of BoNT-A is a Food and Drug Administration (FDA)-approved third-line therapy for nDO and idiopathic OAB. Although intradetrusor injection of onaBoNT-A 200 U is already approved for nDO treatment, most researchers would like to manage PD and post-stroke patients by using onaBoNT-A 100 U intradetrusor injection to achieve long-term efficacy and reduce adverse effects. However, in contrast to its inclusion in the International Continence Society guidelines for PD treatment, the clinical use of BoNT-A for post-stroke patients is limited to experimental use due to the development of urinary retention in about one-fifth of patients. For treating urethral pseudodyssynergia, half of patients may respond to onaBoNT-A 100 U urethral injection. However, refinement is needed to reduce unwanted urinary incontinence.

Low-Energy Shock Wave Suppresses Prostatic Pain and Inflammation by Modulating Mitochondrial Dynamics Regulators on a Carrageenan-Induced Prostatitis Model in Rats.

A low-energy shock wave (LESW) has therapeutic effects on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); however, its mechanism of action remains unclear. We explored the effects of LESW on the prostate and mitochondrial dynamics regulators in a rat model of carrageenan-induced prostatitis. The imbalance of mitochondrial dynamics regulators may affect the inflammatory process and molecules and contribute to CP/CPPS. Male Sprague-Dawley rats received intraprostatic 3% or 5% carrageenan injections. The 5% carrageenan group also received LESW treatment at 24 h, 7 days, and 8 days. Pain behavior was evaluated at baseline, 1 week, and 2 weeks after a saline or carrageenan injection. The bladder and the prostate were harvested for immunohistochemistry and quantitative reverse-transcription polymerase chain reaction analysis. Intraprostatic carrageenan injection induced inflammatory reaction in the prostate and the bladder, decreased the pain threshold, and resulted in the upregulation of Drp-1, MFN-2, NLRP3 (mitochondrial integrity markers), substance P, and CGRP-RCP, whose effects were maintained for 1-2 weeks. LESW treatment suppressed carrageenan-induced prostatic pain, inflammatory reaction, mitochondrial integrity markers, and expression of sensory molecules. These findings support a link between the anti-neuroinflammatory effects of LESW in CP/CPPS and the reversal of cellular perturbations caused by imbalances in mitochondrial dynamics in the prostate.

Impaired insulin signaling at the bladder mucosa facilitates metabolic syndrome-associated bladder overactivity in rats with maternal and post-weaning fructose exposure.

BACKGROUND/PURPOSE: Metabolic syndrome (MetS) and overactive bladder might share common pathophysiologies. Environmental fructose exposure during pre- and postnatal periods of rats may program MetS-associated bladder overactivity. We explored the dysregulated insulin signalling at bladder mucosa, as a common mechanism, in facilitating bladder overactivity in rats with MetS induced by maternal and post-weaning fructose diet. METHODS: Male offspring of Sprague-Dawley rats were subject into 4 groups by maternal and post-weaning diets (i.e., Control/Control, Fructose/Control, Control/Fructose and Fructose/Fructose by diets). Micturition behavior was evaluated. Acidic ATP solution was used to elicit cystometric reflex along with insulin counteraction. Concentration-response curves to insulin were plotted. The canonical signalling pathway of insulin was evaluated in the bladder mucosal using Western blotting. Levels of detrusor cGMP and urinary NO2 plus NO3 were measured. RESULTS: Male offspring with any fructose exposure presents traits of MetS and bladder overactivity. We observed all fructose exposure groups have the poor urodynamic response to insulin during ATP solution stimulation and poor insulin-activated detrusor relaxation in organ bath study. Compared to controls, the Control/Fructose and Fructose/Fructose groups showed the increased phosphorylation levels of IRS1 (Ser307) and IRS2 (Ser731); thus, suppressed the downstream effectors and urinary NOx/detrusor cGMP levels. The Fructose/Control group showed the compensatory increase of phospho-AKT (Ser473) and phospho-eNOS/eNOS levels, but decreased in eNOS, phospho-eNOS, urinary NOx, and detrusor cGMP levels. CONCLUSION: Our results show dysregulated insulin signalling at bladder mucosa should be a common mechanism of MetS-associated bladder overactivity programmed by pre-and postnatal fructose diet.

Vinpocetine Ameliorates Metabolic-Syndrome-Associated Bladder Overactivity in Fructose-Fed Rats by Restoring Succinate-Modulated cAMP Levels and Exerting Anti-Inflammatory Effects in the Bladder Detrusor Muscle.

Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the effects of vinpocetine (a phosphodiesterase-1 inhibitor) and celecoxib (a selective cyclooxygenase-2 inhibitor) on MetS-associated bladder overactivity. Phenotypes of the overactive bladder, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with elevated succinate levels in the liver and serum and the downregulation of GPR91 in the liver and urinary bladder. Treatments with vinpocetine and celecoxib improved tissue fibrosis and ameliorated the overexpression of the inflammatory cytokines, such as IL-1ß, in the liver and bladder. In bladder organ bath studies, vinpocetine, but not celecoxib, treatment restored the contraction and relaxation responses of the detrusor muscle strip in response to KCl, carbachol, and forskolin stimulation. At a molecular level, vinpocetine and celecoxib treatments modulated the downstream messengers of GPR91 (i.e., ERK1/2 and JNK), suppressed NF-κB and IL-1ß expressions in the bladder, and prevented the fibrogenesis observed in FFRs. The exogenous application of succinate to a bladder organ bath significantly reduced the forskolin-induced cAMP production by the detrusor muscle, which was notably restored in the presence of vinpocetine. Together, these results suggest that vinpocetine may alleviate the MetS-associated bladder overactivity by restoring the succinate-modulated detrusor cAMP production and exerting the anti-inflammatory effects in the bladder detrusor muscle.

Protection by -Biotics against Hypertension Programmed by Maternal High Fructose Diet: Rectification of Dysregulated Expression of Short-Chain Fatty Acid Receptors in the Hypothalamic Paraventricular Nucleus of Adult Offspring.

The role of short-chain fatty acids (SCFAs) in the brain on the developmental programming of hypertension is poorly understood. The present study explored dysregulated tissue levels of SCFAs and expression of SCFA-sensing receptors in the hypothalamic paraventricular nucleus (PVN), a key forebrain region engaged in neural regulation of blood pressure of offspring to maternal high fructose diet (HFD) exposure. We further investigated the engagement of SCFA-sensing receptors in PVN in the beneficial effects of -biotics (prebiotic, probiotic, synbiotic, and postbiotic) on programmed hypertension. Maternal HFD during gestation and lactation significantly reduced circulating butyrate, along with decreased tissue level of butyrate and increased expression of SCFA-sensing receptors, GPR41 and olfr78, and tissue oxidative stress and neuroinflammation in PVN of HFD offspring that were rectified by oral supplement with -biotics. Gene silencing of GPR41 or olfr78 mRNA in PVN also protected adult HFD offspring from programmed hypertension and alleviated the induced oxidative stress and inflammation in PVN. In addition, oral supplement with postbiotic butyrate restored tissue butyrate levels, rectified expressions of GPR41 and olfr78 in PVN, and protected against programmed hypertension in adult HFD offspring. These data suggest that alterations in tissue butyrate level, expression of GPR41 and olfr78, and activation of SCFA-sensing receptor-dependent tissue oxidative stress and neuroinflammation in PVN could be novel mechanisms that underlie hypertension programmed by maternal HFD exposure in adult offspring. Furthermore, oral -biotics supplementation may exert beneficial effects on hypertension of developmental origin by targeting dysfunctional SCFA-sensing receptors in PVN to exert antioxidant and anti-inflammatory actions in the brain.

Metabolic Syndrome and Overactive Bladder Syndrome May Share Common Pathophysiologies.

Metabolic syndrome (MetS) is defined by a group of cardiovascular risk factors, including impaired glucose tolerance, central obesity, hypertension, and dyslipidemia. Overactive bladder (OAB) syndrome consists of symptoms such as urinary urgency, frequency, and nocturia with or without urge incontinence. The high prevalences of metabolic syndrome (MetS) and overactive bladder (OAB) worldwide affect quality of life and cause profound negative impacts on the social economy. Accumulated evidence suggests that MetS might contribute to the underlying mechanisms for developing OAB, and MetS-associated OAB could be a subtype of OAB. However, how could these two syndromes interact with each other? Based on results of animal studies and observations in epidemiological studies, we summarized the common pathophysiologies existing between MetS and OAB, including autonomic and peripheral neuropathies, chronic ischemia, proinflammatory status, dysregulation of nutrient-sensing pathways (e.g., insulin resistance at the bladder mucosa and excessive succinate intake), and the probable role of dysbiosis. Since the MetS-associated OAB is a subtype of OAB with distinctive pathophysiologies, the regular and non-specific medications, such as antimuscarinics, beta-3 agonist, and botulinum toxin injection, might lead to unsatisfying results. Understanding the pathophysiologies of MetS-associated OAB might benefit future studies exploring novel biomarkers for diagnosis and therapeutic targets on both MetS and OAB.

Salvage Radiotherapy Plus Androgen Deprivation Therapy for High-Risk Prostate Cancer with Biochemical Failure after High-Intensity Focused Ultrasound as Primary Treatment.

We conduct a retrospective analysis of salvage radiotherapy plus androgen deprivation therapy (SRT+ADT) for high-risk prostate cancer patients with biochemical failure after high-intensity focused ultrasound (HIFU) as the primary treatment. A total of 38 patients, who met the criteria of biochemical failure and were consecutively treated with SRT+ADT, were enrolled. All patients received intensity modulated radiotherapy with a median dose of 70 Gy to the clinical target volume. ADT was given before, during or after the course of SRT with the duration of ≦6 months (n = 14), 6−12 months (n = 12) or >12 months (n = 12). The median follow-up was 45.9 months. A total of 10 (26.3%) patients had biochemical failure after SRT+ADT. The cumulative 5-year biochemical progression free survival (b-PFS) and overall survival (OS) rate was 73.0% and 80.3%, respectively. A nadir prostate-specific antigen (nPSA) value 0.02 ng/mL was observed to predict the b-PFS in multivariate analysis. The 5-year b-PFS was 81.6% for those with nPSA < 0.02 compared with 25.0% with nPSA ≧ 0.02. The adverse effects related to SRT+ADT were mild in most cases and only three (8%) patients experienced grade 3 urinary toxicities. For high-risk prostate cancer after HIFU as primary treatment with biochemical failure, our study confirms the feasibility of SRT+ADT with high b-PFS, OS and low toxicity.

Maternal Acetate Supplementation Reverses Blood Pressure Increase in Male Offspring Induced by Exposure to Minocycline during Pregnancy and Lactation.

Emerging evidence supports that hypertension can be programmed or reprogrammed by maternal nutrition. Maternal exposures during pregnancy, such as maternal nutrition or antibiotic use, could alter the offspring's gut microbiota. Short-chain fatty acids (SCFAs) are the major gut microbiota-derived metabolites. Acetate, the most dominant SCFA, has shown its antihypertensive effect. Limited information exists regarding whether maternal acetate supplementation can prevent maternal minocycline-induced hypertension in adult offspring. We exposed pregnant Sprague Dawley rats to normal diet (ND), minocycline (MI, 50 mg/kg/day), magnesium acetate (AC, 200 mmol/L in drinking water), and MI + AC from gestation to lactation period. At 12 weeks of age, four groups (n = 8/group) of male progeny were sacrificed. Maternal acetate supplementation protected adult offspring against minocycline-induced hypertension. Minocycline administration reduced plasma acetic acid level, which maternal acetate supplementation prevented. Additionally, acetate supplementation increased the protein level of SCFA receptor G protein-coupled receptor 41 in the offspring kidneys. Further, minocycline administration and acetate supplementation significantly altered gut microbiota composition. Maternal acetate supplementation protected minocycline-induced hypertension accompanying by the increases in genera Roseburia, Bifidobacterium, and Coprococcus. In sum, our results cast new light on targeting gut microbial metabolites as early interventions to prevent the development of hypertension, which could help alleviate the global burden of hypertension.

The Prognostic Impact of Tumor Location in pT3N0M0 Upper Urinary Tract Urothelial Carcinoma: A Retrospective Cohort Study.

Background: We aimed to evaluate the impact of tumor location on cancer outcomes in patients with pT3N0M0 upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU) with bladder cuff excision. Materials and Methods: We retrospectively reviewed 302 patients with pT3N0M0 UTUC who underwent RNU with bladder cuff excision at our institution between 2005 and 2019, including 191 renal pelvis tumors and 111 ureteral tumors. Clinicopathologic characteristics were compared between renal pelvis and ureter urothelial carcinomas. Multivariate Cox proportional hazard regression was used to assess the association between outcomes and clinical factors. Outcomes of interest included intravesical recurrence-free survival (IVRFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and cancer-specific survival (CSS), which were measured using the Kaplan-Meier curve with a log-rank test. Results: A total of 302 patients underwent RNU with bladder cuff excision. During the median follow-up of 42.7 months, 70 (23.2%), 95 (31.5%), and 99 (32.8%) patients experienced intravesical recurrence, local recurrence, and distant metastasis, respectively. Seventy (23.2%) patients died from UTUC. Multivariate Cox regression analysis showed that tumor location was an independent predictor of local recurrence (HR = 2.05, p = 0.001), with borderline independent significance in intravesical recurrence (HR = 1.54, p = 0.074) and distant metastasis (HR = 1.45, p = 0.08). Kaplan-Meier analysis showed that ureter tumors had a worse 5-year local recurrence (log-rank p < 0.001) and borderline worse 5-year intravesical recurrence (log-rank p = 0.055) and 5-year distant metastasis (log-rank p = 0.073). Conclusion: Ureter tumors seem to be associated with worse oncological outcomes, especially with local recurrence in UTUC. Further large and long-term studies are warranted for investigating biological differences based on tumor location.

The Impact of Gut Microbiome on Maternal Fructose Intake-Induced Developmental Programming of Adult Disease.

Excessive or insufficient maternal nutrition can influence fetal development and the susceptibility of offspring to adult disease. As eating a fructose-rich diet is becoming more common, the effects of maternal fructose intake on offspring health is of increasing relevance. The gut is required to process fructose, and a high-fructose diet can alter the gut microbiome, resulting in gut dysbiosis and metabolic disorders. Current evidence from animal models has revealed that maternal fructose consumption causes various components of metabolic syndrome in adult offspring, while little is known about how gut microbiome is implicated in fructose-induced developmental programming and the consequential risks for developing chronic disease in offspring. This review will first summarize the current evidence supporting the link between fructose and developmental programming of adult diseases. This will be followed by presenting how gut microbiota links to common mechanisms underlying fructose-induced developmental programming. We also provide an overview of the reprogramming effects of gut microbiota-targeted therapy on fructose-induced developmental programming and how this approach may prevent adult-onset disease. Using gut microbiota-targeted therapy to prevent maternal fructose diet-induced developmental programming, we have the potential to mitigate the global burden of fructose-related disorders.

Low energy shock wave therapy attenuates mitochondrial dysfunction and improves bladder function in HCl induced cystitis in rats.

BACKGROUND: We examine the effects of low energy shock wave (LESW) on bladder and mitochondrial function in a rat model of HCl induced cystitis, and the influence of dynamic bladder filling volume on LESW responses. Dysregulation of mitochondria function may impact the urothelial barrier and contribute to bladder dysfunction in patients with Interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Female Sprague-Dawley rats underwent urethral catheterization and intravesical instillation of 0.2 ml of 0.4 N HCl (N = 32) or 0.2 ml saline (N = 8) kept for 90 s. After HCl instillation, the bladder received LESW treatment while filled with 0 ml, 0.2 ml or 0.4 ml saline or no LESW treatment. Continuous cystometry (CMG) was performed on day 8. The bladder was harvested after CMG for histology and Western blotting. RESULTS: HCl provoked bladder overactivity, bladder wall inflammation marked by infiltration of mast cells, increased bax/bcl2 ratio consistent with increased TUNEL staining and increased release of mitochondrial-integrity markers (cleaved caspase 3 and Cytochrome c). LESW treatment suppressed HCl provoked bladder overactivity in association with lower inflammatory reaction, mast cells infiltration, and a lower bax/bcl2 ratio also reflected by reduced TUNEL staining and mitochondrial-integrity markers irrespective of the volume of saline in bladder at the time of LESW. CONCLUSIONS: These findings support that antiinflammatory effect of LESW in chemical cystitis is associated with the reversal of the molecular-cellular perturbations in mitochondrial dependent intrinsic apoptotic pathway.