Hyperbaric oxygen preconditioning normalizes scrotal temperature, sperm quality, testicular structure, and erectile function in adult male rats subjected to exertional heat injury.

Testicular hyperthermia has been noted in men who work in high ambient temperatures. Scrotal temperatures above the normal range caused germ cell loss in the testes and resulted in male subfertility. In adult male rats, exercising at a higher environmental temperature (36 °C with relative humidity of 50%, 52 min) caused exertional heat stroke (EHS) characterized by scrotal hyperthermia, impaired sperm quality, dysmorphology in testes, prostates and bladders, and erectile dysfunction. Here, we aim to ascertain whether hyperbaric oxygen preconditioning (HBOP: 100% O2 at 2.0 atm absolute [ATA] for 2 h daily for 14 days consequently before the onset of EHS) is able to prevent the problem of EHS-induced sterility, testes, prostates, and bladders dysmorphology and erectile dysfunction. At the end of exertional heat stress compared to normobaric air (NBA or non-HBOP) rats, the HBOP rats exhibited lower body core temperature (40 °C vs. 43 °C), lower scrotal temperature (34 °C vs. 36 °C), lower neurological severity scores (2.8 vs. 5.8), higher erectile ability, (5984 mmHg-sec vs. 3788 mmHg-sec), higher plasma testosterone (6.8 ng/mL vs. 3.5 ng/mL), lower plasma follicle stimulating hormone (196.3 mIU/mL vs. 513.8 mIU/mL), lower plasma luteinizing hormone (131 IU/L vs. 189 IU/L), lower plasma adrenocorticotropic hormone (5136 pg/mL vs. 6129 pg/mL), lower plasma corticosterone (0.56 ng/mL vs. 1.18 ng/mL), lower sperm loss and lower values of histopathological scores for epididymis, testis, seminal vesicle, prostate, and bladder. Our data suggest that HBOP reduces body core and scrotal hyperthermia and improves sperm loss, testis/prostate/bladder dysmorphology, and erectile dysfunction after EHS in rats.

Efficacy and safety of once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in kidney transplant recipients: A meta-analysis and trial sequential analysis.

BACKGROUND: Kidney transplantation is the most important treatment for end-stage renal disease. Immunosuppressive therapies can prevent acute rejection for kidney transplant recipients. Tacrolimus is usually administered to prevent graft rejection after transplantation. Previous studies have indicated that once-daily tacrolimus may improve medication adherence. Therefore, this meta-analysis aimed to compare clinical outcomes between once-daily and twice-daily tacrolimus in de novo renal transplant patients. METHODS: Eligible studies were identified from the Cochrane Library Database, PubMed, and Embase until July 2022. Those randomized controlled trials (RCTs) evaluating once-daily versus twice-daily tacrolimus formulations in de novo renal transplantation were included. A summary risk ratio (RR) and standardized mean difference (SMD) with the 95% confidence interval (CI) were estimated using a random-effects model. RESULTS: In total, nine RCTs were included. There were no differences in biopsy-confirmed acute rejection rates between patients with once-daily and those with twice-daily tacrolimus (RR, 0.91; 95% CI, 0.73-1.13) in 12 months. Regarding renal function, there was no significant difference between the once-daily and twice-daily tacrolimus groups (SMD, -0.03; 95% CI, -0.12 to 0.07). In addition, the risk of graft failure, death, and adverse events in the first year was similar for the once-daily and twice-daily tacrolimus groups. CONCLUSION: Our major findings suggest that de novo renal transplantation recipients receiving once-daily tacrolimus immediately after transplantation have comparable efficacy and safety with those recipients who received twice-daily tacrolimus. Therefore, once-daily tacrolimus medication can be an alternative for de novo renal transplantation recipients.

Uncovering the Inhibitory Molecular Mechanism of Pomegranate Peel to Urinary Bladder Urothelial Carcinoma Using Proteomics Techniques.

Pomegranate (Punica granatum L.) fruit demonstrates the repressive effectiveness of many tumors. Our previous studies showed that the PEP (pomegranate peel extract) E2 fraction obtained from the ethyl acetate layer of the pomegranate peel's ethanol extract exhibited the highest inhibitory activities to induce Urinary bladder urothelial carcinoma (UBUC) cell apoptosis. The ethyl acetate layer could lower the volume and weight of T24 tumors and initiate apoptosis in nude mice xenografted bladder tumors. In this study, we intended to clarify the inhibitory molecular process of Taiwanese local pomegranate peel to urinary bladder urothelial carcinoma using a proteomics strategy. Gel-based proteomics (two-dimensional gel electrophoresis coupled with tandem mass spectrometry) was used to get an insight into the molecular mechanisms initiated by PEPE2 to evoke bladder cancer cell apoptosis. We found eleven down-regulated and eight up-regulated proteins in PEPE2-treated T24 cells. Our results implied that these PEPE2-dysregulated proteins belong to cell apoptosis, cell proliferation, death receptor signaling, JAK/STAT signaling, the PPAR pathway, the PPARα/RXR α pathway, Rho family GTPase signaling, and RhoGDI signaling. In addition, HSP90 and PTP1B proteins, associated with apoptosis, were de-regulated in xenografted bladder tumors in nude mice fed with an ethyl acetate layer of ethanol extract. The findings above implied that pomegranate might be a potential chemopreventive resource for UBUC carcinogenesis.

Therapeutic Effect of Platelet-Rich Plasma Improves Bladder Overactivity in the Pathogenesis of Ketamine-Induced Ulcerative Cystitis in a Rat Model.

The present study attempted to elucidate whether intravesical instillation of platelet-rich plasma (PRP) could decrease bladder inflammation and ameliorate bladder hyperactivity in ketamine ulcerative cystitis (KIC) rat model. Female Sprague Dawley (S-D) rats were randomly divided into control group, ketamine-treated group, ketamine with PRP treated group, and ketamine with platelet-poor plasma (PPP) treated group. Cystometry and micturition frequency/volume studies were performed to investigate bladder function. The morphological change of bladder was investigated by Mason's trichrome staining. Western blotting analysis were carried out to examine the protein expressions of inflammation, urothelial differentiation, proliferation, urothelial barrier function, angiogenesis and neurogenesis related proteins. The results revealed that treatment with ketamine significantly deteriorated bladder capacity, decreased voiding function and enhanced bladder overactivity. These pathological damage and interstitial fibrosis may via NF-κB/COX-2 signaling pathways and muscarinic receptor overexpression. PRP treatment decreased inflammatory fibrotic biosynthesis, attenuated oxidative stress, promoted urothelial cell regeneration, and enhanced angiogenesis and neurogenesis, thereafter recovered bladder dysfunction and ameliorate the bladder hyperactivity in KIC rat model. These findings suggested that the PRP therapy may offer new treatment options for those clinical KIC patients.

Zerumbone Suppresses the LPS-Induced Inflammatory Response and Represses Activation of the NLRP3 Inflammasome in Macrophages.

Zerumbone is a natural product isolated from the pinecone or shampoo ginger, Zingiber zerumbet (L.) Smith, which has a wide range of pharmacological activities, including anti-inflammatory effects. However, the effects of zerumbone on activation of the NLRP3 inflammasome in macrophages have not been examined. This study aimed to examine the effects of zerumbone on LPS-induced inflammatory responses and NLRP3 inflammasome activation using murine J774A.1 cells, murine peritoneal macrophages, and murine bone marrow-derived macrophages. Cells were treated with zerumbone following LPS or LPS/ATP treatment. Production of nitric oxide (NO) was measured by Griess reagent assay. The levels of IL-6, TNF-α, and IL-1ß secretion were analyzed by ELISA. Western blotting analysis was performed to determine the expression of inducible NO synthase (iNOS), COX-2, MAPKs, and NLRP3 inflammasome-associated proteins. The activity of NF-κB was determined by a promoter reporter assay. The assembly of NLRP3 was examined by immunofluorescence staining and observed by confocal laser microscopy. Our experimental results indicated that zerumbone inhibited the production of NO, PGE2 and IL-6, suppressed the expression of iNOS and COX-2, repressed the phosphorylation of ERK, and decreased the activity of NF-κB in LPS-activated J774A.1 cells. In addition, zerumbone suppressed the production of IL-1ß and inhibited the activity of NLRP3 inflammasome in LPS/ATP- and LPS/nigericin-activated J774A.1 cells. On the other hand, we also found that zerumbone repressed the production of NO and proinflammatory cytokines in LPS-activated murine peritoneal macrophages and bone marrow-derived macrophages. In conclusion, our experimental results demonstrate that zerumbone effectively attenuates the LPS-induced inflammatory response in macrophages both in vitro and ex vivo by suppressing the activation of the ERK-MAPK and NF-κB signaling pathways as well as blocking the activation of the NLRP3 inflammasome. These results imply that zerumbone may be beneficial for treating sepsis and inflammasome-related diseases.

Exertional heat stroke on fertility, erectile function, and testicular morphology in male rats.

The association of exertional heat stroke (EHS) and testicular morphological changes affecting sperm quality, as well as the association of EHS and hypothalamic changes affecting sexual behavior, has yet to be elucidated. This study aimed to elucidate the effects of EHS on fertility, erectile function, and testicular morphology in male rats. Animals were exercised at higher room temperature (36 ℃ relative humidity 50%) to induce EHS, characterized by excessive hyperthermia, neurobehavioral deficits, hypothalamic cell damage, systemic inflammation, coagulopathy, and multiple organ injury. In particular, EHS animals had erectile dysfunction (as determined by measuring the changes of intracavernosal pressure and mean arterial pressure in response to electrical stimulation of cavernous nerves). Rats also displayed testicular temperature disruption, poorly differentiated seminiferous tubules, impaired sperm quality, and atrophy of interstitial Leydig cells, Sertoli cells, and peri-tubular cells in the testicular tissues accompanied by no spermatozoa and broken cells with pyknosis in their seminal vesicle and prostatitis. These EHS effects were still observed after 3 days following EHS onset, at least. Our findings provide a greater understanding of the effect of experimentally induced EHS on masculine sexual behavior, fertility, stress hormones, and morphology of both testis and prostate.

AICAR Induces Apoptosis and Inhibits Migration and Invasion in Prostate Cancer Cells Through an AMPK/mTOR-Dependent Pathway.

Current clinical challenges of prostate cancer management are to restrict tumor growth and prohibit metastasis. AICAR (5-aminoimidazole-4-carbox-amide-1-ß-d-ribofuranoside), an AMP-activated protein kinase (AMPK) agonist, has demonstrated antitumor activities for several types of cancers. However, the activity of AICAR on the cell growth and metastasis of prostate cancer has not been extensively studied. Herein we examine the effects of AICAR on the cell growth and metastasis of prostate cancer cells. Cell growth was performed by MTT assay and soft agar assay; cell apoptosis was examined by Annexin V/propidium iodide (PI) staining and poly ADP ribose polymerase (PARP) cleavage western blot, while cell migration and invasion were evaluated by wound-healing assay and transwell assay respectively. Epithelial-mesenchymal transition (EMT)-related protein expression and AMPK/mTOR-dependent signaling axis were analyzed by western blot. In addition, we also tested the effect of AICAR on the chemosensitivity to docetaxel using MTT assay. Our results indicated that AICAR inhibits cell growth in prostate cancer cells, but not in non-cancerous prostate cells. In addition, our results demonstrated that AICAR induces apoptosis, attenuates transforming growth factor (TGF)-ß-induced cell migration, invasion and EMT-related protein expression, and enhances the chemosensitivity to docetaxel in prostate cancer cells through regulating the AMPK/mTOR-dependent pathway. These findings support AICAR as a potential therapeutic agent for the treatment of prostate cancer.

A Highly Sensitive Pressure-Sensing Array for Blood Pressure Estimation Assisted by Machine-Learning Techniques.

This work describes the development of a pressure-sensing array for noninvasive continuous blood pulse-wave monitoring. The sensing elements comprise a conductive polymer film and interdigital electrodes patterned on a flexible Parylene C substrate. The polymer film was patterned with microdome structures to enhance the acuteness of pressure sensing. The proposed device uses three pressure-sensing elements in a linear array, which greatly facilitates the blood pulse-wave measurement. The device exhibits high sensitivity (-0.533 kPa-1) and a fast dynamic response. Furthermore, various machine-learning algorithms, including random forest regression (RFR), gradient-boosting regression (GBR), and adaptive boosting regression (ABR), were employed for estimating systolic blood pressure (SBP) and diastolic blood pressure (DBP) from the measured pulse-wave signals. Among these algorithms, the RFR-based method gave the best performance, with the coefficients of determination for the reference and estimated blood pressures being R² = 0.871 for SBP and R² = 0.794 for DBP, respectively.

Synthesis of In-Plane Artificial Lattices of Monolayer Multijunctions.

Recently, monolayers of van der Waals materials, including transition metal dichalcogenides (TMDs), are considered ideal building blocks for constructing 2D artificial lattices and heterostructures. Heterostructures with multijunctions of more than two monolayer TMDs are intriguing for exploring new physics and materials properties. Obtaining in-plane heterojunctions of monolayer TMDs with atomically sharp interfaces is very significant for fundamental research and applications. Currently, multistep synthesis for more than two monolayer TMDs remains a challenge because decomposition or compositional alloying is thermodynamically favored at the high growth temperature. Here, a multistep chemical vapor deposition (CVD) synthesis of the in-plane multijunctions of monolayer TMDs is presented. A low growth temperature synthesis is developed to avoid compositional fluctuations of as-grown TMDs, defects formations, and interfacial alloying for high heterointerface quality and thermal stability of monolayer TMDs. With optimized parameters, atomically sharp interfaces are successfully achieved in the synthesis of in-plane artificial lattices of the WS2 /WSe2 /MoS2 at reduced growth temperatures. Growth behaviors as well as the heterointerface quality are carefully studied in varying growth parameters. Highly oriented strain patterns are found in the second harmonic generation imaging of the TMD multijunctions, suggesting that the in-plane heteroepitaxial growth may induce distortion for unique material symmetry.

An Effective and Well Tolerated Strategy of Bladder Preservation Therapy in Cisplatin-Ineligible Patients With Muscle-Invasive Bladder Cancer.

UNLABELLED: To investigate bladder preservation therapy with a well tolerated strategy, 30 patients with bladder cancer underwent concomitant chemoradiotherapy with weekly carboplatin. The 2-year overall survival was 75% for all patients, 43% and 95% for patients without adjuvant chemotherapy or with adjuvant chemotherapy separately. This strategy was well tolerated with 7% of Grade 3/4 late bladder toxicity. BACKGROUND: The purpose of this study was to determine the feasibility and clinical effectiveness of concurrent weekly carboplatin chemotherapy in conjunction with definite radiation with or without adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer. PATIENTS AND METHODS: Between April 2010 and December 2013, 30 patients with muscle-invasive bladder cancer were evaluated retrospectively in this study. Concurrent chemoradiotherapy (CCRT) with weekly carboplatin was initiated. CCRT was followed by 2 courses of carboplatin and gemcitabine limited to patients with Eastern Cooperative Oncology Group performance status < 3 and age < 80 years. RESULTS: Thirty patients were treated and all completed the CCRT protocol. Seven of 8 patients (88%) achieved a pathological complete response (pCR) with CCRT alone, and 18 of 22 patients (82%) treated with CCRT followed by adjuvant chemotherapy had a pCR. The median follow-up was 23.2 (range, 8.3-40.7) months. The median progression-free survival was 15.9 months for the CCRT group, and not sufficient to evaluate CCRT followed by adjuvant chemotherapy. The median overall survival with CCRT was 18.8 months, and had not yet been reached for CCRT with adjuvant chemotherapy. The protocol was well tolerated for adverse events. CONCLUSION: Our study has shown that concomitant chemotherapy using weekly carboplatin in the management of muscle-invasive bladder cancer is feasible and well tolerated, even in older patients. Additional adjuvant chemotherapy with 2 cycles of carboplatin and gemcitabine should be encouraged in physically fit patients. These results provide a basis for randomized studies to compare this approach with conventional therapy for patients who wish to preserve the bladder.

Synthesis of lateral heterostructures of semiconducting atomic layers.

Atomically thin heterostructures of transition-metal dichalcogenides (TMDs) with various geometrical and energy band alignments are the key materials for next generation flexible nanoelectronics. The individual TMD monolayers can be adjoined laterally to construct in-plane heterostructures, which are difficult to reach with the laborious pick-up-and-transfer method of the exfoliated flakes. The ability to produce copious amounts of high quality layered heterostructures on diverse surfaces is highly desirable but it has remained a challenging issue. Here, we have achieved a direct synthesis of lateral heterostructures of monolayer TMDs: MoS(2)-WS(2) and MoSe(2)-WSe(2). The synthesis was performed using ambient-pressure chemical vapor deposition (CVD) with aromatic molecules as seeding promoters. We discuss possible growth behaviors, and we examine the symmetry and the interface of these heterostructures using second-harmonic generation and atomic-resolution scanning TEM. We found that the one-dimensinal (1D) interface of the lateral heterostructures picks the zigzag direction of the lattice instead of the armchair direction. Our method offers a controllable synthesis to obtain high-quality in-plane heterostructures of TMD atomic layers with 1D interface geometry.

Increased risk of erectile dysfunction in patients with sudden sensorineural hearing loss: a nationwide, population-based cohort study.

OBJECTIVES: Previous studies have proposed that impaired cochlear blood perfusion and microvascular damage are important etiopathogenetic events in the development of sudden sensorineural hearing loss (SSHL). The purpose of this study was to test the hypothesis that SSHL is a risk factor for the development of erectile dysfunction (ED). STUDY DESIGN: A retrospective cohort study. SETTING: Population-based study of Taiwan National Health Insurance Research Database. METHODS: We compared male patients newly diagnosed with SSHL between January 1, 2001, and December 31, 2006 (N = 23,212), with age-matched controls (1:2) (N = 46,424). MAIN OUTCOME MEASURES: The incidence of ED at the end of 2009 was determined. RESULTS: After adjusting for potential confounding factors, we found an adjusted hazard ratio (HR) of 1.942 (95% confidence interval, 1.688-2.233, p < 0.05), showing that patients with SSHL were more likely to experience ED than the control population. When stratified by patients' age, the incidence of ED was 1.90-, 2.25-, and 1.84-fold higher for SSHL-diagnosed patients 16 to 34 years old (p = 0.0408), 35 to 49 years old (p < 0.0001), and 50 to 64 years old (p < 0.0001), respectively, than in the non-SSHL group. Hypertension and chronic renal disease comorbidities in patients with SSHL seemed to be associated with an increased risk of developing ED. CONCLUSION: SSHL may confer an independent risk of ED. This observation supports the assumption of the underlying vascular mechanism regarding the development of SSHL. Thus, clinicians managing SSHL patients should be aware of the potential of the development of ED. EVIDENCE LEVEL: 2B.