Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform.

Peritoneal mesothelioma (PM) is a rare malignancy with poor prognosis, representing about 10-15% of all mesothelioma cases. Herein we apply PM patient-derived tumor organoids (PTOs) in elucidating personalized HIPEC responses to bypass rarity of disease in generating preclinical data. Specimens were obtained from PM patients undergoing cytoreductive surgery with HIPEC. PTOs were fabricated with tumor cells suspended in ECM-hydrogel and treated with HIPEC regimen parameters. Viability and characterization analyses were performed post-treatment. Treatment efficacy was defined as ≥ 50% viability reduction and p < 0.05 compared to controls. From October 2020 to November 2022, 17 tumors from 7 patients were biofabricated into organoids, with 16/17 (94.1%) sites undergoing comparative 37° and 42° treatments with cisplatin and mitomycin C (MMC). Hyperthermic cisplatin and MMC enhanced cytotoxicity which reduced treatment viability by 25% and 22%, respectively, compared to normothermia. Heated cisplatin displayed the greatest cytotoxicity, with efficacy in 12/16 (75%) tumors and an average viability of 38% (5-68%). Heated MMC demonstrated efficacy in 7/16 (43.8%) tumors with an average treatment viability of 51% (17-92.3%). PTOs fabricated from distinct anatomic sites exhibited site-specific variability in treatment responses. PM PTOs exhibit patient and anatomic location treatment responses suggestive of underlying disease clonality. In PM organoids cisplatin is superior to MMC in HIPEC.

Effects of Xinjierkang on Nrf2/HO-1 expression in viral myocarditis mice models.

In this study, the changes of Nrf2/HO-1 and cytokines TNF-α, IL-6, IL-17 and IL-1ß in cardiac muscle cells of Viral myocarditis (VMC) mice were detected in order to clarify the mechanism of action of Xinjierkang (XJEK). One hundred and fifty healthy male BALBC mice were randomly divided into the normal group, model group, low-, medium- and high-dose XJEK groups, with 30 in each group. Replication of the VMC model in mice inoculated with CVB3m. Serum inflammatory factors TNF-α, IL-6, IL-17 and IL-1ß, Nrf2 and HO-1 protein levels in myocardial tissue were compared. The results showed that no apoptotic cells were found in the myocardium of normal mice. The percentage of cardiomyocyte apoptosis in the low, medium and high dose groups of XJEK was significantly lower than the model group (P <0.05). At 3, 7, 14, 21, and 28 days after inoculation, compared with the normal group, the TNF-α, IL-6, IL-17 and IL-1ß levels in the model group significantly increased (p < 0.05). After the administration of XJEK, compared with the model group, the TNF-α, IL-6, IL-17, and IL-1ß levels in the low-, middle-, and high-dose XJEK groups significantly decreased (p < 0.05). At 28 days after inoculation, compared with the normal group, the expressions of Nrf2 and HO-1 proteins in the myocardial tissue of the model group were significantly down-regulated (p < 0.05); and compared with the model group, the expressions of Nrf2 and HO-1 proteins in the low-, medium-, and high-dose XJEK groups were significantly up-regulated (p < 0.05) in a concentration-dependent manner. In conclusion, XJEK can prevent myocardial injury in VMC mice, and its mechanism of action may be related to improving myocardial cell apoptosis, inhibiting inflammatory response, and up-regulating the expression of Nrf2 and HO-1 proteins in myocardial tissue.

Efficacy of Eutectic Mixture of Local Anesthetics on Pain Control During Extracorporeal Shock Wave Lithotripsy: A Systematic Review and Meta-Analysis.

BACKGROUND The efficacy of a eutectic mixture of local anesthetics (EMLA) for pain control in extracorporeal shock wave lithotripsy is unclear. The aim of this study was to assess the effect of EMLA cream on pain control during extracorporeal shock wave lithotripsy. MATERIAL AND METHODS We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials to identify relevant randomized controlled trials that compared the pain control efficacies of EMLA vs. placebo. Study eligibility criteria, participants, and interventions: Randomized controlled trials that compared the effect of EMLA with placebo cream for patients underwent extracorporeal shock wave lithotripsy. Study appraisal and synthesis methods: Two review authors extracted data independently using a designed data extraction form and risk of bias by Cochrane Collaboration's tool. RESULTS Nine studies, including 10 randomized controlled trials with 1167 patients, were eligible. The EMLA group experienced less pain (mean difference, -0.47; 95% confidence interval, -0.78 to -0.16; p=0.003) and shorter duration of lithotripsy (mean difference, -1.70, 95% confidence interval: -2.31 to -1.10, p<0.0001) than the placebo group. There were no significant differences in the number of patients who needed extra intravenous medication (p=0.610), number of patients with insufficient extracorporeal shock wave lithotripsy pain control (p=0.530), and number of patients with opioid adverse effects (p=0.320). Limitations: Long interval between the studies, different kinds of lithotripters. CONCLUSIONS EMLA can reduce pain during the ESWL procedure.

The neuronal (pro)renin receptor and astrocyte inflammation in the central regulation of blood pressure and blood glucose in mice fed a high-fat diet.

We report here that the neuronal (pro)renin receptor (PRR), a key component of the brain renin-angiotensin system (RAS), plays a critical role in the central regulation of high-fat-diet (HFD)-induced metabolic pathophysiology. The neuronal PRR is known to mediate formation of the majority of angiotensin (ANG) II, a key bioactive peptide of the RAS, in the central nervous system and to regulate blood pressure and cardiovascular function. However, little is known about neuronal PRR function in overnutrition-related metabolic physiology. Here, we show that PRR deletion in neurons reduces blood pressure, neurogenic pressor activity, and fasting blood glucose and improves glucose tolerance without affecting food intake or body weight following a 16-wk HFD. Mechanistically, we found that a HFD increases levels of the PRR ligand (pro)renin in the circulation and hypothalamus and of ANG II in the hypothalamus, indicating activation of the brain RAS. Importantly, PRR deletion in neurons reduced astrogliosis and activation of the astrocytic NF-κB p65 (RelA) in the arcuate nucleus and the ventromedial nucleus of the hypothalamus. Collectively, our findings indicate that the neuronal PRR plays essential roles in overnutrition-related metabolic pathophysiology.

The Association between Metabolic Syndrome and Elevated Alanine Aminotransferase Levels in an Indigenous Population in Northern Taiwan: A Community-Based and Cross-Sectional Study.

Our study aims to determine the prevalence of metabolic syndrome (MetS) among the Northern Taiwanese indigenous population and to explore the relationship between MetS and liver enzyme, especially serum alanine transaminase (ALT). This is an observational and cross-sectional study that was conducted in remote villages of an indigenous community in Northern Taiwan between 2010 and 2015. MetS was defined based on the revised NCEP/ATPIII criteria from Taiwan Health Promotion Administration. A total of 454 participants were included in the analysis. There were 277 people with MetS and 177 people without. The prevalence of MetS was 61.01%. The average age was 49.50 years. People with MetS had a significantly higher liver enzyme (ALT) level than those without MetS. In addition, the study showed that participants with higher ALT had a tendency towards a higher prevalence of MetS (76.7% vs. 57.3%, p = 0.001). The adjusted odds ratio (OR) of ALT levels >36 U/L for MetS was 2.79 (95% CI = 1.24-6.27, p = 0.01). The area under the ROC curve (AUC) of the ALT level was 0.63 (95% CI = 0.58-0.68, p < 0.001), which showed that the ALT level was positively associated with MetS. The overall prevalence of MetS was 61.01% in the highland indigenous population in Northern Taiwan; this study indicated that higher serum ALT levels were associated with an increased risk of MetS.

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2.

Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-ß (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tract-binding protein 1 (PTBP1) promotes the retention of an intron in the 5'-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.

Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.

Isolation, purification, and properties of a novel small heat shock protein from the hyperthermophile Sulfolobus solfataricus.

The isolation, purification, and properties of a putative small heat shock protein (sHsp), named SsHSP14.1, from the hyperthermophilic archaeon Sulfolobus solfataricus have been investigated. The sHsp was successfully expressed and purified from Escherichia coli. In vivo chaperone function of SsHSP14.1 for preventing aggregation of proteins during heating was investigated. It was found that recombinant SsHSP14.1 with a molecular mass of 17.8 kDa prevented E. coli proteins from aggregating in vivo at 50 degrees C. This result suggested that SsHSP14.1 confers a survival advantage on mesophilic bacteria by preventing protein aggregation at supraoptimal temperatures. In vitro, the purified SsHSP14.1 protein was able to prevent Candida antarctica lipase B from aggregation for up to 60 min at 80 degrees C. Moreover, the SsHSP14.1 enhanced thermostability of bromelain extending its half-life at 55 degrees C by 67%.