AT-IAP (1-{6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one) was identified as a novel potent non-alanine small molecule dual inhibitor of cIAP1/XIAP protein. AT-IAP was assessed in preclinical species, demonstrating favorable bioavailability in rodent species and oral efficacy at 30 mg/kg in MDA-MB-231 mouse xenograft models. The major metabolic route of AT-IAP was identified to be CYP3A driven, resulting in low oral exposure in non-human primate (NHP) studies, given the comparatively high expression of equivalent CYP3A. AT-IAP metabolite identification studies determined ring opening of the morpholino or piperazine moiety. An extensive campaign of optimisation resulted in increased polarity by the addition of a hydroxymethyl, which led to the identification of tolinapant (1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H-pyrrolo[3,2- b]pyridin-1-yl)-2-[(2 R,5 R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one) with reduced CYP3A metabolism. Tolinapant showed oral bioavailability in rodents and NHP in the range 12-34% at 5 mg/kg. Non-linear pharmacokinetics in NHP were observed at oral doses in the range 5-75 mg/kg. Pharmacodynamic modulation and efficacy were demonstrated in A375 mouse xenograft models at dose ranges between 5 and 20 mg/kg. On-target engagement, as measured by reduction of cIAP 1 protein levels, was confirmed in NHP surrogate tissues and applied to target activity assessments in tolinapant phase1/2 clinical trials.

One third of epilepsy patients are resistant to treatment with current anti-seizure medications. The ketogenic diet is used to treat some forms of refractory epilepsy, but the mechanism of its action has not yet been elucidated. In this study, we aimed to investigate whether the hydroxycarboxylic acid receptor 2 (HCA2), a known immunomodulatory receptor, plays a role in mediating the protective effect of this diet. We demonstrate for the first time that selective agonists at this receptor can directly reduce seizures in animal models. Agonists also reduce network activity in rodent and human brain slices. Ketogenic diet is known to increase circulating levels of endogenous HCA2 agonists, and we show that the effect of ketogenic diet in reducing seizures in the 6 Hz seizure model is negated in HCA2-deficient mice. Our data support the potential of HCA2 as a target for the treatment of epilepsy and potentially for neurodegenerative diseases.

Cytokine release syndrome (CRS) can occur following cancer immunotherapies, but is most often mild and of limited duration. International Classification of Diseases (ICD)-10 codes allowing identification of CRS were introduced in 2020 but may be underutilized. We evaluated the performance of a published claims-based algorithm to detect CRS (any grade) and high-grade CRS (HG, grades 2-5), as well as identified indicators of HG CRS in retrospective data. Adults with low-grade and HG CRS during an encounter coinciding with administrations of blinatumomab or chimeric antigen receptor-T therapy were identified in three types of retrospective databases (hospital chargemaster data, electronic health records, and administrative claims). The algorithm's sensitivity in detecting any CRS and HG CRS was reported. A least absolute shrinkage and selection operator (LASSO) regression model was developed to identify indicators of HG CRS. Performance of the model was evaluated using area under the curve (AUC). The sensitivity of the algorithm to detect any grade CRS ranged between 77%-100% and between 8%-80% for HG CRS, depending on the type of database. The LASSO model identified hypotension, positive pressure (including mechanical ventilation), tocilizumab, and vasopressors as indicators of HG CRS. AUC varied between 60% and 75%. The algorithm accurately detected any grade CRS for over three-quarters of instances, but was not as reliable for HG CRS. Results varied based on database attributes. Hypotension, vasopressors, positive pressure, and tocilizumab were associated with HG CRS and may be methodologically helpful signals of CRS severity in retrospective data.

Patients with breast cancer experience various types of adverse events (AEs) during their treatment journey. We aimed to evaluate the incidence, characteristics, and impact of serious AEs in breast cancer patients receiving antineoplastic treatment in the ambulatory setting. A 4-month prospective observational study that included patients with breast cancer treated in the chemotherapy infusion clinics. Patients were assessed for serious AEs, defined as any AE that resulted in a visit to the emergency department (ED) with or without hospital admission, or required any clinical intervention, which were considered as the addition of supportive medications or modifications to the treatment protocol. Characteristics of the patients and antineoplastic regimens as well as the type of AEs were recorded. During the study period, 1168 patients received 2547 cycles. The mean age was 50 ± 11.6 (SD) years and patients had received a median (IQR) of 3 (1-5) treatment cycles prior to enrollment. Among the study cohort, 465 patients(40%) developed at least one serious AE. A total of 660 (26%) cycles were associated with 757 AEs, which required ED visits, addition of supportive medications, and modifications to the treatment protocol in 58%, 29%, and 17% of the cycles, respectively. Most common AEs were musculoskeletal (n = 132, 17%) and gastrointestinal (n = 125, 16.5%). Taxane-based regimens were associated with the most AEs (n = 286, 38%). In a cohort of patients with breast cancer treated in the ambulatory setting, 4 out of 10 patients developed at least one serious AE during the study period. Future research should identify measures to reduce the incidence and severity of such complications.

This sub-study sought to characterize the pharmacokinetics (PK) of favipiravir (FPV) within Thai adults and quantitatively assess differences in exposure to those previously reported in other populations as a basis to understand putative differences in efficacy between studies conducted in different regions. It was nested within a prospective trial of adults with symptomatic COVID-19 infection without pneumonia receiving 1800 mg FPV twice-daily on day 1 and 800 mg twice-daily thereafter. Individual PK profiles were fitted with a one-compartment disposition model (first-order absorption). Eight adults (seven female) with a median age of 39 years and BMI of 27.9 kg/m were included. Seven adults achieved plasma concentrations above the EC in vitro target (25 mg/L), with minimum-maximum concentrations decreasing with repeat dosing. The mean FPV apparent clearance observed in this study was 1.1 L/h (coefficient of variation [CV]: 60%), apparent volume of distribution 20.6 L (CV: 40%), absorption rate constant 6.1 h (CV: 100%), and 2.4 daily % change in apparent clearance (CV: 315%). Higher exposures were observed in these Thai adults compared with data from previous studies in Chinese, Japanese, and Turkish populations, respectively. Current FPV doses recommended in Thailand achieved target plasma concentrations with higher exposures than those described previously in other populations. The limited sample size prohibits firm conclusions from being drawn but the presented data warrants confirmation with a view to interrogate the appropriateness of doses used in randomized clinical trials that failed to demonstrate efficacy.

UGT2B10 is a phase II drug metabolizing enzyme with limited information on its role in the metabolism of drugs, especially in the pediatric hematopoietic stem cell transplantation setting. Previously, we investigated UGT2B10's role through in silico analyses and prioritized acetaminophen (APAP), lorazepam (LOR), mycophenolic acid (MPA), and voriconazole N-oxide (VCZ N-oxide) for in vitro investigations. In this report, we present in vitro screening of these candidates and of voriconazole (VCZ) to assess their potential to be substrates and/or inhibitors of UGT2B10. Enzyme kinetics experiments included recombinant UGT2B10 and analytical methods based on ultra high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS). To determine potential substrates, candidates were incubated at various therapeutically observed concentrations with recombinant UGT2B10 to identify the corresponding glucuronide metabolite. Inhibition capacity was tested using the selective probe cotinine for its glucuronidation to cotinine N-ß-d-glucuronide. IC was determined for compounds exhibiting inhibition. Among the tested compounds, LOR (IC = 0.01 μM, R = 0.9257) and MPA (IC = 0.38 mM, R = 0.9212) exhibited inhibition potential for UGT2B10. None of the other tested compounds featured inhibition potential and none of the compounds tested exhibited metabolism through UGT2B10. Further exploration on the clinical relevance of this inhibition using modeling strategies, overlapping nature with other UGT isoforms, and screening other molecules for their inhibition potential on UGT2B10 is warranted.

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre-clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13-week recovery period. In healthy humans receiving 1-25 mg of obicetrapib, the mean terminal half-life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6-fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post-treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half-life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.

Knowledge graphs, powerful tools that explicitly transfer knowledge to machines, have significantly advanced new knowledge inferences. Discovering unknown relationships between diseases and genes/proteins in biomedical knowledge graphs can lead to the identification of disease development mechanisms and new treatment targets. Generating high-quality representations of biomedical entities is essential for successfully predicting disease-gene/protein associations. We developed a computational model that predicts disease-gene/protein associations using the Precision Medicine Knowledge Graph, a biomedical knowledge graph. Embeddings of biomedical entities were generated using two different methods-a large language model (LLM) and the knowledge graph embedding (KGE) algorithm. The LLM utilizes information obtained from massive amounts of text data, whereas the KGE algorithm relies on graph structures. We developed a disease-gene/protein association prediction model, "Cross-Modal Embedding Integrator (CMEI)," by integrating embeddings from different modalities using a multi-head attention mechanism. The area under the receiver operating characteristic curve of CMEI was 0.9662 (± 0.0002) in predicting disease-gene/protein associations. In conclusion, we developed a computational model that effectively predicts disease-gene/protein associations. CMEI may contribute to the identification of disease development mechanisms and new treatment targets.

Acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition involves a complex pathomechanism, including inflammation, apoptosis, and fibrosis where long non-coding RNAs (lncRNAs) play a crucial role in their regulation. However, to date, only a few lncRNAs have been discovered to be involved in the AKI-to-CKD transition. Therefore, this study aims to investigate the dysregulated lncRNAs in the AKI-to-CKD transition in vitro and in vivo. To mimic AKI-to-CKD transition both in vivo and in vitro, bilateral ischemia-reperfusion (IR) kidney injury was performed in Wistar rats (male), and normal rat kidney epithelial cell (NRK52E) cells were treated with exogenous transforming growth factor-β1 (TGF-β1). Further processing and analysis of samples collected from these studies (e.g., biochemical, histopathology, immunofluorescence, and RNA isolation) were also performed, and transcriptomic analysis was performed to identify the dysregulated lncRNAs. Rats subjected to IR showed a significant increase in kidney injury markers (creatinine, blood urea nitrogen (BUN), kidney injury molecule-1(KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) along with altered cell morphology). Apoptosis, inflammation, and fibrosis markers were markedly increased during the AKI-to-CKD transition. Furthermore, transcriptomic analysis revealed 62 and 84 unregulated and 95 and 92 downregulated lncRNAs in vivo and in vitro, respectively. Additionally, functional enrichment analysis revealed their involvement in various pathways, including the tumor necrosis factor (TNF), wingless-related integration site (Wnt), and hypoxia-inducible factor-1 (HIF-1) signaling pathways. These identified dysregulated lncRNAs significantly contribute to AKI-to-CKD transition, and their knockin/out can aid in developing targeted therapeutic interventions against AKI-to-CKD transition.

Transient receptor potential melastatin-4 (TRPM4) forms a complex with N-methyl-D-aspartate receptors (NMDARs) that facilitates NMDAR-mediated neurotoxicity. Here we used pharmacological tools to determine how TRPM4 regulates NMDAR signaling. Brophenexin, a compound that binds to TRPM4 at the NMDAR binding interface, protected hippocampal neurons in culture from NMDA-induced death, consistent with published work. Brophenexin (10 μM) reduced NMDA-evoked whole-cell currents recorded at 22°C by 87% ± 14% with intracellular Ca chelated to prevent TRPM4 activation. Brophenexin inhibited NMDA-evoked currents recorded in Na-free solution by 87% ± 13%, suggesting that brophenexin and TRPM4 modulate NMDAR function. Incubating cultures in Mg-free buffer containing tetrodotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione, and bicuculline for 30 min inhibited NMDA-evoked increases in intracellular Ca concentration ([Ca]) recorded at 22°C by 50% ± 18% and prevented inhibition by brophenexin. In the absence of these inhibitors, brophenexin inhibited the NMDA-evoked response by 51% ± 16%. Treatment with the TRPM4 inhibitor 4-chloro-2-(1-naphthyloxyacetamido)benzoic acid (NBA; 10 μM) increased NMDA-evoked Ca influx by 90% ± 15%. Increasing extracellular NaCl to 237 mM, a treatment that activates TRPM4, inhibited the NMDA-evoked increase in [Ca] by a process that occluded the inhibition produced by brophenexin and was prevented by NBA. In recordings performed at 32°C-34°C, brophenexin inhibited the NMDA-evoked [Ca] response by 42% ± 10% but NBA was without effect. These results are consistent with a model in which TRPM4 interacts with NMDARs to potentiate Ca flux through the NMDAR ion channel and thus provides a potential mechanism for the neuroprotection afforded by NMDAR/TRPM4 interface inhibitors such as brophenexin.

The primary objective of the present review was to report the safety profile of oral ketorolac in adults using the systematic review and meta-analysis methodology based on clinical trials. The present study is a PRISMA-based systematic review and risk ratio (RR) meta-analysis of the adverse events reported in clinical trials that used oral ketorolac; the review includes 50 clinical trials. The RR for the comparison of a single intake of oral ketorolac versus placebo, including all types of adverse events, was RR = 2.59, IC95% (1.5102; 4.4360) with p = 0.02, the RR for the comparison of a multiple intakes of oral ketorolac versus placebo for all types of adverse events was RR = 1.39, IC95% (0.95; 2.05) with p = 0.093, the RR for the comparison of a single intake of oral ketorolac versus active drugs for all types of adverse events was RR = 0.61, IC95% (0.49; 0.77) with p < 0.0001, the RR for the comparison of multiple intakes of oral ketorolac versus active drugs for all types of adverse events was RR = 0.78, IC95%(0.65; 0.93) with p = 0.006. Multiple intakes of 5, 10, or 20 mg of oral ketorolac, in treatment over 1-10 days, do not increase the risk of adverse events compared to placebo and show a tendency to reduce the risk of adverse events compared to active drugs. When a single intake of ketorolac (5, 10, 20, or 30 mg) is compared to a placebo, the risk increases only for trivial and mild adverse events.

With the rapid progression of biotechnology, the significance translational research on glycolysis in molecular pharmacology has become increasingly evident. To deepen students' understanding of glycolytic processes and facilitate their comprehension of drug action mechanisms, we have developed a visual virtual simulation platform dedicated glycolysis. The educational approach commenced with theoretical lectures on glycolysis, followed by practical laboratory sessions where students measured glycolysis-related parameters such as hexokinase, pyruvate kinase, and lactate. Students then engaged with the virtual simulation training platform to explore glycolytic stress tests and positron emission tomography/computed tomography (PET/CT) imaging, with their progress tracked through an assessment mode. The study involved 67 s-year undergraduate students majoring in biomedical sciences, all of whom had received instruction in glucose metabolism theories and completed the associated questionnaires. The results showed that the students gained a deeper understanding of glycolysis and the clinical application of PET/CT imaging in the context of glycolysis. The majority also agreed that the integration of scientific and clinical cases in teaching is beneficial and that the project sparked their interest in scientific research. These findings align with existing literature that emphasizes the importance of innovative educational tools in enhancing student engagement and understanding of the underlying theories of the curriculum. This project designed an innovative glycolytic metabolism teaching system encompassing the monitoring of traditional glycolytic indicators, glycolytic stress tests, and PET/CT imaging based on glycolysis. The visual virtual simulation platform for glycolysis can serve as an innovative educational tool in the molecular pharmacology curriculum or other courses involving glycolysis, assisting students in deeply understanding the molecular mechanisms of glycolysis and its significance in disease and drug action.

Antiviral use has been linked to encephalopathy and elevated serum creatinine concentrations in individuals with chronic kidney disease (CKD) in case reports. Using linked healthcare data in Ontario, we conducted a population-based cohort study on adults aged ≥66 years not receiving dialysis and newly prescribed oral acyclovir, valacyclovir, or famciclovir in the outpatient setting (2008-2022) at higher versus lower doses. The primary composite outcome, a hospital visit with encephalopathy or acute kidney injury (AKI) within 14 days of initiating antiviral treatment, was examined in a primary cohort. AKI was assessed in a secondary cohort of older adults with CKD with available linked hospital-based laboratory (lab) data. We used inverse probability of treatment weighting on the propensity score to balance comparison groups on baseline health. Weighted risk ratios (RR) and risk differences (RD) were obtained using modified Poisson and binomial regression. In the primary cohort, higher- versus lower-dose antiviral was not associated with an increased 14-day risk of hospital visit with encephalopathy or AKI. However, Higher- versus lower-dose antiviral was associated with a higher risk of a hospital visit with AKI when assessed using lab values (weighted number of events, 70 of 8407 [0.83%] versus 18 of 8230 [0.22%], respectively; weighted RR, 3.83 [95% CI, 1.87-7.87]; weighted RD, 0.62% [95% CI, 0.37%-0.86%]). In older adults with CKD, starting an antiviral at a higher versus lower dose was associated with a higher risk of AKI, although the absolute risk of this event was <1%.

The study objective was to validate febuxostat dosage and administration in pediatric patients with hyperuricemia including gout, using an integrated population pharmacokinetic (PopPK) analysis in the Japanese population. Integrated PopPK analysis of febuxostat used a nonlinear mixed-effects modeling (NONMEM) program on plasma febuxostat concentration data for 2611 samples from Japanese pediatric patients with hyperuricemia including gout (n = 29) and from adult subjects who are healthy or have renal dysfunction (n = 113). We described febuxostat pharmacokinetics using an integrated PopPK model applicable both to pediatric patients and to the adult population. The covariates of body weight and eGFR were identified for CL/F and the covariate of fasted/fed status for bioavailability. The range of steady-state exposures (C and AUC) for 5, 10, 20, and 30 mg of febuxostat in fed pediatric patients weighing 20 to 40 kg was within that for 10, 20, 40, and 60 mg of febuxostat in fed pediatric patients and adults weighing 40 to 120 kg. Post hoc estimates of CL/F, adjusted by body weight, differed little between pediatric patients and the adult population in the renal function categories of normal, mild dysfunction, and moderate dysfunction. We successfully validated the febuxostat dose that provided the same level of exposure in pediatric patients as in the adult population: half the adult dose for pediatric patients weighing <40 kg and the full adult dose for pediatric patients weighing ≥40 kg. As in adults, the results support the use of febuxostat without dose adjustment in pediatric patients who have mild to moderate renal dysfunction.

The endocannabinoid system has garnered attention as a potential therapeutic target in a range of pathological disorders. Cannabinoid receptors type 2 (CB2) are a class of G protein-coupled receptors responsible for transmitting intracellular signals triggered by both endogenous and exogenous cannabinoids, including those derived from plants (phytocannabinoids) or manufactured synthetically (synthetic cannabinoids). Recent recognition of the role of CB2 receptors in fibrosis has fueled interest in therapeutic targeting of CB2 receptors in fibrosis. Fibrosis is characterized by the alteration of the typical cellular composition within the tissue parenchyma, resulting from exposure to diverse etiological factors. The pivotal function of CB2 agonists has been widely recognized in the regulation of inflammation, fibrogenesis, and various other biological pathologies. The modulation of CB2 receptors, whether by enhancing their expression or activating their function, has the potential to provide benefits in numerous conditions, particularly by avoiding any associated adverse effects on the central nervous system. The sufficient activation of CB2 receptors resulted in the complete suppression of gene expression related to transforming growth factor β1 and its subsequent fibrogenic response. Multiple reports have also indicated the diverse functions that CB2 agonists possess in mitigating chronic inflammation and subsequent fibrosis development in various types of tissues. While currently in the preclinical stage, the advancement of CB2 compounds has garnered significant attention within the realm of drug discovery. This review presents a comprehensive synthesis of various independent experimental studies elucidating the pivotal role of identified natural and synthetic CB2 agonists in the pathophysiology of organ fibrosis, specifically in the cardiac, hepatic, and renal systems.

Post-traumatic epilepsy (PTE) is a life-long complication of traumatic brain injury (TBI). The development of PTE is associated with neurological morbidity and increases the risk of mortality. An aim of EpiBioS4Rx (Epilepsy Bioinformatics Study for Antiepileptogenic Therapy) was to test potential therapies to prevent the development of PTE in the lateral fluid percussion injury (LFPI) rat model of TBI, in which rats were subjected to injury at the left parietal cortex. Sodium selenate has been reported to be antiepileptogenic post-TBI in rodent models by activating protein phosphatase 2A and reducing phosphorylated tau (p-tau) protein. We aimed to characterize the pharmacokinetics (PK) and brain uptake of sodium selenate using naïve control and LFPI rats. Rats received either a single bolus dose or a single bolus dose followed by a 7-day subcutaneous minipump infusion of sodium selenate. Sodium selenate and selenium concentrations in plasma and brain were analyzed and used for PK estimation and brain exposure assessment. Selenium concentrations rapidly increased after sodium selenate administration, demonstrating biotransformation from sodium selenate to selenium. Sodium selenate and selenium PK parameters were estimated using non-compartmental analysis. Sodium selenate clearance (CL/F) and volume of distribution (V/F) varied by dose and route of administration, suggesting differences in bioavailability and nonlinear pharmacokinetics at the doses tested. Brain-to-plasma partition coefficients (AUC/AUC) for sodium selenate and selenium were found to be 0.7-1.3 and 0.1-0.3 following single-dose injection, respectively, indicating active transport of sodium selenate across the blood-brain barrier (BBB).

Depression is the most frequent psychiatric condition experienced in stroke survivors. Selective serotonin reuptake inhibitors (SSRIs) are frequently used as first-line antidepressants; however, they have been strongly associated with hyponatremia which, in poststroke patients, can worsen outcomes. This study aims to determine and compare the incidence and magnitude of hyponatremia and potential risk factors in patients receiving either escitalopram or sertraline for the management of poststroke depression (PSD). A retrospective observational study involving all hospitalized patients who received either escitalopram or sertraline for the treatment of PSD. Electronic medical records were reviewed over a 5-year period with data collected on various demographic, laboratory, comorbidity, and medication-related variables. Data were analyzed using multivariate logistic regression. A total of 401 patients met the inclusion criteria. Overall, 36.7% of patients experienced hyponatremia, with 67 (38.3%) cases in patients receiving escitalopram and 76 (33.6%) in sertraline group. The median drop in sodium level from baseline was 5 mmol/L in both groups; with the majority of cases being of mild nature (73.1% and 69.7% for escitalopram and sertraline, respectively). Findings from the multivariate logistic regression did not yield a model with significant association (p = 0.353). Escitalopram and sertraline were both associated with an increased risk of hyponatremia in poststroke patients, with most cases being mild. There was no significant difference between treatment arms regarding the incidence or magnitude of hyponatremia. Caution should be exercised when prescribing escitalopram or sertraline.

Hypoxic pulmonary hypertension (HPH), a chronic condition affecting the cardiopulmonary system, has high mortality. Echinacoside (ECH) is a phenylethanoid glycoside, which is used to ameliorate pulmonary vascular remodeling and pulmonary vasoconstriction in rats. Accordingly, we aimed to explore the mechanism of ECH in preventing and treating HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber for 28 days to obtain the HPH model. The experimental rats were randomly allocated into the following several groups: normoxia group, chronic hypoxia group, and ECH group. The therapeutic results of ECH (10, 20, and 40 mg/kg) showed that ECH reduced mPAP, Hb, Hct, and RVHI in HPH rats. Then this work employed label-free quantitative proteomic analysis, western blotting, and RT-PCR to investigate the mechanism by which ECH prevents HPH. The results found that in the chronic hypoxia group, the levels of ACSL1, COL6A1, COL4A2, COL1A1, and PC increased compared to the normoxia group. However, the opposite effect was observed in the chronic hypoxia group treated with ECH. The study indicates that the administration of ECH may slow the pathological progression of HPH by suppressing the inflammatory response, inhibiting smooth muscle cell proliferation, and minimizing the deposition of extracellular matrix.

Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre-clinical studies showed benefit with a histone-neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose-adjusted, open-label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady-state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug-related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half-life values ranged from 5 to 7 h. The mean (±SD) terminal half-life for non-RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.

The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.