Search Results (1,436)

Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product. It plays an appreciable part in the carcinogenesis and pathogenesis of neurodegeneration, such as Alzheimer’s disease and infantile neurodegeneration. This mitochondrial, homo-tetrameric protein is a central hub in various metabolic pathways, e.g., branched-chain amino acid degradation and neurosteroid metabolism. It can bind to other proteins carrying out diverse physiological functions, e.g., tRNA maturation. It has also previously been proposed to be an Aβ-binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ-binding protein (ERAB), although those reports are controversial due to data analyses. For example, the reported k_m value of some substrate of ABAD/ERAB was five times higher than its natural solubility in the assay employed to measure k_m. Regarding any reported “one-site competitive inhibition” of ABAD/ERAB by Aβ, the k_ivalue estimations were likely impacted by non-physiological concentrations of 2-octanol at high concentrations of vehicle DMSO and, therefore, are likely artefactual. Certain data associated with ABAD/ERAB were found not reproducible, and multiple experimental approaches were undertaken under non-physiological conditions. In contrast, 17β-HSD10 studies prompted a conclusion that Aβ inhibited 17β-HSD10 activity, thus harming brain cells, replacing a prior supposition that “ABAD” mediates Aβ neurotoxicity. Furthermore, it is critical to find answers to the question as to why elevated levels of 17β-HSD10, in addition to Aβ and phosphorylated Tau, are present in the brains of AD patients and mouse AD models. Addressing this question will likely prompt better approaches to develop treatments for Alzheimer’s disease. Full article

Prolactin is a hormone with demonstrated roles in the brain, including neurogenesis, neuroprotection, learning, stress response or memory consolidation. To determine the prolactin expression in the rat hippocampus during aging and to resolve some controversies related to the presence of prolactin in the hippocampus, the aim of this study was to analyze whether changes occur in the expression of prolactin during different stages of life. To determine this, we designed an experimental study in which we analyzed the expression and location of prolactin in the rat hippocampus, Ammon’s horn and Dentate Gyrus, during different stages of life (prepubertal, postpubertal, young adult, adult and old) and checked if there are differences related to sex. Overall, the results obtained show that prolactin is present in the rat hippocampus and that prolactin is synthesized, as deduced from the findings obtained via ELISA, immunohistochemistry, qPCR and in situ hybridization. After analyzing the correlation between serum and hippocampal prolactin levels and comparing the amounts of Prl mRNA and the hormone, the results obtained suggest that hippocampal prolactin has a dual origin: local synthesis of the hormone and its passage from the blood. On the other hand, the amounts of prolactin and its mRNA in the hippocampus vary with sex and age, suggesting the existence of age-related sexual dimorphism. The results obtained suggest that hippocampal aging is related to a decrease in the hippocampal prolactin system, which helps to better understand brain aging. Full article

Objectives: The present cross-sectional analysis aimed to investigate whether Large Language Model-based chatbots can be used as reliable sources of information in orthodontics by evaluating chatbot responses and comparing them to those of dental practitioners with different levels of knowledge. Methods: Eight true and false frequently asked orthodontic questions were submitted to five leading chatbots (ChatGPT-4, Claude-3-Opus, Gemini 2.0 Flash Experimental, Microsoft Copilot, and DeepSeek). The consistency of the answers given by chatbots at four different times was assessed using Cronbach’s α. Chi-squared test was used to compare chatbot responses with those given by two groups of clinicians, i.e., general dental practitioners (GDPs) and orthodontic specialists (Os) recruited in an online survey via social media, and differences were considered significant when p < 0.05. Additionally, chatbots were asked to provide a justification for their dichotomous responses using a chain-of-through prompting approach and rating the educational value according to the Global Quality Scale (GQS). Results: A high degree of consistency in answering was found for all analyzed chatbots (α > 0.80). When comparing chatbot answers with GDP and O ones, statistically significant differences were found for almost all the questions (p < 0.05). When evaluating the educational value of chatbot responses, DeepSeek achieved the highest GQS score (median 4.00; interquartile range 0.00), whereas CoPilot had the lowest one (median 2.00; interquartile range 2.00). Conclusions: Although chatbots yield somewhat useful information about orthodontics, they can provide misleading information when dealing with controversial topics. Full article

Recent breakthroughs in cancer immunotherapy have shown remarkable success, yet treatment efficacy varies significantly among individuals. Emerging evidence highlights the gut microbiota as a key modulator of immunotherapy response, while vitamin D (VD), an immunomodulatory hormone, has garnered increasing attention for its potential interactions with gut microbiota and immunotherapy outcomes. However, the precise mechanisms and clinical applications of VD in this context remain controversial. This study systematically analyzed peer-reviewed evidence from PubMed, Scopus, Web of Science, PsycINFO, and MEDLINE (January 2000–May 2025) to investigate the complex interplay among VD, gut microbiota, and cancer immunotherapy. This review demonstrates that VD exerts dual immunomodulatory effects by directly activating immune cells through vitamin D receptor (VDR) signaling while simultaneously reshaping gut microbial composition to enhance antitumor immunity. Clinical data reveal paradoxical outcomes: optimal VD levels correlate with improved immunotherapy responses and reduced toxicity in some studies yet are associated with immunosuppression and poorer survival in others. The bidirectional VD–microbiota interaction further complicates this relationship: VD supplementation enriches beneficial bacteria, which reciprocally regulate VD metabolism and amplify immune responses, whereas excessive VD intake may disrupt this balance, leading to dysbiosis and compromised therapeutic efficacy. These findings underscore the need to elucidate VD’s dose-dependent and microbiota-mediated mechanisms to optimize its clinical application in immunotherapy regimens. Future research should prioritize mechanistic studies of VD’s immunoregulatory pathways, personalized strategies accounting for host–microbiota variability, and large-scale clinical trials to validate VD’s role as an adjuvant in precision immunotherapy. Full article

Introduction: Gynoid lipodystrophy (GL) affects most women, manifesting itself from puberty to adulthood. Its multifactorial etiology generates controversy in the literature about the most suitable treatment. Several methods are used, from the smallest to the most invasive, in the search for an effective fight against the severity of GL. The positive effect of ultrasound therapy (US) in decreasing subcutaneous adipose tissue is in increasing the skin permeability of pharmacological molecules, and it has aroused interest in the effect of a combination of the two techniques on the severity of GL. However, the results of this technique associated with an exercise program are unknown. Objective(s): To analyze the effect of three sessions of US + 5% caffeine in association with the realization of an exercise program, in females, on the level of severity of GL in the gluteal region and on the posterior proximal third part of the thigh. Methods: A total of 36 healthy women, aged between 18 and 55, who were considered to have GL, were randomly allocated in two experimental groups and one placebo group. The placebo group (PG) performed only physical exercise during the study. Experimental group 1 (EP1) performed US with 5% caffeine alongside a physical exercise protocol and experimental group 2 (EP2) performed US with a conventional US gel alongside a physical exercise protocol. The three groups completed three intervention sessions over 3 weeks, with one session per week. In addition to the level of severity assessed by the Cellulite Several Scale (CSS), anthropometric measures, body composition, and lipid profile of the participants were evaluated. The first assessment was carried out before the intervention (M0) and the last assessment after the three interventions (M1). The results were analyzed using the ANOVA test. The Tukey test was used for multiple comparisons of the groups in all variables, except for those related to the CSS, where the Kruskal–Wallis test was used with a significance level of 0.05. Results: A total of 29 women completed the study. There was a significant decrease inside the PG related to triglycerides (p = 0.012). In M1, all groups started to present median values below 200 mg of triglycerides. In cholesterol, a significant reduction was observed in all groups (p = 0.05). On the gluteal level at 5 cm, there was a decrease in EP1 and EP2 between M0 and M1 with p = 0.006 and p = 0.002, respectively. On the CSS there were no significant differences between groups or between moments. Conclusions: Three sessions of 5% caffeine and US in association with a physical exercise protocol have no effect on reducing the level of severity of GL. Full article

Accumulating studies have shown that astrocytes are essential for regulating neurons at both synaptic and circuit levels. The main mechanism of brain astrocytic intracellular Ca²⁺ activity is through the release of Ca²⁺ via the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) from the endoplasmic reticulum (ER). Studies using IP3R2 knockout mouse models (Itpr2^−/−) have shown that eliminating IP3R2 leads to a significant reduction in astrocytic Ca²⁺ activity However, there is ongoing controversy regarding the effect of this IP3R2-dependent reduction in astrocytic Ca²⁺ transients on neuronal activity. In our study, we employed dual-color two-photon Ca²⁺ imaging to study astrocytes and neurons simultaneously in vibrissa somatosensory cortex (vS1) in awake-behaving wild-type and Itpr2^−/− mice. We systematically characterized and compared both recorded astrocytic and neuronal Ca²⁺ activities in wild-type and Itpr2^−/− mice during various animal behaviors, particularly during the transition period from stillness to locomotion. We report that vS1 astrocytic Ca²⁺ elevation in both wild-type and Itpr2^−/− mice was significantly modulated by free whisking and locomotion. However, vS1 neurons were only significantly modulated by locomotion in wild-type mice, but not in Itpr2^−/− mice. Our study suggests a non-synaptic modulatory mechanism on functions of astrocytic IP3R2-dependent Ca²⁺ transients to local neurons. Full article

Background/Objectives: Portal hypertension (PH) is a common complication in children with chronic liver diseases. Primary and secondary prophylaxis of variceal bleeding in these patients remains controversial. Our study aims to evaluate the management of gastrointestinal (GI) varices in children with PH in Italy. Methods: A questionnaire was sent to 21 major pediatric hepatology centers. It included 34 questions referring to the medical, endoscopic, radiological, and surgical management of GI varices. Results: Out of 21 centers, 16 returned a completed questionnaire (survey response rate 76%) with a high level of completeness. A total of 1206 children with PH were under follow-up. Splenomegaly associated with hypersplenism was the main indication for endoscopic surveillance in all centers (100%). Primary prophylaxis was performed with endoscopy plus non-selective beta-blockers (NSBBs) in 50%, endoscopy alone in 38%, and NSBBs alone in 12%. All centers managed acute variceal bleeding with endoscopy within 24 h, acid suppression, and octreotide infusion. Secondary prophylaxis of variceal bleeding was conducted using endoscopy (100%) and NSBBs (87%). Transjugular intrahepatic portosystemic shunt (TIPS) was considered a good option when endoscopic treatment failed in 94% of centers. Conclusions: In Italy, there is broad consensus among centers regarding the management of gastrointestinal varices in children with portal hypertension. All participating centers endorsed the use of endoscopic screening for children presenting with clinical signs of portal hypertension. Nonetheless, further research is essential to establish evidence-based guidelines and to improve overall quality of care. Full article

Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange but, when impaired, can result in life-threatening hypoxemia. Moreover, under conditions of generalized alveolar hypoxia, HPV can result in pulmonary hypertension. Voltage-gated K⁺ channels (K_v channels) are key to HPV: a change in the intracellular hydrogen peroxide (H₂O₂) levels during acute hypoxia is assumed to modulate these channels’ activity to trigger HPV. However, there are longstanding conflicting findings on whether H₂O₂ inhibits or activates K_v channels. Therefore, we hypothesized that H₂O₂ affects K_v channels depending on the experimental conditions, i.e., the H₂O₂ concentration, the channel’s subunit configuration or the experimental clamping potential in electrophysiological recordings. Therefore, cRNAs encoding the K_v1.5 channel and the auxiliary K_vβ subunits (K_vβ1.1, K_vβ1.4) were generated via in vitro transcription before being injected into Xenopus laevis oocytes for heterologous expression. The K⁺ currents of homomeric (Kv1.5) or heteromeric (K_v1.5/K_vβ1.1 or K_v1.5/K_vβ1.4) channels were assessed by two-electrode voltage clamp. The response of the K_v channels to H₂O₂ was markedly dependent on (a) the clamping potential, (b) the H₂O₂ concentration, and (c) the K_v channel’s subunit composition. In conclusion, our data highlight the importance of the choice of experimental conditions when assessing the H₂O₂ sensitivity of K_v channels in the context of HPV, thus providing an explanation for the long-lasting controversial findings reported in the literature. Full article

Sepsis causes millions of deaths each year. Rapid, targeted therapy can reduce mortality rates. Both bacterial and viral pathogens can trigger sepsis, but the utility of commonly used inflammatory markers for differentiation remains controversial. Moreover, little is known about the time courses of alternative inflammatory parameters. The aim of this prospective, two-center observational study was to investigate the differences in the course of soluble Neuropilin-1 (sNRP-1) levels between bacterial and viral sepsis over a 7-day period. To be included, adult patients had to meet the SEPSIS-3 criteria and be diagnosed with either a bacterial or viral pathogen. Immunosuppressed patients were excluded. While IL-6, PCT, and CRP levels decreased consistently over time, sNRP-1 levels remained elevated in the bacterial group throughout the entire ICU stay. PCT (p < 0.001) and CRP (p = 0.016) levels were significantly associated with the course of sNRP-1. The AUC of sNRP-1 was 0.777 for discriminating between bacterial and viral infections on day 1. sNRP-1 remained stable and significantly higher in bacterial than in viral infections. Furthermore, the AUC values for discrimination ranged from acceptable to good, depending on the day of the ICU stay. sNRP-1 may serve as a potential tool to differentiate between bacterial and viral pathogens in sepsis. Full article

While the interest and participation in general endurance training and recreational sports competitions have continuously increased in recent decades, the number of recreational master-level endurance athletes has additionally multiplied. Athletes, active men and women older than 40 years of age, who participate in competitive athletics are usually referred to by the term master athletes (MAs). Previous research revealed the significant benefits of regular moderate physical activity, i.e., its positive influence on cardiovascular risk factors and cardiovascular health; however, recent data have raised concerns that long-term endurance exercise participation is associated with cardiac remodeling and potential adverse cardiovascular outcomes. Previous research also indicated potential structural, functional, and electrical remodeling in MAs due to prolonged and repeated exposure to high-intensity endurance exercise—a condition known as athlete’s heart. In this review, we focus on the association between extreme levels of endurance exercise and potential cardiovascular controversies, such as arrhythmogenesis due to new-onset atrial fibrillation, accelerated coronary artery atherosclerosis, and exercise-induced cardiac remodeling. Additionally, the exercise-dependent modulation of immunological response, such as proteomic response and cytokine alterations, is discussed. Furthermore, we discuss the impact of nutritional supplements in MAs and their potential benefits and harmful interactions. We aim to provide sports medicine practitioners with knowledge of these contemporary longevity controversies in sports cardiology and to highlight the importance of shared decision making in situations of clinical uncertainty. Full article

Inhaled treprostinil is approved for the treatment of pulmonary hypertension-associated interstitial lung disease (PH-ILD); however, it has not shown significant benefit in patients with a pulmonary vascular resistance (PVR) < 4 WU. As such, treatment for non-severe PH-ILD remains controversial. A total of 16 patients with non-severe PH-ILD were divided into two groups based on changes in PVR during exercise: a dynamic PVR group (n = 10), characterized by an increase in PVR with exertion, and a static PVR group (n = 6), with no increase in PVR with exercise. The dynamic PVR group received inhaled treprostinil, while the static PVR group was monitored off therapy. Baseline and 16-week follow-up values were compared within each group. At 16 weeks, the dynamic PVR group demonstrated significant improvements in mean 6 min walk distance (6MWD) (+32.5 m, p < 0.05), resting PVR (−1.04 WU, p < 0.05), resting mean pulmonary arterial pressure (mPAP) (−5.8 mmHg, p < 0.05), exercise PVR (−1.7 WU, p < 0.05), exercise mPAP (−13 mmHg, p < 0.05), and estimated right ventricular systolic pressure (−9.2 mmHg, p < 0.05). In contrast, the static PVR group remained clinically stable. These observations suggest that an exercise-induced increase in PVR, identified through Level 3 CPET, may help select patients with non-severe PH-ILD who are more likely to benefit from early initiation of inhaled treprostinil. Full article

Background/Objectives: Low-density lipoprotein cholesterol (LDL-C) is a causal factor in the development of atherosclerosis and a predictor of cardiovascular disease. However, the association between LDL-C levels and cardiovascular outcomes in patients undergoing dialysis remains controversial, with current guidelines advising against initiating statin therapy in this population. This study investigated the relationship between LDL-C levels and cardiovascular outcomes in Korean adults undergoing dialysis, using nationwide data. Methods: A total of 21,692 patients with end-stage kidney disease undergoing dialysis between 2009 and 2017 were identified from the Korean National Health Insurance Service database. Statin non-users (primary cohort) and users (secondary cohort) comprised 15,414 and 6278 patients, respectively. LDL-C levels were categorized, and cardiovascular outcomes including composites of cardiovascular death, myocardial infarction, and ischemic stroke were analyzed. Results: Among statin non-users, LDL-C levels > 100 mg/dL were significantly associated with an increased risk of the composite outcome, in a dose-dependent manner, compared with LDL-C levels < 70 mg/dL. Specifically, participants with LDL-C levels ≥ 160 mg/dL demonstrated a 43% increased risk of the composite outcome and a 2.25-fold higher risk of myocardial infarction compared to those with LDL-C levels < 70 mg/dL. Among statin users, LDL-C levels > 130 mg/dL were associated with an increased risk of the composite outcome. Conclusions: This study highlights the significant association between elevated LDL-C levels and adverse cardiovascular outcomes in patients undergoing dialysis. These findings underscore the importance of close monitoring and proactive management of LDL-C levels in this high-risk population. Future research should focus on developing tailored lipid-lowering strategies to improve cardiovascular outcomes in these patients. Full article

Over the past decades, bile acids have been recognized as important signaling molecules with significant roles in metabolic health and disease. Many of their beneficial effects are mediated through the activation of the Takeda G protein-coupled receptor 5 (TGR5), a G protein-coupled receptor ubiquitously expressed in both humans and animals. Upon activation, TGR5 stimulates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels and subsequent activation of protein kinase A (PKA). PKA then phosphorylates and activates several downstream signaling pathways, including exchange protein directly activated by cAMP (EPAC), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT). Through these pathways, TGR5 acts as a key molecular link between bile acid signaling and the regulation of energy metabolism. TGR5 activation has been associated with body weight loss in obese models, primarily by reducing food intake, enhancing thermogenesis in adipose tissue and muscle to increase energy expenditure, and improving insulin secretion. This review highlights recent advances in our understanding of TGR5 biology and critically examines its therapeutic potential, limitations, and controversies in the context of energy metabolism, offering new perspectives and opportunities for treating metabolic disorders. Full article

Background: The efficacy of postoperative exercise rehabilitation after spine surgery is controversial, and a protocol for exercise treatment and detailed outcomes based on functional activity have not yet been established. This study aimed to determine the efficacy of exercise rehabilitation after lumbar spine surgery. Methods: A prospective, randomized controlled trial was conducted in 40 patients who underwent lumbar spine surgery (20 patients each in the exercise and control groups) for 12 weeks. Clinical outcomes were assessed using the visual analog scale (VAS) for pain and EuroQol-5 Dimensions 5-Level version (EQ-5D-5L). Body proportions, including body mass index, total muscle mass, and body fat percentage were analyzed. Functional activity was evaluated based on the range of motion of the lumbar spine, strength and endurance of lumbar flexion/extension, flexibility, 6 min walking test, single-leg stance, coordination, and gait pattern analysis. Results: The exercise group showed significantly greater improvement in VAS for pain (66.67% versus 20.00%, p < 0.001) and EQ-5D-5L (45.56% versus 20.00, p = 0.039) compared to the control group. Serial assessment revealed significant improvement in strength of lumbar flexion/extension, 6 min walking test, single-leg stance, coordination, and gait patterns in the exercise group compared to the control group. In particular, the single-leg stance time for the affected leg improved more markedly in the exercise group (280.9% versus 48.7%, p < 0.001). Conclusion: Tailored postoperative exercise after lumbar spine surgery is effective in reducing pain and enhancing functional recovery, including strength and balance. Full article

Background/Objectives: As the population of women with endometriosis increases, approximately 10% of those of reproductive age experience symptoms such as pelvic pain, painful menstruation, and infertility. Individuals with endometriosis usually undergo multiple surgeries due to the high recurrence rate of the condition. However, ovarian surgery tends to reduce the ovarian reserve, presenting a dilemma when deciding whether to recommend surgery or medical treatment for women of reproductive age. The impact of endometriomas on the residual volume of ovarian tissue remains controversial, and it is unclear whether endometriosis itself or endometriomas are the primary problem. In this study, we aimed to investigate whether women with endometriosis have lower levels of anti-Müllerian hormone than women with healthy ovaries before treatment initiation. Methods: A total of 298 participants enrolled in the endometriosis cohort at Severance Hospital, Korea, from 1 October 2020 to 1 July 2024 were included in this study. Of these, 63 participants were from a retrospective study, and 235 were from a prospective study. Due to the use of different assay methods between the reference values and anti-Müllerian hormone measurements from Severance Hospital, a correction was applied using the regression equation. The mean anti-Müllerian hormone levels for individuals with endometriosis were corrected with the regression equation and compared to those of the reference group for each age group using a one-sample t-test. Results: Anti-Müllerian hormone levels decreased with age in the endometriosis group. When comparing mean anti-Müllerian hormone concentrations between the endometriosis group and reference values, among 168 participants aged 20–31 years, the corrected mean anti-Müllerian hormone concentration was 5.96 ± 3.22 ng/mL, higher than the reference value of 4.94 ± 0.17 ng/mL (p < 0.01). Among 31 participants aged 35–37 years, the corrected average anti-Müllerian hormone value was 4.33 ± 3.06 ng/mL, compared to the reference anti-Müllerian hormone level of 3.22 ± 0.15 ng/mL (p = 0.05). There were no significant differences in corrected anti-Müllerian hormone levels between the 32–34-, 38–40-, 41–43-, and ≥44 years age groups. Conclusions: Patients with endometriosis, especially those aged 20–31 years, tended to have higher anti-Müllerian hormone levels than did individuals with healthy ovaries. In other age groups, there were no differences. Given that these levels do not differ significantly across age groups, it is difficult to conclude that patients with endometriosis have a reduced ovarian reserve. Full article