The clinical antiprotozoal drug nitazoxanide has been demonstrated to improve the experimental diabetes mellitus, lipid metabolism disorders, atherosclerosis and inhibit inflammation. Since the pathogenesis of heart failure with preserved ejection (HFpEF) is multifactorial and closely associated with the aforementioned diseases, we aim to study the effect of nitazoxanide on high-fat diet (HFD) plus L-NAME (N ω-nitro-l-arginine methyl ester)-induced HFpEF and metabolic syndrome in mice. We found that oral nitazoxanide improved cardiac hypertrophy, cardiac fibrosis, cardiac diastolic dysfunction, increased blood pressure, impaired exercise tolerance, impaired glucose handling, serum lipid disorders, hepatic steatosis, increased weight of white adipose tissues and kidney fibrosis in HFD + L-NAME-treated mice. In the established HFD + L-NAME-induced HFpEF and metabolic syndrome mouse model, therapeutic treatment with nitazoxanide rescued HFD + L-NAME-induced pathological phenotypes as mentioned above. The in vitro experiments revealed that tizoxanide, the active metabolite of nitazoxanide, increased the basal mitochondria metabolism of cardiomyocytes, inhibited cardiomyocyte hypertrophy and collagen secretion from cardiac fibroblasts, and relaxed phenylephrine- and U46619-induced constriction of rat mesenteric arteries, indicating that the direct effect of tizoxanide might partly contribute to the protective effect of nitazoxanide against HFpEF in vivo. The present study suggests that nitazoxanide might be a potential drug for HFpEF and metabolic syndrome therapy.

Objective:To investigate the effect of continuous renal replacement therapy (CRRT) on energy metabolism and thermal balance in ICU patients with acute kidney injury (AKI).Methods:This study was a prospective observational study, which included AKI patients who underwent CRRT in ICU of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine from May 2020 to December 2023. The patients' general clinical characteristics, comorbidities, body temperature, disease severity score, CRRT treatment time and filter lifespan were recorded. The concentrations of glucose and lactate in blood and ultrafiltrate, and the citrate level in the ultrafiltrate when regional citrate anticoagulation adopted were analyzed regularly. Subgroup analysis was carried out according to different anticoagulation modes and whether the patients with diabetes or shock. The changes of energy metabolism and thermal balance corresponding to the changes in glucose, lactate, citrate and body temperature induced by CRRT were calculated daily.Results:This study included 420 AKI patients undergoing CRRT. When the blood lactate was between 14-18 mmol/L, there was a loss of approximately 200-250 kcal of energy per day, while the blood lactate was between 6.5-11.5 mmol/L, the daily corresponding energy loss was about 100-150 kcal. During CRRT on the first day, the patients with diabetes or shock had a mild decrease of blood glucose, while patients without diabetes and shock had mild increase of blood glucose. When the target of blood glucose was gradually achieved, the mean daily increase of energy corresponding to blood glucose intake was about 100-130 kcal in patients undergoing CRRT. The mean daily increase of energy corresponding to citrate intake was approximately 330 kcal, when the patient was undertaken by CRRT with regional citrate anticoagulation. For every 1℃ decrease in body temperature, the mean daily heat loss caused by extracorporeal thermal radiation during CRRT was about 200 kcal.Conclusions:When conducting nutritional assessment and prescription for AKI patients supported by CRRT in the ICU, it is essential to fully consider the impact of CRRT on the patient's energy metabolism and heat balance. This includes the clearance of lactate, the balance of blood glucose, the intake of citrate, and the reduction in body temperature. Additionally, the type and stage of the disease, as well as individual differences, must be taken into account to achieve personalized nutritional assessment and precise implementation.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Objective:To analyze the characteristics of sleep disordered breathing (SDB) in children with allergic rhinitis (AR), and improve the diagnosis and treatment at AR combined with obstructive sleep apnea (OSA).Methods:The clinical data of 120 patients with AR and OSA (AR and OSA group) admitted to the respiratory department at Shenzhen Children′s Hospital from May 2019 to December 2020 were retrospectively analyzed.A total of 120 children diagnosed with OSA and excluded AR during the same period were selected as control group.The SDB day and night symptoms, sleep structure characteristics and sleep breathing events were compared between two groups.Results:The average course of disease in children with AR and OSA was significantly longer than that in control group ( P=0.030). The main manifestations of children in AR and OSA group were mouth breathing (100.0%), snoring (99.2%), nasal obstruction (88.5%), and restless sleep (68.0%). There was no significant difference in sleep structure between two groups ( P>0.05), but the sleep efficiency of AR and OSA group was significantly lower than that of control group ( P=0.028). The respiratory events apnea hypopnea index, obstructive apnea index, obstructive apnea hypopnea index, hypopnea index and oxygen desaturation index of each sleep period in AR and OSA group were significantly higher than those in control group ( P<0.05). Among the children in AR and OSA group, moderate and severe OSA were the main manifestations, and the difference between two groups was statistically significant ( P<0.001). Conclusion:The combination of AR delayed the course of OSA in children.The main characteristics of sleep disordered breathing in children with AR are mouth opening, restless sleep, snoring and nasal obstruction.The sleep efficiency is decreased.Obstructive hypopnea and apnea are the most common respiratory events, and oxygen deficiency often occurs in rapid eye movement phase.Children with AR are more likely to have moderate or severe obstructive sleep apnea.

Eczema is a common clinical inflammatory skin disease characterized by severe itching and recurrent attacks.Its etiology is complex, including a variety of internal and external factors.The main mechanism is related to the imbalance of Th2immune response, and related inflammatory factors play an important role.Epithelial-derived factor like thymic stromal lymphopoietin and interleukin-33could trigger Th2immune imbalance and promote the secretion of type inflammatory factors such as interleukin-4, interleukin-5, and interleukin-13.These inflammatory factors will further induce eosinophilic granulocytosis and IgE formation.In this paper, the research progress of mechanism of type 2related inflammatory factors in eczema were reviewed, which provided the great significance for treatment.

To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P < 0.05) was found, but significant effect on the P(app) values was not shown between 10.0 mg x L(-1) and 16.0 mg x L(-1) (P > 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app).