Guided by molecular networking, nine novel curvularin derivatives (1-9) and 16 known analogs (10-25) were isolated from the hydrothermal vent sediment fungus Penicillium sp. HL-50. Notably, compounds 5-7 represented a hybrid of curvularin and purine. The structures and absolute configurations of compounds 1-9 were elucidated via nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction, electronic circular dichroism (ECD) calculations, ¹³C NMR calculation, modified Mosher's method, and chemical derivatization. Investigation of anti-inflammatory activities revealed that compounds 7-9, 11, 12, 14, 15, and 18 exhibited significant suppressive effects against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine macrophage RAW264.7 cells, with IC₅₀ values ranging from 0.44 to 4.40 μmol·L^-1. Furthermore, these bioactive compounds were found to suppress the expression of inflammation-related proteins, including inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), NLR family pyrin domain-containing protein 3 (NLRP3), and nuclear factor kappa-B (NF-κB). Additional studies demonstrated that the novel compound 7 possessed potent anti-inflammatory activity by inhibiting the transcription of inflammation-related genes, downregulating the expression of inflammation-related proteins, and inhibiting the release of inflammatory cytokines, indicating its potential application in the treatment of inflammatory diseases.
Penicillium/chemistry* ; Mice ; Animals ; Anti-Inflammatory Agents/isolation & purification* ; RAW 264.7 Cells ; Nitric Oxide/metabolism* ; Hydrothermal Vents/microbiology* ; Macrophages/immunology* ; Molecular Structure ; Nitric Oxide Synthase Type II/immunology* ; Cyclooxygenase 2/immunology* ; Geologic Sediments/microbiology* ; NF-kappa B/immunology* ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology*

Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic.
Infant, Newborn ; Humans ; Hair Cells, Auditory, Inner/physiology* ; Ear, Inner/physiology* ; Hair Cells, Auditory/physiology* ; Regeneration/genetics* ; Stem Cells

Objective:To investigate the prevalence of cataracts, the surgical coverage, and postoperative visual acuity of adults in Ningxia.Methods:A cross-sectional study using multistage cluster random sampling was conducted.Ten survey sites in Ningxia were selected and the population aged 18 years and over was surveyed with questionnaire, height and weight measurements, visual acuity, intraocular pressure, fundus photography and slit-lamp examinations.Cataract prevalence and its influencing factors were analyzed.Cataract prevalence, surgical coverage and presenting visual acuity (PVA) and best corrected visual acuity (BCVA) after surgery were investigated in different age groups of the examined population.The study adhered to the Declaration of Helsinki and was approved by the Ethics Committee of the People's Hospital of Ningxia Hui Autonomous Region (No.[2023]-LL-010).Participants signed informed consent prior to the examination.Results:A total of 6 145 people should be examined, and 5 721 people were actually examined, with an examination rate of 93.10%.The study population consisted of 2 558 males, accounting for 44.71%, and 3 163 females, accounting for 55.28%, with ages ranging from 18 to 93 years old and an average age of (64.27±13.48) years.Among them, 1 180 patients diagnosed with cataract, with a cataract prevalence of 20.62%.The prevalence of cataract increased with age and decreased with education level, showing statistically significant differences ( χ2=1 091.32, 581.92; both at P<0.01).The prevalence of cataract was significantly higher among people with hypertension, diabetes mellitus, hyperlipidemia, and coronary heart disease than those without these diseases ( χ2=274.65, 118.15, 78.05, 182.71; all at P<0.01).Cataract surgery was performed in 245 cases in the cataract patient population, with a surgical coverage rate of 20.76%.Of the 245 cases, 229 cases were implanted with IOLs, with an implantation rate of 93.40%.The social burden rate of cataract blindness was 2.29%, and increased with age.Of the 339 eyes that underwent cataract surgery, 241 had a PVA≥0.3, accounting for 71.09%, and 272 had a BCVA≥0.3, accounting for 80.24%. Conclusions:In Ningxia, cataracts are still the main cause of vision impairment and blindness in the elderly, and the social burden rate of cataract blindness is high.Moreover, the coverage rate of cataract surgery is low, so both the coverage and quality of surgery need improvement.

Objective To observe the value of myocardial contrast echocardiography(MCE)combined with speckle tracking imaging(STI)for evaluating the protective effect of 2-aminoethoxydiphenyl borate(2-APB)on heart of arsenic poisoned rats.Methods Forty rats were randomly divided into low-and high-dose 2-APB intervention after arsenic trioxide(ATO)poisoned group(2-APBL group and 2-APBH group),simple ATO poisoned group(ATO group),simple 2-APB intervention group(2-APB group)and control group(each n=8).5 mg/kg ATO were intraperitoneally injected in 2-APBL group,2-APBH group and ATO group,while equal dose physiological saline were injected in 2-APB group and control group,respectively.Then 2,4 and 4 mg/kg 2-APB were intraperitoneally injected in 2-APBL group,2-APBH group and 2-APB group,while equal doses physiological saline were injected in ATO group and control group,respectively.MCE and STI were performed,serum myocardial injury markers were tested,sarcoplasmic reticulum Ca2+-ATPase(SERCA)was examinated,and finally myocardial pathological examination was performed.The above indexes were compared among groups and between each 2 groups,and correlation analysis was performed.Results Significant differences of left ventricular fractional shortening(LVFS),left ventricular ejection fraction(LVEF),wash in slope(WIS),peak intensity(PI),WIS×PI,area under the curve(AUC),global circumferential strain(GCS)in each layer of myocardium,as well as glutamic-oxaloacetic transaminase(GOT),creatine kinase(CK),lactate dehydrogenase(LDH)and SERCA were found among 5 groups(all P＜0.05).The above indexes substantially increased or decreased sequentially ATO group,2-APBL group,2-APBH group and 2-APB group/control group(all P＜0.05).WIS,PI,WIS × PI and GCS of rat endo-myocardium,GSC of mid-myocardium and GCS of epi-myocardium all positively correlated with SERCA(r=0.874,0.893,0.920,0.916,0.848,0.783,all P＜0.05).Conclusion MCE combined with STI,especially WISXPI and GCS of endo-myocardium could be used to evaluate the protective effect of 2-APB on heart of arsenic poisoned rats.

Objective:To establish an epidemiological cut-off value (ECV) for antifungal drugs against Cryptococcus neoformans in East China through a multicenter in vitro drug susceptibility test. Methods:A retrospective collection of 479 clinical isolates of Cryptococcus neoformans was conducted by the East China Invasive Fungal Infection Group (ECIFIG) from January 1, 2017 to December 31, 2022. Mass spectrometry and gene sequencing were used for identification. A unified drug susceptibility testing system was established in the fungal laboratories across three sub centers in Shanghai, Jiangxi, and Jiangsu provinces. Drug susceptibility testings of Cryptococcus neoformans were independently completed in each center after passing consistency evaluation. Epidemiological breakpoints were established against fluconazole, voriconazole, amphotericin B, 5-fluorocytosine, isaconazole, posaconazole and itraconazole following the principles and procedures of the Clinical and Laboratory Standards Institute (CLSI) M57. Results:External consistency evaluation revealed that the minimum inhibitory concentration values ??for all drugs in each center did not differ by more than one dilution gradient. A new ECV type of Cryptococcus neoformans in East China was established, including fluconazole 16 mg/L, voriconazole 0.12 mg/L, amphotericin B 1 mg/L, 5-fluorocytosine 8 mg/L, isavuconazole 0.12 mg/L, posaconazole 0.5 mg/L, and itraconazole 0.5 mg/L. Conclusion:This study preliminarily revealed the drug susceptibility characteristics of clinical Cryptococcus neoformans in East China and established the ECVs for antifungal drugs against Cryptococcus neoformans in the region.

Objective To observe the value of vector flow mapping(VFM)technique for assessing changes of left ventricular diastolic function in ovarian cancer(OC)patients who underwent postoperative chemotherapy.Methods Totally 37 OC patients who received postoperative chemotherapy were prospectively enrolled in chemotherapy group,while 40 healthy adults were taken as controls(control group).Routine echocardiography and VFM were performed for chemotherapy group before chemotherapy,after 3 and 6 cycles of chemotherapy,also for controls at enrollment,and comparison was performed between groups before chemotherapy,as well as among different time points within chemotherapy group,and the correlations of VFM results with hemoglobin and routine echocardiographic results in chemotherapy group were analyzed.Results No significant difference of age,body mass,body surface area(BSA),nor hemoglobin level,routine echocardiographic and VFM results before chemotherapy was found between groups(all P＞0.05).With the process of chemotherapy,hemoglobin level gradually decreased,the isovolumic relaxation period(IR),atrial systole period(AS)intraventricular pressure difference(IVPD)and intraventricular pressure gradient(IVPG)of the left ventricle gradually increased(adjusted P＜0.05),whereas routine echocardiography only showed that the left atrial volume index(LAVI)and the ratio of early mitral inflow velocity and the mean mitral annular early diastolic velocity(E/e')increased after 6 cycles of chemotherapy compared with those pre-chemotherapy(adjusted P＜0.05).In chemotherapy group,VFM results in all diastolic subphases were strongly correlated with hemoglobin levels(|r|=0.718 to 0.836,all P＜0.05),weakly to moderately correlated with LAVI(|r|=0.375 to 0.525,all P＜0.05)and moderately correlated with E/e'(|r|=0.424 to 0.537,all P＜0.05).Conclusion The diastolic function of left ventricle was probably damaged in early stage after postoperative chemotherapy in OC patients.VFM might detect slight changes of early diastolic function of left ventricle more sensitively than routine echocardiography.

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC₅₀ value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

OBJECTIVE To establish and optimize tablets adding mechanism of automatic tablet dispensing machine in the inpatient pharmacy, realize tablets checking and fine management for tablets inventory and expiration date in process of tablets adding, reduce incidence of errors, improve work efficiency, and ensure the safety of tablets use for patients. METHODS Intelligent software combined with barcode scanning technology was used to carry out intelligent intervention on the error-prone link in the process of tablets adding of automatic drug dispensing machine. The error ratio of tablets adding(%), average of daily tablets adding time(min), error ratio of tablets quantity in monthly inventory check(%) were compared before and after intelligent intervention. RESULTS Compared with before optimization, the error ratio of tablets adding decreased from 0.11 % to 0%, average of daily tablets adding time decreased from (96.50±21.84)min to (64.23±19.59)min(P<0.01), which saved 32.27 min on average, and error ratio of tablets quantity in monthly inventory check decreased from (9.42±1.13)% to (3.42±0.88)%(P<0.01) after optimizing the dosing process of the automatic drug dispensing machine. CONCLUSION The optimized process of tablets adding of automatic drug dispensing machine is simple and rapid to operate, which has high accuracy. The tablets inventory and expiration date can be tracked and managed in real time, which ensures the safety of tablets use for patients, promotes development of digital pharmacy management system, and improves quality of pharmaceutical care.

OBJECTIVE To evaluate the clinical efficacy and safety of original and generic entecavir(ETV) in the treatment of chronic hepatitis B. METHODS Domestic and foreign literatures were systematically reviewed to evaluate the efficiency and safety. Qualitative combined with quantitative methods were used to evaluate and analyze. RESULTS Meta-analysis results showed that there were no significant differences in HBV-DNA negative conversion rate, ALT normalization rate, serum HBeAg negative conversion rate, HBeAg serum conversion rate, HBeAg/HBeAb serum conversion rate and incidence of adverse reactions between generic and original ETVs after 12 and 48 weeks of medication. Subgroup analysis of different treatment courses showed no statistical significance in each index. CONCLUSION The results of this study shows no significant differences between the two drugs in terms of clinical efficacy and safety considerations. However, limited by the quality and quantity of included literature, a large sample and multicenter RCT is still needed to confirm the conclusion.