Involvement of E3 ubiquitin ligase NEDD4-mediated YY1 ubiquitination in alleviating idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disease characterized by progressive lung scarring. This study aims to elucidate the role of the E3 ubiquitin ligase NEDD4 in the ubiquitination of YY1 and its subsequent impact on TAB1 transcription, revealing a possible molecular mechanism in the development of IPF. Through bioinformatics analysis and both in vitro and in vivo experiments, we observed differential expression levels of NEDD4 and YY1 between normal and IPF samples, identifying NEDD4 as an upstream E3 ubiquitin ligase of YY1. Furthermore, binding sites for the transcription factor YY1 on the promoter region of TAB1 were discovered, indicating a direct interaction. In vitro experiments using HEPF cells showed that NEDD4 mediates the ubiquitination and degradation of YY1, leading to suppressed TAB1 transcription, thereby inhibiting cell proliferation and fibrogenesis. These findings were corroborated by in vivo experiments in an IPF mouse model, where the ubiquitination pathway facilitated by NEDD4 attenuated IPF progression through the downregulation of YY1 and TAB1 transcription. These results suggest that NEDD4 plays a crucial role in the development of IPF by modulating YY1 ubiquitination and TAB1 transcription, providing new insights into potential therapeutic targets for treating IPF.

Anxiety and depression status in patients with idiopathic pulmonary fibrosis and outcomes of nintedanib treatment: an observational study.

BACKGROUND: Anxiety and depression are common comorbidities in idiopathic pulmonary fibrosis (IPF) that impair health-related quality of life. However, there is a lack of studies focusing on the mental disorder of IPF after antifibrotic treatment and their related predictive factors. METHODS: Patients with an initial diagnosis of IPF were enrolled. Data on demographics, lung function, Generalized Anxiety Disorder-7 (GAD-7) Scale, Patient Health Questionnaire 9 (PHQ-9), Patient Health Questionnaire-15 (PHQ-15), and St. George's Respiratory Questionnaire total score(SGRQ-T) were collected. Changes in anxiety, depression, somatic symptoms, and quality of life scores before and after nintedanib treatment were compared, and the related predictive factors were analyzed. RESULTS: A total of 56 patients with a first diagnosis of IPF were enrolled, with 42 and 35 patients suffering from anxiety and depression, respectively. The GAD-7, PHQ-9, PHQ-15, and SGRQ scores were higher in the anxiety and depression groups. SGRQ total score (SGRQ-T) [OR = 1.075, 95%CI= (1.011, 1.142)] was an independent predictor of IPF combined with anxiety (p < 0.05); SGRQ-T [OR = 1.080, 95%CI= (1.001, 1.167)] was also an independent predictor of IPF combined with depression (p < 0.05). After treatment, GAD-7, PHQ-9, PHQ-15, and SGRQ scores decreased (p < 0.05). ΔSGRQ-T significantly affected ΔGAD-7 (ß = 0.376, p = 0.009) and ΔPHQ-9 (ß = 0.329, p = 0.022). CONCLUSION: Anxiety and depression in IPF patients are closely related to somatic symptoms, pulmonary function, and quality of life. The SGRQ-T score is of great value for assessing anxiety and depression in patients with IPF. Short-term treatment with nintedanib antifibrotic therapy can alleviate anxiety and depression in IPF patients.

Body mass index and weight loss as risk factors for poor outcomes in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

OBJECTIVE: The association between nutritional status and prognosis of idiopathic pulmonary fibrosis (IPF) remains unclear. This systematic review and meta-analysis aimed to explore the effect of body mass index (BMI) and weight loss on the prognosis of IPF patients. METHODS: We accumulated studies on IPF, BMI, and weight loss from databases including PubMed, Embase, Web of science, Scopus, Ovid and Cochrane Library up to 4 August 2023. Using Cox proportional hazard regression model for subgroup analysis, hazard ratio (HR) and 95% confidence intervals (CI) for BMI in relation to mortality, acute exacerbation (AE), and hospitalization in IPF patients were calculated, and HR, odds ratio (OR), and 95% CI for weight loss corresponding to IPF patient mortality were assessed. Sensitivity analysis was peformed by eliminating every study one by one, and publication bias was judged by Egger's test and trim-and-fill method. RESULTS: A total of 34 eligible studies involving 18,343 IPF patients were included in the meta-analysis. The pooled results by univariate Cox regression analysis showed that baseline BMI was a predictive factor for IPF mortality (HR = 0.93, 95%CI = [0.91, 0.94]). Furthermore, the results by the multivariable regression model indicated that baseline BMI was an independent risk factor for predicting IPF mortality (HR = 0.94, 95%CI = [0.91, 0.98]). Weight loss was identified as a risk factor for IPF mortality (HR = 2.74, 95% CI = [2.12, 3.54]; OR = 4.51, 95% CI = [1.72, 11.82]) and there was no predictive value of BMI for acute exacerbation (HR = 1.00, 95% CI= [0.93, 1.07]) or hospitalization (HR = 0.95, 95% CI = [0.89, 1.02]). CONCLUSION: Low baseline BMI and weight loss in the course of IPF may indicate a high risk of mortality in patients with IPF, so it is meaningful to monitor and manage the nutritional status of IPF patients, and early intervention should be conducted for low BMI and weight loss.

Serum ferritin as a significant biomarker for patients with idiopathic inflammatory myopathy-associated interstitial lung disease: A systematic review and meta-analysis.

OBJECTIVE: The biomarkers for predicting the occurrence, progression, and death of idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) remain unclear. Serum ferritin (SF) is a potential candidate and this systematic review and meta-analysis aimed to reveal the clinical significance of SF in IIM-ILD. METHODS: Eligible English studies were selected from PubMed, Embase, Web of science and Scopus up to 9 June 2023. The SF levels in patients with IIM-ILD were extracted and pooled. Subgroup analysis was performed based on disease types, sensitivity analysis was conducted by excluding one class of literature at a time, and publication bias was assessed by funnel plot and Egger's test. RESULTS: Pooled analysis of 1,933 patients with IIM from 19 studies showed that SF levels were significantly higher in IIM-ILD group (WMD=263.53ng/mL, 95% CI: 146.44-380.62, p<0.001) than IIM without ILD, subgroup analysis showed that SF levels in DM-ILD (WMD = 397.67ng/mL, 95% CI:142.84-652.50, p = 0.002) and PM/DM-ILD (WMD = 117.68 ng/mL, 95% CI: 86.32-149.04, p < 0.001) were significantly higher compared to those without ILD. SF levels were significantly higher in rapidly progressive interstitial lung disease group (RP-ILD)(WMD = 484.99 ng/mL, 95% CI: 211.12-758.87, p= 0.001) than chronic ILD(C-ILD) group, subgroup analysis showed that SF levels in DM-RP-ILD (WMD= 509.75 ng/mL, 95% CI: 215.34-804.16, p=0.001) were significantly higher than those in DM-C-ILD group. SF levels were significantly higher in death group (WMD= 722.16 ng/mL, 95% CI: 572.32-872.00, p< 0.001) compared to the survival group, subgroup analysis showed that death patients with DM-ILD(WMD= 735.62 ng/mL, 95% CI:574.92-896.32, p<0.001) and PM-ILD (WMD= 632.56 ng/mL, 95% CI:217.92-1047.19, p=0.003) had significantly higher SF levels than survival group respectively. CONCLUSION: Increased SF levels can serve as a biomarker for predicting the occurrence, progression and death of patients with IIM-ILD, which can provide early warning sign for intervention and prognosis evaluation for IIM-ILD patients.

Influence Mechanism of Drug-Polymer Compatibility on Humidity Stability of Crystalline Solid Dispersion.

This study investigates the influence of humidity on the dissolution behavior and microstructure of drugs in crystalline solid dispersions (CSDs). Using Bifonazole (BFZ) as a model drug, CSDs were prepared through spray drying with carriers such as Poloxamer 188 (P188), Poloxamer 407 (P407), and polyethylene glycol 8000 (PEG8000). The solubilization effect and mechanism were initially evaluated, followed by an examination of the impact of humidity (RH10%) on the dissolution behavior of CSDs. Furthermore, the influence of humidity on the microstructure of CSDs was investigated, and factors affecting the humidity stability of CSDs were summarized. Significant enhancements in the intrinsic dissolution rate (IDR) of BFZ in CSDs were observed due to changes in crystalline size and crystallinity, with the CSD-P188 system exhibiting the best performance. Following humidity treatment, the CSD-P407 system demonstrated the least change in the IDR of BFZ, indicating superior stability. The CSD-P407 system was followed by the CSD-P188 system, with the CSD-PEG8000 system exhibiting the least stability. Further analysis of the microstructure revealed that while humidity had negligible effects on the crystalline size and crystallinity of BFZ in CSDs, it had a significant impact on the distribution of BFZ on the CSD surface. This can be attributed to the water's potent plasticizing effect, which significantly alters the molecular mobility of BFZ. Additionally, the compatibility of the three polymers with BFZ differs, with CSD-P407 > CSD-P188 > CSD-PEG8000. Under the continuous influence of water, stronger compatibility leads to lower molecular mobility and more uniform drug distribution on the CSD surface. Enhancing the compatibility of drugs with polymers can effectively reduce the mobility of BFZ in CSDs, thereby mitigating changes caused by water and ultimately stabilizing the surface composition and dissolution behavior of drugs in CSDs.

[The value of non-invasive prenatal testing for the identification of numerical and structural chromosomal abnormalities and copy number variations in the fetuses].

OBJECTIVE: To assess the value of non-invasive prenatal testing (NIPT) for the identification of numerical and structural chromosomal abnormalities and copy number variations (CNVs) in fetuses. METHODS: 46 197 pregnant women undergoing NIPT at the Prenatal Diagnosis Center of Chenzhou First People's Hospital from January 2018 to December 2021 were selected as the study subjects. Positive cases were subjected to chromosomal karyotyping and copy number variation sequencing (CNV-seq) following amniocentesis. RESULTS: Nearly 50% of common chromosomal aneuploidies were found in the elder pregnant women. Among these, sex chromosome aneuploidies were mainly found in pregnant women with advanced age as well as borderline risks by serological screening. Rare autosomal aneuploidies and CNVs were mainly found in those with borderline or high risks by serological screening. The positive predictive values (PPV) for fetal chromosomal abnormalities indicated by NIPT were as follows: T21 (92.37%, 109/118), T18 (53.85%, 14/26), sex chromosome aneuploidies (45.04%, 59/131), T13 (34.62%, 9/26), CNVs (29.17%, 14/48), and rare autosomal aneuploidies (2.60%, 2/77). CONCLUSION: NIPT has a high detection rate for T21, T18, T13 and sex chromosome aneuploidies. It can also detect rare autosomal aneuploidies and CNVs, including some rare structural abnormalities, though verification is required by analyzing amniotic fluid samples.

Successful treatment of auto-trilevel positive airway pressure plus trazodone for obstructive sleep apnea complicated by anxiety disorder: a case report.

Obstructive sleep apnea (OSA) is a highly prevalent type of sleep-disordered breathing, which is often comorbid with affective disorders such as anxiety. A 61-year-old woman who was diagnosed with OSA affected by anxiety disorder complained of poor sleep quality at night and anxiety symptoms, and showed chest tightness, dyspnea, snoring, and apnea events during sleep. The patient initially received treatment with positive airway pressure (PAP) combined with trazodone, and subsequently switched to auto-trilevel PAP (AtPAP) combined with trazodone therapy. The initial attempt to treat the patient's disease by auto-adjusting PAP combined with trazodone failed because of central sleep apnea (CSA), which frequently occurred at night. After switching to AtPAP combined with trazodone therapy, CSA was effectively eliminated. In addition, sleep quality, hypoxia, and anxiety disorders were improved. The first report of successful therapy of AtPAP combined with trazodone for OSA complicated by anxiety disorder provides a new therapeutic strategy for this patient population.

Pulmonary aspergillus infection with abnormal imaging successfully treated with omalizumab: A case report.

BACKGROUND: Pulmonary aspergillosis is a pulmonary infectious disease that is clinically difficult to diagnose and treat. When the lower respiratory tract is invaded by Aspergillus, the clinical manifestations and imaging features vary among patients with different immune states. The use of antifungal drugs and glucocorticoids are important, but some patients do not respond satisfactorily to treatment. CASE PRESENTATION: A 59-year-old female had a long history of asthma and poor symptom control, with long-term use of long-acting inhaled glucocorticoids combined with a long-acting ß2 receptor agonists (ICS + LABA) (salmeterol fluticasone inhalation powder). The ground glass shadow, tree-in-bud sign, and bronchiectasis in the middle lobe of the right lung and the lower lobe of both lungs were first detected by chest CT over 5 years ago. Atelectasis in the middle lobe of the right lung was detected over 3 years ago. Over 2 years ago, the patient was hospitalized and a repeat chest CT showed persistent atelectasis in the middle lobe of the right lung, and more lesions in bilateral lower lungs than before. Aspergillus fumigatus was detected in alveolar lavage fluid and sputum pathogenic culture, which confirmed the diagnosis of pulmonary aspergillosis. After treatment with voriconazole and amphotericin B, the middle lobe of the right lung partially reopened, but the lesions in bilateral lower lungs persisted. After 21 weeks of treatment, the antifungal drugs were stopped because the patient refused to use oral/intravenous glucocorticoids, and omalizumab was finally chosen for treatment. After 1 month of treatment, the patient's clinical symptoms began to ease. After 1 year of treatment, imaging reexamination of lung showed that the lesions were completely cleared, accompanied by significant improvement in nutritional status and airway function. CONCLUSIONS: We reported the case of a patient with pulmonary Aspergillus infection who was treated with omalizumab and showed significant improvement in clinical symptoms and imaging abnormalities, which provides a new option for patients with pulmonary Aspergillus infection who show unsatisfactory response with first-line drugs.

Development and Validation of a Diagnostic Nomogram for Pneumocystis jirovecii Pneumonia in Non-HIV-Infected Pneumonia Patients Undergoing Oral Glucocorticoid Treatment.

Purpose: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic but potentially fatal infection with increasing prevalence in HIV-free patients. Glucocorticoid therapy is one of the most important risk factors for PJP. The delay in diagnosis contributes to poor outcomes. Hence, the aim of this study was to develop and validate a nomogram for the diagnosis of PJP in patients with non-HIV-infected pneumonia who are undergoing oral glucocorticoid treatment. Patients and Methods: This study was a retrospective, cross-sectional research. The development group included 434 patients who were admitted with pneumonia from 6 hospitals. Demographics, symptomatic features, laboratory and computed tomography data were analyzed using the least absolute shrinkage and selection operator (LASSO) to select potential diagnostic indicators. Binary logistic regression was used to develop a diagnostic nomogram. Another 119 patients with pneumonia admitted at Sichuan Provincial People's Hospital was used as the validation group. The diagnostic performance of the nomogram was measured by area under the receiver-operating-characteristics curve (AUC), calibration curves, and the net benefit by decision curve. Results: PJP prevalence was 25.3% in the development group. LASSO regression revealed that age, lymphocyte count, fever, dry cough, respiratory failure, ground-glass opacity in lungs, glucocorticoid therapy duration, and immunosuppressive therapy were indicators of PJP. The nomogram showed robust discrimination, with an AUC of 0.82 (95% CI 0.77-0.86) in the development group and an AUC of 0.87 (95% CI 0.80-0.94) in the validation group, both showing acceptable calibration. In the decision curve analysis, our model consistently achieved a greater net benefit across almost all ranges of clinical thresholds. Conclusion: We developed a nomogram with good diagnostic power for PJP diagnosis in pneumonia patients receiving oral glucocorticoids. This nomogram may help promote timely treatment of PJP and thus reduce the mortality rate in these patients.

Antifungal activity and potential mechanism of action of caspofungin in combination with ribavirin against Candida albicans.

The number of invasive fungal infections has increased dramatically, resulting in high morbidity and mortality among immunocompromised patients. With increasing use of caspofungin (CAS), resistant strains have emerged frequently and led to limitations in the treatment of patients with severe invasive Candida albicans infections. Combination therapy is an important method to deal with this issue. As such, this study investigated the activity of CAS in combination with ribavirin (RBV) against C. albicans. The results of this in-vitro study showed that the minimum inhibitory concentrations (MICs) of CAS and RBV when they were used as monotherapy were 0.5-1 µg/mL and 2-8 µg/mL, respectively, while the MIC of CAS decreased from 0.5-1 µg/mL to 0.0625-0.25 µg/mL when used in combination with RBV, with a fractional inhibitory concentration index (FICI) ≤0.5. In addition, the RBV + CAS combination group displayed synergistic effects against C. albicans biofilm over 4 h; the sessile MIC (sMIC) of CAS decreased from 0.5-1 µg/mL to 0.0625-0.25µg/mL and the sMIC of RBV decreased from 4-16 µg/mL to 1-2 µg/mL, with FICI <0.5. The survival of C. albicans-infected Galleria mellonella was prolonged, the fungal burden was decreased, and the area of tissue damage was reduced after combination therapy. Further study showed that the mechanisms of action of the synergistic effect were related to the inhibition of biofilm formation, the inhibition of hyphal growth, and the activation of metacaspases, but were not related to the accumulation of reactive oxygen species. It is hoped that these findings will contribute to the understanding of drug resistance in C. albicans, and provide new insights for the application of RBV.

The antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy.

INTRODUCTION: Candida species have been regarded as global health threats due to their ability to cause invasive infections. It is challenging to treat Candida bloodstream infections, which are associated with high mortality levels. Monotherapy with antifungals is sometimes not effective against severe Candida infections, and combination therapy is needed in clinical practice. AREAS COVERED: This review was undertaken based on data from a PubMed search for English language reports published before March 2021 by using the terms 'caspofungin,' 'Candida species,' 'combination therapy,' 'antifungal effect,' and 'novel antifungal agent.' EXPERT OPINION: Combination therapy is an empirical strategy for treating refractory Candida infections. Caspofungin has been recommended to treat candidaemia. Caspofungin in combination therapy has some applications, while the efficacy of combination therapy in the treatment of refractory Candida infections needs more study, such as randomized controlled trials. In addition, novel compounds or drugs with potential antifungal activities have been examined, and some of them exhibit synergistic interactions with caspofungin. Thus, the antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy is summarized.

NEDD4L-induced ß-catenin ubiquitination suppresses the formation and progression of interstitial pulmonary fibrosis via inhibiting the CTHRC1/HIF-1α axis.

Interstitial pulmonary fibrosis (IPF) is a severe progressive lung disease with limited therapeutic options and poor prognosis. Initially, we found the downregulated level of neural precursor cell expressed developmentally down-regulated 4-like protein (NEDD4L) in IPF-related expression microarray dataset, and this study was thus performed to explore the molecular mechanism of NEDD4L in IPF. The expression of NEDD4L was subsequently validated in lung tissues of IPF patients and mouse models. Then, mouse primary lung fibroblasts (LFs) were collected for in vitro functional experiments, with CCK-8, Transwell, and immunofluorescence assays used to examine the viability, migration, and differentiation of LFs. The in vitro findings were further assessed using in vivo mouse models. The expression of NEDD4L was down-regulated in lung tissues of IPF patients and mouse models. Overexpression of NEDD4L restricted the formation and progression of IPF in mice and attenuated the proliferative, invasive and differentiative abilities of LFs. Further, NEDD4L halted LFs activity by enhancing ß-catenin ubiquitination and down-regulating the CTHRC1/HIF-1α axis. Also, in vivo experiments then validated that NEDD4L silencing repressed ß-catenin ubiquitination and activated the CTHRC1/HIF-1α axis, thereby aggravating IPF in mice. NEDD4L may suppress the formation and progression of IPF through augmenting ß-catenin ubiquitination and inhibiting the CTHRC1/HIF-1α axis.

Case Report: Successful Treatment of Pulmonary Talaromyces marneffei Infection with Posaconazole in a Renal Transplant Recipient.

Talaromyces marneffei (T. marneffei), formerly Penicillium marneffei, is a dimorphic fungus prevalent in Southeast Asia that can cause severe systemic infection, especially in immunocompromised patients. There are few reports about the use of posaconazole in T. marneffei infection. Here, we present a case of pulmonary T. marneffei infection in a renal transplant recipient. The patient responded rapidly to oral posaconazole administration but experienced serum creatinine fluctuation because of the interaction between posaconazole and immunosuppressants. Seven months after adjusting the dose of immunosuppressants, the patient recovered completely. Posaconazole is a potentially promising therapy for T. marneffei infection, but it should be administered under close monitoring.

Transcription factor YY1 inhibits the expression of THY1 to promote interstitial pulmonary fibrosis by activating the HSF1/miR-214 axis.

Interstitial pulmonary fibrosis (IPF) is a progressive disease of diverse etiology manifesting with proliferation of lung fibroblasts and accumulation of extracellular matrix deposition in pulmonary interstitium. Recent studies show aberrant expression of mRNAs and microRNAs (miRNAs) in human embryonic pulmonary fibroblasts (HEPFs). In this study, we investigated effects of the YY1/HSF1/miR-214/THY1 axis on the functions of HEPFs and IPF. Loss- and gain-of-function tests were conducted to identify roles of YY1, HSF1, miR-214, and THY1 in IPF. As determined by RT-qPCR or western blot assay, silencing YY1 down-regulated HSF1 expression and attenuated the expression of pro-proliferative and fibrosis markers in HEPFs. Meanwhile, viability of HEPFs was impeded by YY1 knockdown. The binding relationship between miR-214 and THY1 was verified using dual-luciferase reporter assay. In HEPFs, down-regulation of HSF1 reduced miR-214 expression to repress proliferation and fibrogenic transformation of HEPFs, while inhibition of miR-214 expression could restrain the fibrogenic transformation property of HEPFs by up-regulating THY1. Subsequently, IPF model in mice was induced by bleomycin treatment. These animal experiments validated the protective effects of YY1 knockdown against IPF-induced lung pathological manifestations, which could be reversed by THY1 knockdown. Our study demonstrates the important involvement of YY1/HSF1/miR-214/THY1 axis in the development of IPF.

Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans.

The incidence of resistant Candida isolates, especially Candida albicans, has increased continuously. To overcome the resistance, research on antifungal agent sensitizers has attracted considerable attention. Omeprazole and lansoprazole were found to inhibit the growth of sensitive C. albicans and hyphae formation in a high dose, respectively. This study aimed to determine the interactions of common clinically proton pump inhibitors (PPIs) and fluconazole both in vitro and in vivo and to further explore the possible mechanisms. In vitro, the tested PPIs all acted synergistically with fluconazole against both resistant C. albicans planktonic cells and biofilms preformed for ≤12 h with the minimum inhibitory concentration of fluconazole decreased from >512 µg/mL to 1-4 µg/mL. In vivo, PPIs plus fluconazole prolonged the survival rate of infected Galleria mellonella larvae by two-fold compared with that for the fluconazole monotherapy group and significantly reduced the tissue damage of infected larvae. Mechanism studies showed that PPIs significantly suppressed efflux pump activity, which is the common resistance mechanism of C. albicans, and significantly inhibited the virulence factors: phospholipase activity and morphology switching. These findings will provide new insights into antifungal agent discovery and potential approaches for the treatment of candidiasis caused by resistant C. albicans.

Antifungal activity of ribavirin used alone or in combination with fluconazole against Candida albicans is mediated by reduced virulence.

The incidence of fungal infections has increased continuously in recent years, and drug resistance, especially resistance to fluconazole (FLC), has emerged. To overcome this challenge, research on the antifungal activities of non-antifungal agents has gained more attention. In this study, we determined the anti-Candida activity of ribavirin (RBV), an antiviral drug commonly used in the clinic, and found that RBV displayed potent antifungal activity when used alone or in combination with FLC in vitro and in vivo. In vitro, the MIC80 values of RBV were 2-4 µg/mL for FLC-susceptible Candida albicans and 8 µg/mL for FLC-resistant C. albicans. When RBV at a dose of 1 µg/mL was combined with FLC, significant synergistic effects were exhibited against FLC-resistant C. albicans, and the MICs of FLC decreased from >512 µg/mL to 0.25-1 µg/mL. Synergism was also exhibited against C. albicans biofilms. In vivo, RBV plus FLC significantly improved the survival of infected Galleria mellonella larvae compared with the FLC-treated group over a 4-day period and attenuated the damage of FLC-resistant C. albicans to G. mellonella larvae tissue. Furthermore, mechanistic studies indicated that the antifungal effects of RBV used alone or in combination with FLC might be associated with inhibition of biofilm formation, reduced extracellular phospholipase activity and inhibition of hyphal growth, but is not related to promotion of FLC uptake and inhibition of FLC efflux. These results provide a promising direction for overcoming drug resistance and for expanding the clinical application of existing drugs.

The Role of MicroRNAs in the Pathogenesis of Diabetic Nephropathy.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients; it is also an important cause of renal dysfunction, renal fibrosis, and end-stage renal disease. Unfortunately, the pathogenesis of DN is complex and has not yet been fully elucidated; hence, the pathogenesis of DN to determine effective treatments of crucial importance is deeply explored. Early DN research focuses on hemodynamic changes and metabolic disorders, and recent studies have shown the regulatory role of microRNAs (miRNAs) in genes, which may be a new diagnostic marker and therapeutic target for diabetic nephropathy. In this review, we summarize the recent advances in the clinical value and molecular mechanisms of miRNAs in DN, providing new ideas for the diagnosis and treatment of DN.

Anti-Candida activity of existing antibiotics and their derivatives when used alone or in combination with antifungals.

Fungal infections are a growing challenge in immunocompromised patients, especially candidiasis. The prolonged use of traditional antifungals to treat Candida infection has caused the emergence of drug resistance, especially fluconazole. Therefore, new therapeutic strategies for Candida infection are warranted. Recently, attention has been paid to the anti-Candida activity of antibiotics and their derivatives. Studies revealed that a series of antibiotics/derivatives displayed potential anti-Candida activity and some of them could significantly increase the susceptibility of antifungals. Interestingly, the derivatives of aminoglycosides were even more active than fluconazole/itraconazole/posaconazole. This article reviews the anti-Candida activities and mechanisms of antibiotics/derivatives used alone or in combination with antifungals. This review will helpfully provide novel insights for overcoming Candida resistance and discovering new antifungals.

Next-generation sequencing improves molecular epidemiological characterization of thalassemia in Chenzhou Region, P.R. China.

OBJECTIVES: Thalassemia is a highly prevalent monogenic inherited disease in southern China. It is important to collect epidemiological data comprehensively for proper prevention and treatment. METHODS: In this study, blood samples collected from 15 807 residents of Chenzhou were primarily screened by hematological tests. A total of 3973 samples of suspected thalassemia carriers were further characterized by combined next-generation sequencing (NGS) and Gap-PCR. RESULTS: In total, 1704 subjects were diagnosed as thalassemia carriers with a total prevalence rate of 10.78%, including 943 α-thalassemia carriers, 708 ß-thalassemia carriers, and 53 composite α and ß-thalassemia carriers. The prevalence rates of α-thalassemia, ß-thalassemia, and composite α and ß-thalassemia were 5.97%, 4.48%, and 0.34%, respectively. Meanwhile, we characterized 19 α-thalassemia variations and 21 ß-thalassemia variations in thalassemia carriers. Approximately 2.88% of thalassemia carriers would be missed by traditional genetic analysis. In addition, four novel thalassemia mutations and one novel abnormal hemoglobin mutation were identified. CONCLUSIONS: Our data suggest a high prevalence of thalassemia and a diverse spectrum of thalassemia-associated variations in Chenzhou. Also, combined NGS and Gap-PCR is an effective thalassemia screening method. Our findings might be helpful for prevention and treatment of thalassemia in this region.