Heat shock protein 110: A novel candidate for disease diagnosis and targeted therapy.

The heat shock protein 110 (Hsp110) family in eukaryotes plays a pivotal role in maintaining cellular proteostasis. As a unique class of molecular chaperones, Hsp110s act as both independent chaperones and cochaperones for other essential molecular chaperones. Malfunction of Hsp110s is involved in many diseases. Thus targeting Hsp110s or its interactions with client proteins may provide new approaches for developing therapeutics. In this review, we describe the current understanding of the role and molecular mechanism of Hsp110s in disease development, and discuss the recent exploration of Hsp110s as potential targets to provide a novel direction for disease diagnosis and targeted therapy.

Allosteric site identification, virtual screening and discovery of a sulfonamide Hsp110-STAT3 interaction inhibitor for the treatment of hypoxic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disorder marked by vascular remodeling, which is linked to the malignant phenotypes of pulmonary vascular cells. The prevailing therapeutic approaches for PAH tend to neglect the potential role of vascular remodeling, leading to the clinical prognosis remains poor. Previously, we first demonstrated that heat shock protein (Hsp110) was significantly activated to boost Hsp110-STAT3 interaction, which resulted in abnormal proliferation and migration of human pulmonary arterial endothelial cells (HPAECs) under hypoxia. In the present study, we initially postulated the allosteric site of Hsp110, performed a virtual screening and biological evaluation studies to discover novel Hsp110-STAT3 interaction inhibitors. Here, we identified compound 29 (AN-329/43448068) as the effective inhibitor of HPAECs proliferation and the Hsp110-STAT3 association with good druggability. In vitro, 29 significantly impeded the chaperone function of Hsp110 and the malignant phenotypes of HPAECs. In vivo, 29 remarkably attenuated pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-induced PAH rats (i.g). Altogether, our data support the conclusion that it not only provides a novel lead compound but also presents a promising approach for subsequent inhibitor development targeting Hsp110-STAT3 interaction.

Broad bandwidth and excellent thermal stability in BiScO3-PbTiO3 high-temperature ultrasonic transducer for non-destructive testing.

High-temperature ultrasonic transducer (HTUT) is essential for non-destructive testing (NDT) in harsh environments. In this paper, a HTUT based on BiScO3-PbTiO3 (BS-PT) piezoelectric ceramics was developed, and the effect of different backing layers on its bandwidth were analyzed. The HTUT demonstrates a broad bandwidth and excellent thermal stability with operation temperature up to 400 °C. By using a 10 mm thick porous alumina backing layer, the HTUT achieves a broad -6 dB bandwidth of 100 %, which is about 4 times superior to the transducer with an air backing layer. The center frequency (fc) of the HTUT remains stable with fluctuations of less than 10 % across the temperature range from room temperature to 400 °C. The HTUT successfully detected simulated defects in pulse-echo mode for NDT over 200 °C. This research not only advances high-temperature ultrasonic transducer technology but also expands the NDT applications in harsh environmental conditions.

Discovery and Optimization of Hsp110 and sGC Dual-Target Regulators for the Treatment of Pulmonary Arterial Hypertension.

Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.

A bioactive xyloglucan polysaccharide hydrogel mechanically enhanced by Pluronic F127 micelles for promoting chronic wound healing.

Chronic wounds represent a formidable global healthcare challenge due to the bacteria infections and uncontrollable inflammation responses, while developing wound healing materials capable of resolving these issues remains a challenge. In this study, we integrated xyloglucan (XG) with Pluronic F127 diacrylate (F127DA)to develop a composite hydrogel for wound healing, where the XG introduced anti-inflammation and anti-bacterial properties to the construct, and F127DA provides the photocurable properties essential for hydrogel formation and robust mechanical characteristics to achieve physical strength that matches tissue regeneration. The material characterizations suggested that XG/F127DA hydrogels had great biostability, blood compatibility and antibacterial effects, which was suitable to be used as a wound healing material. The in vitro analysis by culturing L929 fibroblasts on the hydrogel surface demonstrated that the inclusion of XG could promote the cellular proliferation rate, migration rate, and re-epithelialization-related marker expression, while downregulate the inflammation process. The XG/F127DA hydrogel was further used for the full-thickness skin wound healing test on mice, where the inclusion of XG significantly increased the wound closure rate through reducing the inflammation responses, and promote re-epithelialization and angiogenesis. These results indicated that XG/F127DA hydrogel has great potential to be used for wound healing in future clinical translation.

Clinical, radiological, and laboratory features of HIV-negative pulmonary cryptococcosis with regard to serum lateral flow assay.

Introduction: Cryptococcosis is the second most common invasive yeast infection in China. Pulmonary cryptococcosis (PC) is difficult to diagnose due to the lack of specific clinical features and the limitation of diagnostic techniques. Although lateral flow assay was very useful in diagnosing cryptococcal infection, quite a few patients with PC presented negative serum lateral flow assay (sLFA). Methods: We conducted a retrospective study of HIV-negative patients who were diagnosed with PC in our hospital over the past decade to explore the potential relationship between the clinical profiles and sLFA in PC. Results: In total, 112 patients with sLFA tested were enrolled in this study, of which 58.93% were male. The positivity rate of sLFA for PC was 91.07%. The extent of pulmonary lesions was positively correlated with sLFA grade (Spearman r = 0.268, p < 0.01). Solitary nodule (SN) and pneumonia were the most common imaging findings in PC with negative and positive sLFA respectively. Among 65 symptomatic PC patients, 14 presented with fever and had higher hypersensitive C-reactive protein (hsCRP) level and more extensive pulmonary involvement (Mann-Whitney U test, p < 0.05) than those without fever. Symptomatic PC patients were more likely to have positive results of sLFA (Mann-Whitney U test, p = 0.05) compared against asymptomatic ones. Discussion: In conclusion, negative sLFA cannot exclude PC in patients with a solitary nodule in lung. Positive sLFA is more reliable in diagnosing PC in symptomatic patients with diffused lesions in lung who generally experience a more severe systemic inflammatory reaction.

Advances in TRPV6 inhibitors for tumors by targeted therapies: Macromolecular proteins, synthetic small molecule compounds, and natural compounds.

TRPV6, a Ca2+-selective member of the transient receptor potential vanilloid (TRPV) family, plays a key role in extracellular calcium transport, calcium ion reuptake, and maintenance of a local low calcium environment. An increasing number of studies have shown that TRPV6 is involved in the regulation of various diseases. Notably, overexpression of TRPV6 is closely related to the occurrence of various cancers. Research confirmed that knocking down TRPV6 could effectively reduce the proliferation and invasiveness of tumors by mainly mediating the calcium signaling pathway. Hence, TRPV6 has become a promising new drug target for numerous tumor treatments. However, the development of TRPV6 inhibitors is still in the early stage, and the existing TRPV6 inhibitors have poor selectivity and off-target effects. In this review, we focus on summarizing and describing the structure characters, and mechanisms of existing TRPV6 inhibitors to provide new ideas and directions for the development of novel TRPV6 inhibitors.

A Fetus with Maternal Uniparental Disomy on Chromosome 20: Case Report with Genetic Analysis and Prenatal Diagnosis.

BACKGROUND: A fetus with increased copy number of chromosome 20 was identified by NIPT. Here we utilize several genetic tests and analyses to illuminate the etiology of such aneuploidy. METHODS: Amniotic fluid cells were extracted from pregnant woman and sent for karyotype and chromosomal microarray analysis (CMA). Trio pedigree analysis was conducted with Chromosome Analysis Suite and uniparental disomy (UPD)-tool software. RESULTS: CMA identified consistent results, which were 2 regions of homozygosity: arr[GRCh37]20p12.2q11.1 (11265096_26266313)hmz and arr[GRCh37]20q11.21q13.2(29510306_54430467)hmz. The trio pedigree analysis discovered that the fetal chromosome 20 was the entire maternal UPD mosaic with isodisomy and heterodisomy. CONCLUSIONS: When a large segment of chromosome is homozygous, appropriate genetic tests are required to find the potential mechanisms for UPD formation.

Performance of Cryptococcal Antigen Lateral Flow Assay in Bronchoalveolar Lavage Fluid in HIV-Negative Patients.

OBJECTIVE: We presented the performance of cryptococcal antigen lateral flow assay test using bronchoalveolar lavage fluid (BALF) samples in the HIV-negative Chinese population. METHODS: From January 2019 to June 2022, cryptococcal antigen was detected in both serum and BALF samples from 113 patients with suspected pulmonary cryptococcosis. RESULTS: 49 patients were finally diagnosed with pulmonary cryptococcosis. The sensitivity of cryptococcal antigen lateral flow assay test in serum and BALF specimens from confirmed cases was 90.0% and 96.0%, respectively, and the specificity was 87.3% and 95.5%, respectively. When the diameter of the lung lesion was less than 15 mm, the antigen positivity rate of BALF was higher than that of serum. Moreover, the result of the cryptococcal antigen test was associated with the lymphocytes count of BALF. CONCLUSION: Our data demonstrate that cryptococcal antigen Lateral Flow Assay for BALF specimens might contribute to the early diagnosis of pulmonary cryptococcosis.

Inhibition of Hsp110-STAT3 interaction in endothelial cells alleviates vascular remodeling in hypoxic pulmonary arterial Hypertension model.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary vascular remodeling which is associated with the malignant phenotypes of pulmonary vascular cells. Recently, the effects of heat shock protein 110 (Hsp110) in human arterial smooth muscle cells were reported. However, the underlying roles and mechanisms of Hsp110 in human pulmonary arterial endothelial cells (HPAECs) that was disordered firstly at the early stage of PAH remain unknown. METHODS: In this research, the expression of Hsp110 in PAH human patients and rat models was investigated, and the Hsp110 localization was determined both in vivo and in vitro. The roles and mechanism of elevated Hsp110 in excessive cell proliferation and migration of HPAECs were assessed respectively exposed to hypoxia. Small molecule inhibitors targeting Hsp110-STAT3 interaction were screened via fluorescence polarization, anti-aggregation and western blot assays. Moreover, the effects of compound 6 on HPAECs abnormal phenotypes in vitro and pulmonary vascular remodeling of hypoxia-indued PAH rats in vivo by interrupting Hsp110-STAT3 interaction were evaluated. RESULTS: Our studies demonstrated that Hsp110 expression was increased in the serum of patients with PAH, as well as in the lungs and pulmonary arteries of PAH rats, when compared to their respective healthy subjects. Moreover, Hsp110 levels were significantly elevated in HPAECs under hypoxia and mediated its aberrant phenotypes. Furthermore, boosted Hsp110-STAT3 interaction resulted in abnormal proliferation and migration via elevating p-STAT3 and c-Myc in HPAECs. Notably, we successfully identified compound 6 as potent Hsp110-STAT3 interaction inhibitor, which effectively inhibited HPAECs proliferation and migration, and significantly ameliorated right heart hypertrophy and vascular remodeling of rats with PAH. CONCLUSIONS: Our studies suggest that elevated Hsp110 plays a vital role in HPAECs and inhibition of the Hsp110-STAT3 interaction is a novel strategy for improving vascular remodeling. In addition, compound 6 could serve as a promising lead compound for developing first-in-class drugs against PAH.

Retrospective analysis of pulmonary cryptococcosis and extrapulmonary cryptococcosis in a chinese tertiary hospital.

Cryptococcosis is an invasive fungal disease with increased morbidity in China over the past two decades. Cryptococci can infect immunocompromised hosts as well as immunocompetent ones. In this study, we reviewed data of 71 inpatients with cryptococcosis at Ningbo First Hospital from May 2010 to May 2020 and compared the clinical profiles of pulmonary cryptococcosis (PC) and extrapulmonary cryptococcosis (EPC). Of 71 patients (38 males, 33 females), 70 were non-HIV. The annual inpatient population increased dramatically, especially in the PC group. PC was confirmed in 77.46% (55/71) of cases by pathology. The rest were EPC including intracranial infection (15.49%, 11/71) and cryptococcemia (7.04%, 5/71). Compared with PC, a larger proportion of EPC patients were found to have immunocompromised conditions judged by predisposing factors (p < 0.01), or detectable humoral or cellular immunodeficiency. Fever and headache were more common in EPC patients (p < 0.001). Patients with EPC had lower serum sodium level (p = 0.041), lower monocyte counts (p = 0.025) and higher C-reactive protein (p = 0.012). In our study, the sensitivity of cryptococcus antigen detection for EPC was 100% regardless of sample type, while serum lateral flow assay (LFA) tested negative in 25% (5/20) of PC. Immunocompromised hosts are more likely to suffer from EPC than PC.

A first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi.

Proteins of the Hsp110 family are molecular chaperones that play important roles in protein homeostasis in eukaryotes. The pathogenic fungus Candida albicans, which causes infections in humans, has a single Hsp110, termed Msi3. Here, we provide proof-of-principle evidence supporting fungal Hsp110s as targets for the development of new antifungal drugs. We identify a pyrazolo[3,4-b] pyridine derivative, termed HLQ2H (or 2H), that inhibits the biochemical and chaperone activities of Msi3, as well as the growth and viability of C. albicans. Moreover, the fungicidal activity of 2H correlates with its inhibition of in vivo protein folding. We propose 2H and related compounds as promising leads for development of new antifungals and as pharmacological tools for the study of the molecular mechanisms and functions of Hsp110s.

Baicalein Inhibits Plasmid-Mediated Horizontal Transmission of the blaKPC Multidrug Resistance Gene from Klebsiella pneumoniae to Escherichia coli.

Carbapenem-resistant bacterial infections pose an urgent threat to public health worldwide. Horizontal transmission of the ß-lacatamase Klebsiella pneumoniae carbapenemase (blaKPC) multidrug resistance gene is a major mechanism for global dissemination of carbapenem resistance. Here, we investigated the effects of baicalein, an active ingredient of a Chinese herbal medicine, on plasmid-mediated horizontal transmission of blaKPC from a meropenem-resistant K. pneumoniae strain (JZ2157) to a meropenem-sensitive Escherichia coli strain (E600). Baicalein showed no direct effects on the growth of JZ2157 or E600. Co-cultivation of JZ2157 and E600 caused the spread of meropenem resistance from JZ2157 to E600. Baicalein at 40 and 400 µg/mL significantly inhibited the spread of meropenem resistance. Co-cultivation also resulted in plasmid-mediated transmission of blaKPC from JZ2157 to E600, which was inhibited by baicalein. Therefore, baicalein may be used in clinical practice to prevent or contain outbreaks of carbapenem-resistant infections by inhibiting the horizontal transfer of resistance genes across bacteria species.

Clinical features of patients with talaromycosis marneffei and microbiological characteristics of the causative strains.

BACKGROUND: Talaromyces marneffei (T. marneffei) is a temperature-dependent dimorphic fungus that is mainly prevalent in Southeast Asia and South China and often causes disseminated life-threatening infections. This study aimed to investigate the clinical features and improve the early diagnosis of talaromycosis marneffei in nonendemic areas. METHODS: We retrospectively analyzed the medical records of six cases of T. marneffei infection. We describe the clinical manifestations, laboratory tests, and imaging manifestations of the six patients. RESULTS: Talaromyces marneffei infection was confirmed by sputum culture, blood culture, tissue biopsy, and metagenomic next-generation sequencing (mNGS). In this study, there were five disseminated-type patients and two HIV patients. One patient died within 24 h, and the others demonstrated considerable improvement after definitive diagnosis. CONCLUSIONS: Due to the lack of significant clinical presentations of talaromycosis marneffei, many cases may be easily misdiagnosed in nonendemic areas. It is particularly important to analyze the imaging manifestations and laboratory findings of infected patients. With the rapid development of molecular biology, mNGS may be a rapid and effective diagnostic method.

The diagnostic utility of IL-10, IL-17, and PCT in patients with sepsis infection.

Objective: The purpose of this study is to determine the diagnostic value and net clinical benefit of interleukin-10 (IL-10), interleukin-17 (IL-17), procalcitonin (PCT), and combination tests in patients with sepsis, which will serve as a standard for sepsis early detection. Patients and methods: An investigation of 84 sepsis patients and 81 patients with local inflammatory diseases admitted to the ICU of Tongji University Hospital in 2021. In addition to comparing inter-group variability, indicators relevant to sepsis diagnosis and therapy were screened. Results: LASSO regression was used to examine PCT, WBC, CRP, IL-10, IFN-, IL-12, and IL-17. Multivariate logistic regression linked IL-10, IL-17, and PCT to sepsis risk. The AUC values of IL-10, IL-17, PCT, and the combination of the three tests were much higher than those of standard laboratory infection indicators. The combined AUC was greater than the sum of IL-10, IL-17, and PCT (P < 0.05). A clinical decision curve analysis of IL-10, IL-17, PCT, and the three combined tests found that the three combined tests outperformed the individual tests in terms of total clinical benefit rate. To predict the risk of sepsis using IL-10, IL-17, and PCT had an AUC of 0.951, and the model's predicted probability was well matched. An examination of the nomogram model's clinical value demonstrated a considerable net therapeutic benefit between 3 and 87%. Conclusion: The IL-10, IL-17, and PCT tests all have a high diagnostic value for patients with sepsis, and the combination of the three tests outperforms the individual tests in terms of diagnostic performance, while the combined tests have a higher overall clinical benefit rate.

Spherical piezoelectric transducers of functionally graded materials.

In this work, a functionally graded spherical piezoelectric transducer (FG-sPET) is proposed and an accurate theoretical model is constructed, mainly composed of a three-port electromechanical equivalent circuit model (EECM). The EECM of FG-sPET can be connected to that of other vibration systems according to the boundary conditions (force and vibration velocity), making it easier to evaluate the whole mechanical vibration system. The validity of the EECM for FG-sPET is verified by comparison with other literature. The effects of geometric dimensions and non-uniform coefficients on the vibration characteristics (resonance/anti-resonance frequencies and effective electromechanical coupling coefficient) of FG-sPET are also studied, contributing to systematically evaluating the key factors determining the vibration characteristics of FG-sPET. The proposed analytical system is of excellent guidance for the structural optimization design of functionally graded piezoelectric devices.

TPN171H alleviates pulmonary hypertension via inhibiting inflammation in hypoxia and monocrotaline-induced rats.

Pulmonary hypertension (PH) is a progressive and life-threatening disease with poor prognosis despite many advances in medical therapy over the past 20 years. Novel therapies which target on the underlying pathology of PH are still urgent to be met. TPN171H is a recently found new compound that exhibits potent pharmacological effects in PH via inhibiting phosphodiesterase type 5 (PDE-5). However, as one icariin derivative, the anti-inflammatory effects of TPN171H for treating PH are not clear. The present study was designed to investigate the therapeutical effect of TPN171H against inflammation in PH and reveal the underlying mechanism. Hypoxia and monocrotaline (MCT)-induced PH rat models were established, which were treated by oral administration of TPN171H (5, 25 mg/kg/d) or sildenafil (25 mg/kg/d). The right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and vascular remodeling were measured. The results suggested that TPN171H significantly reduced RVSP and RVHI, and reversed pulmonary vascular remodeling in rats with both models. Furthermore, in in vivo and in vitro research, our data suggested that TPN171H remarkably suppressed cathepsin B-mediated NLRP3 inflammasome activation, which may contribute to its therapeutical function for PH.

Identification of selective homeodomain interacting protein kinase 2 inhibitors, a potential treatment for renal fibrosis.

Homeodomain interacting protein kinase 2 (HIPK2) has emerged as a promising target for the discovery of anti-renal fibrosis drugs. Herein, to develop specific pharmacologic inhibitors of HIPK2, we designed and synthesized a series of compounds containing benzimidazole and pyrimidine scaffolds via fragment-based drug design strategy. Kinase assay was applied to evaluate the inhibitory activity of target compounds against HIPKs enzyme. The molecular docking study suggest the contribution of tyrosine residues beside the active sites of HIPK1-3 to the selectivity of active compounds. Compound 15q displayed good selectivity and potent inhibitory activity against HIPK2 compared to other two subtype enzymes. 15q could downregulate phosphorylated p53, the direct substrate of HIPK2, and decrease the fibrosis-related downstream of HIPK2, such as p-Smad3 and α-SMA in NRK-49F cells. 15q showed no effect on the cell apoptosis in fibrotic or cancer cell lines, suggesting little cancer risk of 15q. Notably, 15q displayed encouraging in vivo anti-fibrotic effects in the unilateral ureteral obstruction mouse model, which could be used as a potential lead for structural optimization and candidate for the development of selective HIPK2 inhibitors.