The therapeutic potential of phosphodiesterase 9 (PDE9) inhibitors: a patent review (2018-present).

INTRODUCTION: Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer's disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates. AREA COVERED: This review provides an overview of PDE9 inhibitors in patents from 2018 to the present. EXPERT OPINION: Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

Synthetic macrolides overcoming MLSBK-resistant pathogens.

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Battery-free optoelectronic patch for photodynamic and light therapies in treating bacteria-infected wounds.

Light therapy is an effective approach for the treatment of a variety of challenging dermatological conditions. In contrast to existing methods involving high doses and large areas of illumination, alternative strategies based on wearable designs that utilize a low light dose over an extended period provide a precise and convenient treatment. In this study, we present a battery-free, skin-integrated optoelectronic patch that incorporates a coil-powered circuit, an array of microscale violet and red light emitting diodes (LEDs), and polymer microneedles (MNs) loaded with 5-aminolevulinic acid (5-ALA). These polymer MNs, based on the biodegradable composite materials of polyvinyl alcohol (PVA) and hyaluronic acid (HA), serve as light waveguides for optical access and a medium for drug release into deeper skin layers. Unlike conventional clinical photomedical appliances with a rigid and fixed light source, this flexible design allows for a conformable light source that can be applied directly to the skin. In animal models with bacterial-infected wounds, the experimental group with the combination treatment of metronomic photodynamic and light therapies reduced 2.48 log10 CFU mL-1 in bactericidal level compared to the control group, indicating an effective anti-infective response. Furthermore, post-treatment analysis revealed the activation of proregenerative genes in monocyte and macrophage cell populations, suggesting enhanced tissue regeneration, neovascularization, and dermal recovery. Overall, this optoelectronic patch design broadens the scope for targeting deep skin lesions, and provides an alternative with the functionality of standard clinical light therapy methods.

Mild hyperthermia enhanced synergistic uric acid degradation and multiple ROS elimination for an effective acute gout therapy.

BACKGROUND: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. RESULTS: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. CONCLUSIONS: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.

Global research hotspots, development trends and prospect discoveries of phase separation in cancer: a decade-long informatics investigation.

Liquid-liquid phase separation (LLPS) is a complex and subtle phenomenon whose formation and regulation take essential roles in cancer initiation, growth, progression, invasion, and metastasis. This domain holds a wealth of underutilized unstructured data that needs further excavation for potentially valuable information. Therefore, we retrospectively analyzed the global scientific knowledge in the field over the last decade by using informatics methods (such as hierarchical clustering, regression statistics, hotspot burst, and Walktrap algorithm analysis). Over the past decade, this area enjoyed a favorable development trend (Annual Growth Rate: 34.98%) and global collaboration (International Co-authorship: 27.31%). Through unsupervised hierarchical clustering based on machine learning, the global research hotspots were divided into five dominant research clusters: Cluster 1 (Effects and Mechanisms of Phase Separation in Drug Delivery), Cluster 2 (Phase Separation in Gene Expression Regulation), Cluster 3 (Phase Separation in RNA-Protein Interaction), Cluster 4 (Reference Value of Phase Separation in Neurodegenerative Diseases for Cancer Research), and Cluster 5 (Roles and Mechanisms of Phase Separation). And further time-series analysis revealed that Cluster 5 is the emerging research cluster. In addition, results from the regression curve and hotspot burst analysis point in unison to super-enhancer (a=0.5515, R2=0.6586, p=0.0044) and stress granule (a=0.8000, R2=0.6000, p=0.0085) as the most potential star molecule in this field. More interestingly, the Random-Walk-Strategy-based Walktrap algorithm further revealed that "phase separation, cancer, transcription, super-enhancer, epigenetics"(Relevance Percentage[RP]=100%, Development Percentage[DP]=29.2%), "stress granule, immunotherapy, tumor microenvironment, RNA binding protein"(RP=79.2%, DP=33.3%) and "nanoparticle, apoptosis"(RP=70.8%, DP=25.0%) are closely associated with this field, but are still under-developed and worthy of further exploration. In conclusion, this study profiled the global scientific landscape, discovered a crucial emerging research cluster, identified several pivotal research molecules, and predicted several crucial but still under-developed directions that deserve further research, providing an important reference value for subsequent basic and clinical research of phase separation in cancer.

Lower baseline testosterone level is related to earlier development of castration resistance in metastatic prostate cancer: a multi-center cohort study.

Purpose: In the era of concurrent combination therapy in metastatic hormone sensitive prostate cancer, the impact of the testosterone level before initiating androgen deprivation therapy on treatment outcome is still uncertain. We aimed to investigate its effect on time-to-castration-resistance in a metastatic hormone sensitive prostate cancer cohort. Methods: This is a multi-center retrospective study of 5 databases from China, Japan, Austria and Spain including 258 metastatic hormone sensitive prostate cancer patients with androgen deprivation therapy initiated between 2002 and 2021. Baseline testosterone was divided into high and low groups using 12 nmol/L as cutoff level. Primary outcome was time-to-castration-resistance. Secondary outcomes were survival functions. Kaplan-Meier method was employed to evaluate the correlation between baseline testosterone and time-to-castration-resistance. Subgroup analysis was performed to elucidate the effect of upfront combination-therapy and metastatic volume. Results: Median age was 72 years. Median follow-up time was 31 months. Median pre-treatment prostate-specific-antigen level was 161 ng/mL. Majority of case were graded as International-Society-of-Urological-Pathology grade 5 (63.6%). 57.8% patients had high volume disease and 69.0% received upfront combination treatment. 44.6% of the cohort developed castration-resistance. The low testosterone group demonstrated shorter mean-time-to-castration-resistance (19.0 vs 22.4 months, p=0.031). The variance was more significant in patients without combination therapy (13.2 vs 26.3 months, p=0.015). Cancer-specific and overall survival were inferior in the low baseline testosterone level group without receiving combination therapy (p=0.001). Conclusions: Lower pre-treatment testosterone level is correlated to shorter time-to-castration resistance and worse survival in metastatic prostate cancer patients without upfront combination therapy. Those with low baseline testosterone should be encouraged to adopt combination therapy to delay progression.

Development of the Static and Dynamic Gene Expression Regulation Toolkit in Pseudomonas chlororaphis.

The advancement of metabolic engineering and synthetic biology has promoted in-depth research on the nonmodel microbial metabolism, and the potential of nonmodel organisms in industrial biotechnology is becoming increasingly evident. The nonmodel organism Pseudomonas chlororaphis is a safe plant growth promoting bacterium for the production of phenazine compounds; however, its application is seriously hindered due to the lack of an effective gene expression precise regulation toolkit. In this study, we constructed a library of 108 promoter-5'-UTR (PUTR) and characterized them through fluorescent protein detection. Then, 6 PUTRs with stable low, intermediate, and high intensities were further characterized by report genes lacZ encoding ß-galactosidase from Escherichia coli K12 and phzO encoding PCA monooxygenase from P. chlororaphis GP72 and thus developed as a static gene expression regulation system. Furthermore, the stable and high-intensity expressed PMOK_RS0128085UTR was fused with the LacO operator to construct an IPTG-induced plasmid, and a self-induced plasmid was constructed employing the high-intensity PMOK_RS0116635UTR regulated by cell density, resulting in a dynamic gene expression regulation system. In summary, this study established two sets of static and dynamic regulatory systems for P. chlororaphis, providing an effective toolkit for fine-tuning gene expression and reprograming the metabolism flux.

Realization of digital twin for dynamic control toward sample variation of ion exchange chromatography in antibody separation.

Digital twin (DT) is a virtual and digital representation of physical objects or processes. In this paper, this concept is applied to dynamic control of the collection window in the ion exchange chromatography (IEC) toward sample variations. A possible structure of a feedforward model-based control DT system was proposed. Initially, a precise IEC mechanistic model was established through experiments, model fitting, and validation. The average root mean square error (RMSE) of fitting and validation was 8.1% and 7.4%, respectively. Then a model-based gradient optimization was performed, resulting in a 70.0% yield with a remarkable 11.2% increase. Subsequently, the DT was established by systematically integrating the model, chromatography system, online high-performance liquid chromatography, and a server computer. The DT was validated under varying load conditions. The results demonstrated that the DT could offer an accurate control with acidic variants proportion and yield difference of less than 2% compared to the offline analysis. The embedding mechanistic model also showed a positive predictive performance with an average RMSE of 11.7% during the DT test under >10% sample variation. Practical scenario tests indicated that tightening the control target could further enhance the DT robustness, achieving over 98% success rate with an average yield of 72.7%. The results demonstrated that the constructed DT could accurately mimic real-world situations and perform an automated and flexible pooling in IEC. Additionally, a detailed methodology for applying DT was summarized.

Association of PFDeA exposure with hypertension (NHANES, 2013-2018).

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) is a series of artificial compounds which is associated with human health. However, there are few studies on the relationship between PFASs and hypertension. In this study, we examined the association between different kinds of PFASs and hypertension. Multivariable logistic regression and subgroup analysis were adopted to assess the associations between PFASs and hypertension. Spline smoothing plots and linear regression were used to assess the relationship between PFASs and blood pressure. We found a positive association between serum PFDeA concentrations and the prevalence of hypertension after fully adjusting confounders (OR = 1.2, P = 0.01), but other types of PFASs showed no positive results. Subgroup analysis stratified by ethnicity showed there was a stronger relationship among non-Hispanics than Hispanics. Serum PFDeA concentrations were positively associated with systolic pressure (ß = 0.7, P< 0.01) and diastolic blood pressure (ß = 0.8, P< 0.01) among non-Hispanics who did not take antihypertensive drugs. This study showed that PFDeA exposure was associated with hypertension in Americans who identify as non-Hispanic. There was a positive association between PFDeA and blood pressure in non-Hispanic Americans who did not take antihypertensive drugs.

Infrared Spectrum and Principal Component Analysis of Heavy Tar Cut by Different Fractions from Tar-Rich Coal.

The composition and content of heavy tar vary significantly depending on the pyrolysis conditions and separation methods. This study aimed to effectively identify the main components and content of heavy coal tar and provide a theoretical basis for its subsequent utilization. To achieve this, simulated distillation and infrared spectrum analysis of heavy coal tar were conducted with a focus on understanding the impact of simulated distillation on the composition and structure of tar. The results showed that the fraction content in the tar underwent significant changes after simulated distillation at different temperatures. Specifically, the content of light oil decreased from 4.3 to 0.1%, while the asphalt content increased from 77.6 to 90.6%. Infrared spectrum and peak fitting revealed that the distilled coal tars exhibited similar characteristic peaks in regions associated with hydroxyl, aliphatic hydrocarbon, oxygen-containing functional group, and aromatic hydrocarbon structure. Based on the infrared spectrum of heavy coal tar, principal component analysis was conducted on different fractions. When using two principal components, the cumulative value reached 96.93%. It was found that PC1 displayed strong peak signals around 749 and 687 cm-1, while PC2 exhibited strong peak signals near 2356 and 1143 cm-1.

Mechanism of Ruanmai decoction in treating atherosclerosis based on YWHAZ/p38MAPK/CASP3 signaling pathway / 中国药理学通报

Aim To explore the mechanism of action of Ruanmai decoction in treating atherosclerosis through network pharmacology. Methods The chemical components and targets of Ruanmai decoction were queried using TCMSP. Relevant targets for atherosclerosis were retrieved from DrugBank, GeneCards, OMIM, and TTD databases. The " Drug-Active Ingredient-Target" PPI network was constructed using Cyto-scape software. GO and KEGG enrichment analysis were performed using the David database. Molecular docking verification of key components with core targets was conducted using the Seesar software. Atherosclerosis mouse models were established by feeding ApoE mice with a high-fat diet, and Ruanmai decoction granules were administered orally. Aortic pathological sections were stained, blood lipids were measured, and immunofluorescence was used to detect Mac2 and YWHAZ protein expression. Western blot was used to detect p-p38MAPK and C-CASP3 protein expression. Results Ruanmai decoction screened a total of 72 active drug components corresponding to 168 target genes for the treatment of atherosclerosis. The targets were primarily enriched in biological processes related to lip-id metabolism, inflammation and immunity, oxidative stress, vascular endothelial function, cell proliferation and apoptosis, glycolysis, and ubiquitination. Signaling pathways such as МАРК, TNF, PDK-Akt, and IL-17 were also involved. Animal experiments verified that RMJ could regulate the p38MAPK signaling pathway by down-regulating key targets YWHAZ, p-p38MAPK, and C-CASP3, thereby reducing AS inflammation and inflammation-induced apoptosis. Conclusions Ruanmai decoction can inhibit the expression of YWHAZ and activate the p38MAPK signaling pathway, potentially improving vascular inflammation, lipid metabolism, oxidative stress, and other pathological processes by regulating the МАРК, TNF, PDK-Akt, and IL-17 signaling pathways, thus preventing and treating atherosclerosis.

Immunogenic Radiation Therapy for Enhanced Antitumor Immunity via a Core-Shell Nanosensitizer-Mediated Immunosuppressive Tumor Microenvironment Modulation.

Due to the immunosuppressive tumor microenvironment (TME) and weak radiation absorption, the immune response triggered by radiation therapy (RT) is limited. Herein, a core-shell nanosensitizer UiO@MnS (denoted as UM) was genuinely constructed for the amplification of RT efficacy and induction of immunogenicity via integrating MnS-reprogrammed TME with Hf-based UiO-sensitized RT. The acid-sensitive MnS would produce H2S under acidic TME to improve oxygenation through inhibition mitochondrial respiration and reducing metabolic oxygen consumption, leading to decreased HIF-1α expression and enhanced radiosensitization. In addition, the generated H2S inhibited the catalase activity to increase the H2O2 level, which subsequently enhanced the Mn2+-mediated Fenton-like reaction, resulting in G2/M cell cycle arrest to improve the cellular sensitivity for radiation. This impressive tumor oxygenation, cell cycle arrest, and radiosensitization procedure boosted RT efficacy and resulted in strong antitumor immunogenicity. Taken together, combining the immunosuppressive TME modulation with a sensitizing radiation strategy shows great promise for magnifying immunogenic RT outputs.

BrRD20 improves abiotic stress resistance in chrysanthemum.

RESPONSIVE TO DESSICATION 20 (RD20) is a member of the caleosin family, which is involved in plant growth and development, signal transduction, abiotic stress and plant immunity. However, the molecular mechanism of the biological function of RD20 in turnip is still largely unknown. This study aimed to characterise the roles of BrRD20 during abiotic stress resistance and their responses in various abiotic stresses by isolating BrRD20 (MK896873) from 'Tsuda' turnip. Quantitative polymerase chain reaction analysis showed that the highest expression levels of BrRD20 occurred in the petal, followed by the leaf, bud and red root epidermis, with tissue specificity. The transcript level of BrRD20 was much higher under natural light than under dark conditions in 0-5-day-old turnip seedlings. BrRD20 was also induced to be regulated by abiotic stresses such as high or low temperature, dehydration, osmotic hormone salt and alkali stresses. BrRD20 overexpression (BrRD20 -OE) in Chrysanthemum presented an enhanced tolerance to low temperature, dehydration and salt stress compared with the wild type. The BrRD20 gene was induced to be regulated by abiotic stresses such as high or low temperature, dehydration, osmotic and salt stresses. The BrRD20 gene also improved abiotic stress resistance in chrysanthemum. The above results suggested that BrRD20 plays a crucial role in abiotic stress resistance.

Solvatochromic sensors detect proteome aggregation in stressed liver tissues with hepatic cancer and cirrhosis.

Protein misfolding and aggregation involve complex cellular processes with clinical implications in various diseases. However, the detection of aggregated proteomes without defined 3-D structures in a complex biological milieu is challenging. This study utilizes chromone scaffold-based environment-sensitive fluorophores P1 and P2 to detect misfolded and aggregated proteome in stressed liver cells and the liver tissues diseased patients. The reported crystallization induced emission probes (P1 and P2) exhibit both polarity and viscosity sensitivity, with emission intensity and wavelength linearly correlated to viscosity and polarity. Meanwhile, P1 and P2 selectively and generally fluoresce upon binding to various aggregated proteins. In hepatic cells, P2 outperforms P1 in detecting stress-induced global proteome aggregation. In mouse liver tissue upon drug-induced injury, the fluorescence intensity of P2 correlated with the severity of liver injury, serving as an earlier indicator for liver stress prior to ALT/AST increase. The quantification of emission wavelength reveals lower micro-environmental polarity in liver-injury tissue. In patient-derived tissues with hepatic cancer and cirrhosis, P1 and P2 also report on the presence of aggregated proteome. Together, the reported solvatochromic proteome aggregation sensors can detect hepatic proteome aggregation and analyze its local polarity in cultured cell lines, animal model tissues, and human clinical samples.

Hydrogel with ROS scavenging effect encapsulates BR@Zn-BTB nanoparticles for accelerating diabetic mice wound healing via multimodal therapy.

The strategies for eliminating excess reactive oxygen species (ROS) or suppressing inflammatory responses on the wound bed have proven effective for diabetic wound healing. In this work, a zinc-based nanoscale metal-organic framework (NMOF) functions as a carrier to deliver natural product berberine (BR) to form BR@Zn-BTB nanoparticles, which was, in turn, further encapsulated by hydrogel with ROS scavenging ability to yield a composite system of BR@Zn-BTB/Gel (denoted as BZ-Gel). The results show that BZ-Gel exhibited the controlled release of Zn2+ and BR in simulated physiological media to efficiently eliminated ROS and inhibited inflammation and resulted in a promising antibacterial effect. In vivo experiments further proved that BZ-Gel significantly inhibited the inflammatory response and enhanced collagen deposition, as well as to re-epithelialize the skin wound to ultimately promote wound healing in diabetic mice. Our results indicate that the ROS-responsive hydrogel coupled with BR@Zn-BTB synergistically promotes diabetic wound healing.

Insight into the spatiotemporal distribution of antibiotic resistance genes in estuarine sediments during long-term ecological restoration.

In this study, we aimed to investigate the long-term spatiotemporal changes in hydrodynamics, antibiotics, nine typical subtypes of antibiotic resistance genes (ARGs), class 1 integron gene (intI1), and microbial communities in the sediments of a semi-enclosed estuary during ecological restoration with four treatment stages (influent (#1), effluent of the biological treatment area (#2), oxic area (#3), and plant treatment area (#4)). Ecological restoration of the estuary reduced common pollutants (nitrogen and phosphorus) in the water, whereas variations in ARGs showed noticeable seasonal and spatial features. The absolute abundance of ARGs at sampling site #2 considerably increased in autumn and winter, while it significantly increased at sampling site #3 in spring and summer. The strong intervention of biological treatment (from #1 to #2) and aerators (from #2 to #3) in the estuary substantially affected the distribution of ARGs and dominant antibiotic-resistant bacteria (ARB). The dominant ARB (Thiobacillus) in estuarine sediments may have low abundance but important dissemination roles. Meanwhile, redundancy and network analysis revealed that the microbial communities and intl1 were key factors related to ARG dissemination, which was affected by spatial and seasonal ecological restoration. A positive correlation between low flow velocity and certain ARGs (tetM, tetW, tetA, sul2, and ermC) was observed, implying that flow optimization should also be considered in future ecological restoration to remediate ARGs. Furthermore, the absolute abundance of ARGs can be utilized as an index to evaluate the removal capacity of ARGs by estuarine restoration.

A pH-responsive metal-organic framework for the co-delivery of HIF-2α siRNA and curcumin for enhanced therapy of osteoarthritis.

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.

Survey on current status of noise hazards in key industries in Tianjin in 2020 / 公共卫生与预防医学

Objective To conduct a survey on the status of noise hazards in Tianjin in 2020, to analyze the main distribution characteristics of noise hazards, and to put forward corresponding preventive and control measures. Methods A unified questionnaire was used to investigate the city-wide enterprises with more than 5 employees, normal production and operation, and noise hazards. The χ2 test was used to analyze the survey results. Results There were 8 560 enterprises with noise hazards, which were concentrated in the five outer suburban districts, the four districts around the city and the Binhai New Area, mainly small and medium-sized enterprises. Totally, 223 800 people were exposed to noise. The rates of noise hazard detection and physical examination of workers were 25.88% and 17.66%, and the rate of over standard detection and the rate of abnormal physical examination were 13.09% and 1.62%, respectively. The differences in noise detection rate, over standard detection rate and physical examination rate were significant in different administrative regions, enterprise scales and industries. The detection rate and physical examination rate of enterprises in the five outer suburban districts, micro-scale enterprises, and paper products industries were the lowest, while the rate of exceeding standards was the highest in the railway, shipping, aerospace and other transportation equipment manufacturing industries. Conclusion Noise is a common occupational hazard in enterprises in Tianjin. There are a large number of people who are exposed to noise. The detection rate and physical examination rate of noise are at a low level. Individual industries have a high rate of exceeding the standard. The current situation of noise hazard prevention and control is not optimistic. It is recommended to pay attention to it and take effective intervention measures.

Clinical phenotype characteristics and genetic analysis in children with nephronophthisis and related syndromes caused by different gene mutations / 中国当代儿科杂志

OBJECTIVES@#To improve the understanding of the clinical phenotypes and genetic characteristics of nephronophthisis (NPHP) and related syndromes in children.@*METHODS@#A retrospective analysis was performed on the medical data of eight children with NPHP and related syndromes who were diagnosed and treated in the Department of Pediatrics of the Second Hospital of Hebei Medical University, from January 2018 to November 2022. The clinical characteristics and genetic testing results were analyzed.@*RESULTS@#Among these eight children, there were five boys and three girls, with an age of onset ranging from 15 months to 12 years. All 8 children exhibited different degrees of renal function abnormalities when they attended the hospital. Among the eight children, two had the initial symptom of delayed development, two had the initial symptom of anemia, and two were found to have abnormal renal function during physical examination. The extrarenal manifestations included cardiovascular abnormalities in two children, skeletal dysplasia in two children, liver dysfunction in one child, retinitis pigmentosa in one child, and visceral translocation in one child. All eight children had renal structural changes on ultrasound, and four children had mild to moderate proteinuria based on routine urine test. Of all eight children, five had NPHP1 gene mutations and one each had a gene mutation in the NPHP3, IFT140, and TTC21B genes, and four new mutation sites were discovered.@*CONCLUSIONS@#Children with NPHP and related syndromes often have the initial symptom of delayed development or anemia, and some children also have extrarenal manifestations. NPHP and related syndromes should be considered for children with unexplained renal dysfunction, and high-throughput sequencing may help to make a confirmed diagnosis.

Involvement of Interleukin-1 β/Insulin-Like Growth Factor 1 in Ameliorating Effects of Electroacupuncture on Myocardial Fibrosis Induced by Essential Hypertension / 中国结合医学杂志

OBJECTIVE@#To investigate the effect of electroacupuncture (EA) at Neiguan (PC 6) on myocardial fibrosis in spontaneously hypertensive rats (SHRs), and to explore the contribution of interleukin-1 β (IL-1 β), insulin-like growth factor 1 (IGF-1), and transforming growth factor β 1 (TGF- β 1) to the effects.@*METHODS@#Nine 12-weeks-old Wistar Kyoto (WKY) male rats were employed as the normal group. Twenty-seven SHRs were equally randomized into SHR, SHR+EA, and SHR + sham groups. EA was applied at bilateral PC 6 once a day 30 min per day in 8 consecutive weeks. After 8-weeks EA treatment at PC 6, histopathologic changes of collagen type I (Col I), collagen type 1 (Col 1) and the levels of IGF-1, 1L-1 β, TGF- β 1, matrix metalloproteinase (MMP)-2 and MMP-9 were examined in myocardial tissure respectively.@*RESULTS@#After 8-weeks EA treatment at PC 6, the enhanced myocardial fibrosis in SHRs were characterized by the increased mean fluorescence intensity of Col I and Col 1 in myocardium tissue (P<0.01). All these abnormal alterations above in SHR + EA group was significantly lower compared with the SHR group (P<0.01). Meanwhile, the increased levels of IL-1 β, IGF-1, TGF-β 1 in serum or myocardial tissue of SHRs, diminished MMP 9 mRNA expression in SHRs were also markedly inhibited after 8 weeks of EA treatment (P<0.05 or P<0.01). Furthermore, the contents of IL-1 β, IGF-1, TGF-β 1 in myocardial tissue were positively correlated with the systolic blood pressure and hydroxyproline respectively (P<0.01).@*CONCLUSION@#EA at bilateral PC 6 could ameliorate cardiac fibrosis in SHRs, which might be mediated by regulation of 1L-1 β/IGF-1-TGF- β 1-MMP9 pathway.