Eggshell membrane powder reinforces adhesive polysaccharide hydrogels for wound repair.

Multifunctional polysaccharide hydrogels with strong tissue adhesion, and antimicrobial and hemostatic properties are attractive wound healing materials. In this study, a chitosan-based hydrogel (HCS) was designed, and its properties were enhanced by incorporating oxidized eggshell membrane (OEM). Hydrogel characterization and testing results showed that the hydrogel had excellent antimicrobial properties, cytocompatibility, satisfactory adhesion properties on common substrates, and wet-state adhesion capacity. A rat liver injury model confirmed the significant hemostatic effect of the hydrogel. Finally, the ability of the hydrogel to promote wound healing was verified using rat skin wound repair experiments. Our findings indicate that HCS/OEM hydrogels with added eggshell membrane fibers have better self-healing properties, mechanical strength, adhesion, hemostatic properties, and biocompatibility than HCS hydrogels, in addition to having superior repair performance in wound repair experiments. Overall, the multifunctional polysaccharide hydrogels fabricated in this study are ideal for wound repair.

Comprehensive quantifications of tumour microenvironment to predict the responsiveness to immunotherapy and prognosis for paediatric neuroblastomas.

Treatment strategies for paediatric neuroblastoma as well as many other cancers are limited by the unfavourable tumour microenvironment (TME). In this study, the TMEs of neuroblastoma were grouped by their genetic signatures into four distinct subtypes: immune enriched, immune desert, non-proliferative and fibrotic. An Immune Score and a Proliferation Score were constructed based on the molecular features of the subtypes to quantify the immune microenvironment or malignancy degree of cancer cells in neuroblastoma, respectively. The Immune Score correlated with a patient's response to immunotherapy; the Proliferation Score was an independent prognostic biomarker for neuroblastoma and proved to be more accurate than the existing clinical predictors. This double scoring system was further validated and the conserved molecular pattern associated with immune landscape and malignancy degree was confirmed. Axitinib and BI-2536 were confirmed as candidate drugs for neuroblastoma by the double scoring system. Both in vivo and in vitro experiments demonstrated that axitinib-induced pyroptosis of neuroblastoma cells activated anti-tumour immunity and inhibited tumour growth; BI-2536 induced cell cycle arrest at the S phase in neuroblastoma cells. The comprehensive double scoring system of neuroblastoma may predict prognosis and screen for therapeutic strategies which could provide personalized treatments.

Influence of aeration modes and DO on simultaneous nitrification and denitrification in treatment of hypersaline high-strength nitrogen wastewater using sequencing batch biofilm reactor (SBBR).

Sequencing batch biofilm reactor (SBBR) has the potential to treat hypersaline high-strength nitrogen wastewater by simultaneous nitrification-denitrification (SND). Dissolved oxygen (DO) and aeration modes are major factors affecting pollutant removal. Low DO (0.35-3.5 mg/L) and alternative anoxic/aerobic (A/O) mode are commonly used for municipal wastewater treatment, however, the appropriate DO concentration and operation mode are still unknown under hypersaline environment because of the restricted oxygen transfer in denser extracellular polymeric substances (EPS) barrier and the decreased carbon source consumption during the anoxic phase. Herein, two SBBRs (R1, fully aerobic mode; R2, A/O mode) were used for the treatment of hypersaline high-strength nitrogen wastewater (200 mg/L NH4+-N, COD/N of 3 and 3% salinity). The results showed that the relatively low DO (2 mg/L) could not realize effective nitrification, while high DO (4.5 mg/L) evidently increased nitrification efficiency by enhancing oxygen transfer in denser biofilm that was stimulated by high salinity. A stable SND was reached 16 days faster with a ∼10% increase of TN removal under A/O mode. Mechanism analysis found that denser biofilm with coccus and bacillus were present in A/O mode instead of filamentous microorganisms, with the secretion of more EPS. Corynebacterium and Halomonas were the dominant genera in both SBBRs, and HN-AD process might assist partial nitrification-denitrification (PND) for highly efficient TN removal in biofilm systems. By using the appropriate operation mode and parameters, the average NH4+-N and TN removal efficiency could respectively reach 100% and 70.8% under the NLR of 0.2 kg N·m-3·d-1 (COD/N of 3), which was the highest among the published works using SND-based SBBRs in treatment of saline high-strength ammonia nitrogen (low COD/N) wastewater. This study provided new insights in biofilm under hypersaline stress and provided a solution for the treatment of hypersaline high-strength nitrogen (low COD/N) water.

A conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22.

The CUL3-RING E3 ubiquitin ligases (CRL3s) play an essential role in response to extracellular nutrition and stress stimuli. The ubiquitin ligase function of CRL3s is activated through dimerization. However, how and why such a dimeric assembly is required for its ligase activity remains elusive. Here, we report the cryo-EM structure of the dimeric CRL3KLHL22 complex and reveal a conserved N-terminal motif in CUL3 that contributes to the dimerization assembly and the E3 ligase activity of CRL3KLHL22. We show that deletion of the CUL3 N-terminal motif impairs dimeric assembly and the E3 ligase activity of both CRL3KLHL22 and several other CRL3s. In addition, we found that the dynamics of dimeric assembly of CRL3KLHL22 generates a variable ubiquitination zone, potentially facilitating substrate recognition and ubiquitination. These findings demonstrate that a CUL3 N-terminal motif participates in the assembly process and provide insights into the assembly and activation of CRL3s.

Vibration-Dependent Dual-Phosphorescent Cu4 Nanocluster with Remarkable Piezochromic Behavior.

The dual emission (DE) characteristics of atomically precise copper nanoclusters (Cu NCs) are of significant theoretical and practical interest. Despite this, the underlying mechanism driving DE in Cu NCs remains elusive, primarily due to the complexities of excited state processes. Herein, a novel [Cu4(PPh3)4(C≡C-p-NH2C6H4)3]PF6 (Cu4) NC, shielded by alkynyl and exhibiting DE, was synthesized. Hydrostatic pressure was applied to Cu4, for the first time, to investigate the mechanism of DE. With increasing pressure, the higher-energy emission peak of Cu4 gradually disappeared, leaving the lower-energy emission peak as the dominant emission. Additionally, the Cu4 crystal exhibited notable piezochromism transitioning from cyan to orange. Angle-dispersive synchrotron X-ray diffraction results revealed that the reduced inter-cluster distances under pressure brought the peripheral ligands closer, leading to the formation of new C-H···N and N-H···N hydrogen bonds in Cu4. It is proposed that these strengthened hydrogen bond interactions limit the ligands´ vibration, resulting in the vanishing of the higher-energy peak. In situ high-pressure Raman and vibrationally resolved emission spectra demonstrated that the benzene ring C=C stretching vibration is the structural source of the DE in Cu4.

Long-term outcomes of a novel fully magnetically levitated ventricular assist device for the treatment of advanced heart failure in China.

PURPOSE: Left ventricular assist devices (LVADs) are well-established for treating end-stage heart failure, but this therapy is only available to Chinese patients in recent years. The CH-VAD is the first used fully magnetically levitated pump and the most widely used device in China. This study reports the long-term outcomes of a cohort supported by the CH-VAD for the first time. METHODS: From June 2017 to August 2023, 50 consecutive patients received CH-VAD implantation in Fuwai Hospital. Clinical data were collected during follow-up and retrospectively analyzed. RESULTS: Baseline characteristics included a mean age of 47.9±13.9 years, 90% male, and 26% ischemic etiology. The INTERMACS profile revealed 12% Profile 1, 56% Profile 2, 26% Profile 3 and 6% Profile 4. Mean support duration was 868 ± 630 days (range 33 days-6.4 years). Kaplan-Meier survival rate was 96% (95% confidence interval [CI], 85 to 99) at 6 months, 93% (95% CI, 79-98) at 1 year, 93% (95% CI, 79-98) at 2 years and 89% (95% CI, 71-96) at 3 years. 40 patients (80%) currently remain on support, 3 were bridged to recovery, 2 received transplant, and 5 expired during support. Major adverse events included right heart failure (10%), surgical related bleeding (8%), arrhythmia (8%) and driveline infection (16%). Major hemocompatibility-related adverse events were limited to 3 non-disabling strokes and 1 gastrointestinal bleeding. There was no major device malfunction during the follow-up period. CONCLUSIONS: The largest single-center experience with the leading LVAD in China shows high survival with low complication rates, demonstrating the CH-VAD is safe and efficient in providing long-term support for end-stage heart failure patients.

Short-Term Changes in Weight, Body Composition, and Metabolic Biomarkers After Laparoscopic Sleeve Gastrectomy in Patients with Obesity: A Comparative Prospective Study.

PURPOSE: To investigate the changes in weight, body composition, and metabolic biomarkers in patients with obesity after laparoscopic sleeve gastrectomy (LSG) and compare those changes between patients with and without metabolic syndrome (MS). MATERIALS AND METHODS: This retrospective longitudinal study included 76 patients who underwent LSG, among whom 32 had complete 1-year postoperative body composition and metabolic biomarkers. Body composition was measured by quantitative CT. Weight changes were compared between the MS and non-MS groups at 1-, 3-, 6-, and 12-month post-LSG in all patients; changes in body compositions and metabolic biomarkers from one day pre-LSG to 12-month post-LSG were also compared in those 32 patients. RESULTS: MS occurred in 46% (35/76) of all patients and 44% (14/32) of patients with complete follow-up data. Excess weight loss was lower in the MS group than that in the non-MS group at 1-, 3-, 6-, and 12-month post-LSG; the 12-month difference was significant (MS vs. non-MS: 0.91 ± 0.22 vs. 1.07 ± 0.42, P = 0.04). The greatest rate of visceral fat area (VFA) change occurred 12-month post-LSG in both the non-MS [0.62(0.55,0.7)] and MS [0.6(0.51,0.63)] groups. The most significant reduction in ectopic fat occurred in liver fat (LF) [non-MS, 0.45(0.22,0.58); MS, 0.39(0.23,0.58)]. CONCLUSION: LGS significantly improves weight, body composition, and metabolic biomarkers in populations with obesity, regardless of whether they have MS. Among the body composition, VFA and LF were the most significantly improved body composition measurements.

Efficacy and Safety of Endoscopic Resection for Gastric Gastrointestinal Stromal Tumors Originating from the Muscularis Propria.

BACKGROUND: The role of endoscopic resection (ER) in gastric gastrointestinal stromal tumors (GISTs) has not been fully elucidated. AIMS: The purpose of this work was to evaluate the clinical effectiveness and safety of ER in patients with GISTs originating from the muscularis propria (MP). METHODS: A total of 233 consecutive patients with gastric GISTs originating from the MP layer, who underwent ER between February 2012 and May 2023, were included in this study. Clinical characteristics, tumor features, and outcomes were recorded and compared between patients who underwent en bloc resection and piecemeal resection. RESULTS: Among the 233 patients, the median size of GISTs was 12 mm (range 5-60 mm). Risk assessment categorized 190 patients as very low risk, 26 as low risk, 10 as moderate risk, and 7 as high risk. The procedures performed included endoscopic submucosal excavation (127 cases), endoscopic full-thickness resection (103 cases), and submucosal tunneling endoscopic resection (3 cases). The complete and R0 resection rate was 93.1%. Complications occurred in 4.7% of cases (perioperative perforations 1.7%, perioperative bleeding 1.3%, both 0.9%), resulting in conversion to surgery in 1.3% of cases. Risk factors associated with piecemeal resection were tumor size [odds ratio (OR) 0.402, 95% confidence interval (CI) 0.207-0.783; P = 0.007] and shape (OR 0.045, 95% CI 0.009-0.235; P < 0.001). CONCLUSIONS: ER is proven to be an effective and reasonably safe approach for gastric GISTs originating from the MP. Notably, larger tumor size and irregular shape are identified as risk factors for piecemeal resection during ER procedures.

Clinical characteristics of patients with migraine accompanied by tremor. / åå¤´ç—›ä¼´å‘éœ‡é¢¤æ‚£è€ çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: Migraine and tremor share some genetic mutation sites, and clinical studies have also confirmed their correlation. This study aims to explore the clinical and electrophysiological characteristics of migraine patients with concomitant tremor, and to analyze the relevant influential factors of tremor occurrence. METHODS: We retrospectively analyzed the clinical data of 217 migraine patients who visited the Third Affiliated Hospital of Qiqihar Medical University from June 2022 to October 2023. The Clinical Rating Scale for Tremor (CRST), Numerical Rating Scale (NRS), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) were respectively used to assess the tremor symptoms, degree of headache, anxiety, and depression of patients. All patients underwent routine head MR scanning and electromyography examination, and were divided into a migraine with tremor group and a migraine without tremor group based on the electromyogram examination. RESULTS: The migraine with tremor group and the migraine without tremor group were included 52 patients (23.96%) and 165 patients (76.04%), respectively. Compared with the migraine without tremor group, the migraine with tremor group had a longer course and duration of headache, higher frequency of headache attacks, higher NRS score, GAD-7 score, and PHQ-9 score, and fewer weekly physical exercises. The differences were statistically significant (all P<0.05). There were no statistically significant differences in the presence or absence of prodromal headache and white matter hyperintensities (WMHs) between the 2 groups (both P>0.05). The evaluation results of the CRST showed that out of 217 migraine patients, 39 patients (17.97%) were accompanied by tremors. The electromyographic results showed that all 52 migraine patients with tremors had upper limb tremors, including 28 migraine patients with postural tremors and 24 migraine patients with static tremors. Compared with the migraine patients with static tremors, the migraine patients with postural tremors had lower average frequency, peak frequency, and headache onset frequency (all P<0.05). Multiple linear regression analysis showed that frequency of physical exercise, duration of illness, frequency of headache attacks, NRS score, GAD-7 score, and PHQ-9 score were risk factors for migraine patients with concomitant tremors (all P<0.05). CONCLUSIONS: Patients with migraine mainly experience upper limb postural tremors. Reduced physical exercise, long course of disease, long duration of headache, frequent headache attacks, severe headache, anxiety, and depression are risk factors for migraine patients with concomitant tremors.

Effects of different oxidants on the behaviour of microplastic hetero-aggregates.

Microplastic hetero-aggregates are stable forms of microplastics in the aqueous environment. However, when disinfecting water containing microplastic hetero-aggregates, the response of them in water to different oxidizing agents and the effect on water quality have not been reported. Our results showed that Ca(ClO)2, K2S2O8, and sodium percarbonate (SPC) treatment could lead to the disaggregation of microplastic hetero-aggregates as well as a rise in cell membrane permeability, which caused a large amount of organic matter to be released. When the amount of oxidant dosing is insufficient, the oxidant cannot completely degrade the released organic matter, resulting in DOC, DTN, DTP and other indicators being higher than before oxidation, thus causing secondary pollution of the water body. In comparison, K2FeO4 can purify the water body stably without destroying the microplastic hetero-aggregates, but it only weakly inhibits the toxic cyanobacteria Microcystis and Pseudanabaena, which may cause cyanobacterial bloom as well as algal toxin and odorant contamination in practical application. Compared with the other oxidizers, K2S2O8 provides better inhibition of toxic cyanobacteria and has better ecological safety. Therefore, when treating microplastic-containing water bodies, we should consider both water purification and ecological safety, and select appropriate oxidant types and dosages to optimize the water treatment.

Risk factors of Carbapenem-resistant Enterobacterales intestinal colonization for subsequent infections in hematological patients: a retrospective case-control study.

Objective: Infections caused by Carbapenem-resistant Enterobacterales (CRE) have high treatment costs, high mortality and few effective therapeutic agents. This study aimed to determine the risk factors for progression from intestinal colonization to infection in hematological patients and the risk factors for 30-day mortality in infected patients. Methods: A retrospective case-control study was conducted in the Department of Hematology at Shandong Provincial Hospital affiliated to Shandong First Medical University from April 2018 to April 2022. Patients who developed subsequent infections were identified as the case group by electronic medical record query of patients with a positive rectal screen for CRE colonization, and patients who did not develop subsequent infections were identified as the control group by stratified random sampling. Univariate analysis and logistic regression analysis determined risk factors for developing CRE infection and risk factors for mortality in CRE-infected patients. Results: Eleven hematological patients in the study developed subsequent infections. The overall 30-day mortality rate for the 44 hematological patients in the case-control study was 11.4% (5/44). Mortality was higher in the case group than in the control group (36.5 vs. 3.0%, P = 0.0026), and septic shock was an independent risk factor for death (P = 0.024). Univariate analysis showed that risk factors for developing infections were non-steroidal immunosuppressants, serum albumin levels, and days of hospitalization. In multivariable logistic regression analysis, immunosuppressants [odds ratio (OR), 19.132; 95% confidence interval (CI), 1.349-271.420; P = 0.029] and serum albumin levels (OR, 0.817; 95% CI, 0.668-0.999; P = 0.049) were independent risk factors for developing infections. Conclusion: Our findings suggest that septic shock increases mortality in CRE-infected hematological patients. Hematological patients with CRE colonization using immunosuppressive agents and reduced serum albumin are more likely to progress to CRE infection. This study may help clinicians prevent the onset of infection early and take measures to reduce mortality rates.

Investigation on the interaction mechanism during co-combustion of sewage sludge and coal slime: The effect of coal slime type and pretreatment method.

Co-combustion of sewage sludge (SS) and coal slime (CS) is the preferred method for mitigating their environmental impact and increasing their added value. However, the interaction mechanism between SS and CS during the co-combustion process has not yet developed a unified understanding. This work aims to obtain the effect of CS types on SS-CS co-combustion and reveal the interaction mechanism between SS and CS based on the influence of pretreatment methods on the interaction. The results showed that during co-combustion, SS reduced the ignition and burnout temperatures, and CS with high fixed carbon content (e.g., XCS) improved the comprehensive combustion characteristics. Principal component analysis showed that the effect of CS on co-combustion was more significant. The interaction between SS and CS mainly occurred within 100-700 °C, in which inhibition and synergism coexisted. The large differences in the interactions before and after de-volatilization and pickling treatments revealed that the volatiles and ash in SS were the main interaction factors. The analysis of the interaction mechanisms showed that the free radicals and heat released from the SS volatiles combustion accelerated the weight loss of CS, but the formation of tars from its incomplete combustion may inhibit the decomposition of CS. The interaction in the fixed carbon combustion stage was mainly caused by SS ash, which can catalyze the combustion of CS fixed carbon, but for the high ash CS (e.g., QCS), the combustion of fixed carbon was hindered by the addition of SS ash higher than 10 %. The final manifestation (synergy or inhibition) of SS and CS interactions was the result of the competitive balance of the above interactive behaviors. This work provides a more comprehensive understanding of the interaction between SS and CS during co-combustion.

NOX4 promotes tumor progression through the MAPK-MEK1/2-ERK1/2 axis in colorectal cancer.

BACKGROUND: Metabolic reprogramming plays a key role in cancer progression and clinical outcomes; however, the patterns and primary regulators of metabolic reprogramming in colorectal cancer (CRC) are not well understood. AIM: To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in promoting progression of CRC. METHODS: We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Consensus clustering was used to cluster CRC based on dysregulated metabolic genes. A prediction model was constructed based on survival-related metabolic genes. Sphere formation, migration, invasion, proliferation, apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC. mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells. In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth. RESULTS: We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes. Among these genes, NOX4 was highly expressed in tumor tissues and correlated with worse survival. In vitro, NOX4 overexpression induced clone formation, migration, invasion, and stemness in CRC cells. Furthermore, RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway. Trametinib, a MEK1/2 inhibitor, abolished the NOX4-mediated tumor progression. In vivo, NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis, whereas trametinib treatment can reversed the metastasis. CONCLUSION: Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.

Development of an Interpretable Deep Learning Model for Pathological Tumor Response Assessment After Neoadjuvant Therapy.

BACKGROUND: Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. METHODS: This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. RESULTS: The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. CONCLUSION: This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Downregulation of ABLIM3 confers to the metastasis of neuroblastoma via regulating the cell adhesion molecules pathway.

Neuroblastoma (NB) is the most prevalent extracranial solid tumor in pediatric patients, and its treatment failure often associated with metastasis. In this study, LASSO, SVM-RFE, and random forest tree algorithms, was used to identify the pivotal gene involved in NB metastasis. NB cell lines (SK-N-AS and SK-N-BE2), in conjunction with NB tissue were used for further study. ABLIM3 was identified as the hub gene and can be an independent prognostic factor for patients with NB. The immunohistochemical analysis revealed that ABLIM3 is negatively correlated with the metastasis of NB. Patients with low expression of ABLIM3 had a poor prognosis. High ABLIM3 expression correlated with APC co-stimulation and Type1 IFN response, and TIDE analysis indicated that patients with low ABLIM3 expression exhibited enhanced responses to immunotherapy. Downregulation of ABLIM3 by shRNA transfection increased the migration and invasion ability of NB cells. Gene Set Enrichment Analysis (GSEA) revealed that genes associated with ABLIM3 were primarily enriched in the cell adhesion molecules (CAMs) pathway. RT-qPCR and western blot analyses demonstrated that downregulation of ABLIM3 led to decreased expression of ITGA3, ITGA8, and KRT19, the key components of CAMs. This study indicated that ABLIM3 can be an independent prognostic factor for NB patients, and CAMs may mediate the effect of ABLIM3 on the metastasis of NB, suggesting that ABLIM3 is a potential therapeutic target for NB metastasis, which provides a novel strategy for future research and treatment strategies for NB patients.

Clinical Efficacy of Bisphosphonates in Treating Osteoporosis in Diabetes Patients: A Meta-Analysis.

The aim of the study was to explore the clinical efficacy of bisphosphonates in patients with osteoporosis in diabetes patients by meta-analysis. Six databases were systematically searched from inception to January 30,2023. Studies evaluating the treatment of diabetic osteoporosis with bisphosphonates were included. Key outcome measures, such as bone mineral density (BMD), bone metabolism markers, pain improvement, and safety assessments, were extracted and analyzed. STATA MP V17.0 was used to calculate the combined effect size. After searching Chinese and English databases, 15 studies met the inclusion criteria of this study. The results of the meta-analysis showed that the BMD of patients with osteoporosis in diabetes increased significantly after bisphosphonate treatment, and the lumbar BMD increased by 0.08 g/cm² (95% CI: 0.05-0.11). Femoral neck BMD increased by 0.06 g/cm² (95% CI: 0.01-0.11); Ward's triangle BMD increased 0.07 g/cm² (95% CI: 0.04-0.09); and trochanter BMD increased by 0.06 g/cm² (95% CI: 0.04-0.08). In addition, bone alkaline phosphatase increased 1.95 µg/l (95% CI: 1.18-2.72), while serum tartrate-resistant acid phosphatase-5b decreased 1.28 U/l (95% CI: -1.81-0.75). Moreover, improvements in pain were statistically significant. The effects of bisphosphonates on osteocalcin (MD: -0.07; 95% CI: -1.12-1.25), serum calcium (MD: 0.01; 95% CI: -0.03-0.04), serum phosphorus (MD: 0.04; 95% CI: -0.03-0.10) and medication safety (OR: 1.75; 95% CI: 1.29-2.37) were not statistically significant. Bisphosphonates have a significant positive effect on bone mineral density and bone metabolism in patients with osteoporosis in diabetes and have good safety.

Quantification of the aromatase inhibitor letrozole and its carbinol metabolite in mouse plasma by UHPLC-MS/MS.

A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase inhibitor, and its main carbinol metabolite (CM) in support of murine pharmacokinetic studies. Using polarity switching, simultaneous ESI-MS measurement of letrozole and CM was achieved in positive and negative mode, respectively. The assay procedure involved a one-step protein precipitation and extraction of all analytes from mouse plasma requiring only 5 µL of sample. Separation was optimized on an Accucore aQ column with gradient elution at a flow rate of 0.4 mL/min in 5 min. Two calibration curves per day over four consecutive measurement days showed satisfactory linear responses (r2 > 0.99) over concentration ranges of 5-1000 ng/mL and 20-2000 ng/mL for letrozole and CM, respectively. No matrix effect was found, and the mean extraction recoveries were 103-108 % for letrozole and 99.8-107 % for CM. Precision and accuracy within a single run and over four consecutive measurement days were verified to be within acceptable limits. Application of the developed method to preclinical pharmacokinetic studies in mice receiving oral letrozole at a dose 1 or 10 mg/kg revealed that the systemic exposure to letrozole was dose-, formulation-, and strain-dependent. These findings may inform the future design of preclinical studies aimed at refining the pharmacological profile of this clinically important drug.

Single cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a pro-inflammatory metabolic signature in male mice at late adulthood.

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants that bioaccumulate in the environment. The gut microbiome is an important regulator of liver functions including xenobiotic biotransformation and immune regulation. We recently showed that neonatal exposure to polybrominated diphenyl ether-99 (BDE-99), a human breast milk-enriched PBDE congener, up-regulated pro-inflammation- and down-regulated drug metabolism-related genes predominantly in males in young adulthood. However, the persistence of dysregulation into late adulthood, differential impact of hepatic cell types, and the involvement of the gut microbiome from neonatal BDE-99 exposure remains unknown. To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2-4. At 15 months of age, neonatal BDE-99 exposure down-regulated xenobiotic and lipid metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes. Neonatal BDE-99 exposure also increased the hepatic proportion of neutrophils and led to a predicted increase of macrophage migration inhibitory factor signaling. This was associated with decreased intestinal tight junction protein (Tjp) transcripts, altered gut environment, and dysregulation of inflammation-related metabolites. ScRNA-seq using germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immune tolerance. Microbiota transplant to GF mice using large intestinal microbiome from adults neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in the large intestine. In conclusion, neonatal BDE-99 exposure reprogrammed cell type-specific gene expression and communication in liver towards pro-inflammation, and BDE-99-mediated pro-inflammatory signatures may be partly due to the dysregulated gut environment.

Pegbelfermin for reducing transaminase levels in patients with non-alcoholic steatohepatitis: a dose-response meta-analysis of randomized controlled trials.

Background: The efficacy of Pegbelfermin (PGBF) in treating non-alcoholic steatohepatitis (NASH) remains controversial. Therefore, we conducted a dose-response meta-analysis to explore the effect and pattern of PGBF at different dosages and treatment durations on transaminase reduction in NASH patients. Methods: We conducted searches on PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov, and supplemented the search with gray literature and manual searches. Randomized controlled trials (RCTs) evaluating the efficacy of PGBF in NASH patients were included. Risk of bias was assessed by Cochrane Risk of Bias Tool 2.0. We used random-effects models, generalized least squares regression, constrained maximum likelihood, and restricted cubic splines to explore the dose-response relationship. Egger's linear regression was employed to assess publication bias. The study is registered with PROSPERO, CRD42023448024. Results: Four RCT studies from the period 2018-2023, involving 546 participants, were included. No participants discontinued PGBF treatment due to adverse events. High-dose PGBF treatment significantly reduced transaminase levels in NASH patients compared to the low-dose group (ALT %: MD = 14.94, 95% CI = 2.11-27.77; AST %: MD = 9.05, 95% CI = 3.17-14.92). Longer treatment duration further decreased transaminase levels (ALT%: MD = 8.81, 95% CI = 4.07-13.56; AST%: MD = 6.72, 95% CI = 2.62-10.81). Egger's test did not reveal significant publication bias (p > 0.05). Further investigation indicated a ceiling effect of PGBF dosage on transaminase reduction at 30 mg/week, and NASH patients experienced a rebound in transaminase levels after 28 weeks of continuous treatment. Conclusion: There is a positive correlation between PGBF dosage and transaminase reduction within a certain range, showing an overall non-linear dose-response relationship. This finding provides guidance for the clinical application of PGBF. Clinicians should be mindful of the dosage ceiling at 30 mg/week and monitor changes in transaminase levels after 28 weeks for timely adjustments in PGBF dosage. Systematic review registration: PROSPERO, CRD42023448024. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=448024.

In Vivo Tissue Distribution of Polystyrene or Mixed Polymer Microspheres and Metabolomic Analysis after Oral Exposure in Mice.

BACKGROUND: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. OBJECTIVES: This study aims to investigate the impacts of polymer microspheres on tissue metabolism in mice by assessing the microspheres ability to translocate across the gut barrier and enter into systemic circulation. Specifically, we wanted to examine microsphere accumulation in different organ systems, identify concentration-dependent metabolic changes, and evaluate the effects of mixed microsphere exposures on health outcomes. METHODS: To investigate the impact of ingested microspheres on target metabolic pathways, mice were exposed to either polystyrene (5µm) microspheres or a mixture of polymer microspheres consisting of polystyrene (5µm), polyethylene (1-4µm), and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid) (5µm). Exposures were performed twice a week for 4 weeks at a concentration of either 0, 2, or 4mg/week via oral gastric gavage. Tissues were collected to examine microsphere ingress and changes in metabolites. RESULTS: In mice that ingested microspheres, we detected polystyrene microspheres in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolic differences that occurred in the colon, liver, and brain, which showed differential responses that were dependent on concentration and type of microsphere exposure. DISCUSSION: This study uses a mouse model to provide critical insight into the potential health implications of the pervasive issue of plastic pollution. These findings demonstrate that orally consumed polystyrene or mixed polymer microspheres can accumulate in tissues such as the brain, liver, and kidney. Furthermore, this study highlights concentration-dependent and polymer type-specific metabolic changes in the colon, liver, and brain after plastic microsphere exposure. These results underline the mobility within and between biological tissues of MPs after exposure and emphasize the importance of understanding their metabolic impact. https://doi.org/10.1289/EHP13435.