Human health risks of heavy metal(loid)s mediated through crop ingestion in a coal mining area in Eastern China.

The heavy metal(loid)s (HMs) in soils can be accumulated by crops grown, which is accompanied by crop ingestion into the human body and then causes harm to human health. Hence, the health risks posed by HMs in three crops for different populations were assessed using Health risk assessment (HRA) model coupled with Monte Carlo simulation. Results revealed that Zn had the highest concentration among three crops; while Ni was the main polluting element in maize and soybean, and As in rice. Non-carcinogenic risk for all populations through rice ingestion was at an "unacceptable" level, and teenagers suffered higher risk than adults and children. All populations through ingestion of three crops might suffer Carcinogenic risk, with the similar order of Total carcinogenic risk (TCR): TCRAdults > TCRTeenagers > TCRChildren. As and Ni were identified as priority control HMs in this study area due to their high contribution rates to health risks. According to the HRA results, the human health risk was associated with crop varieties, HM species, and age groups. Our findings suggest that only limiting the Maximum allowable intake rate is not sufficient to prevent health risks caused by crop HMs, thus more risk precautions are needed.

Spontaneous miscarriage and social support in predicting risks of depression and anxiety: a cohort study in UK Biobank.

BACKGROUND: It is still unclear whether social support can moderate the high risk of depression and anxiety due to spontaneous miscarriage. OBJECTIVE: This study prospectively investigated the associations of spontaneous miscarriage with risks of depression and anxiety and evaluated the interactions between spontaneous miscarriage and the degree of social support in relation to depression and anxiety risks. STUDY DESIGN: A total of 179000 participants with pregnancy experience and free of depression or anxiety at baseline from the UK Biobank were included. Spontaneous miscarriage was defined by self-report from participants at enrollment or by the ICD codes. The degree of social support was defined as the number of social support factors including living with a spouse or partner, participation in social activities and confiding. Cox proportional hazard models were used to evaluate the joint association between spontaneous miscarriage and social support on the risks of depression and anxiety. RESULTS: During a median follow-up of 12.3 years, 4939 depression incidents and 5742 anxiety incidents were documented. After adjustment for covariates, compared with participants without a history of spontaneous miscarriage, hazard ratios (95% confidence interval, CI) for depression were 1.10 (1.02-1.19), 1.31 (1.14-1.50) and 1.40 (1.18-1.67) for participants with the number of spontaneous miscarriages of one, two, and three or more, respectively (P-trend <0.001). For anxiety, the HRs (95% CI) were 1.07 (1.00-1.15), 1.04 (0.90-1.19), and 1.21 (1.02-1.44), respectively (P-trend =0.01). Moreover，we found the risk of depression associated with a combination spontaneous miscarriages and low degree of social support in later life was greater than the addition of the risk associated with each individual factor, indicating significant interactions on an additive scale (P-interaction = 0.03). CONCLUSION: Spontaneous miscarriage is associated with higher risks of depression and anxiety and shows an additive interaction with the low degree of social support on the risk of depression.

[Chemical Speciation, Influencing Factors, and Regression Model of Heavy Metals in Farmland of Typical Carbonate Area with High Geological Background, Southwest China].

The speciation of heavy metals in soil is an important factor determining their bioavailability and toxicity, and it is crucial for the scientific assessment of ecological risks posed by heavy metals in soils of typical carbonate areas with high geological background in southwest China. In order to investigate the distribution of speciation of heavy metals in soils of carbonate rock with high geological background, we selected a typical carbonate rock distribution area in Guizhou Province and used the second national soil survey plots as sampling units. A total of 309 topsoil samples were collected from farmland. The improved Tessier seven-step sequential extraction method was used to analyze the seven chemical forms of heavy metals:water-soluble (F1); exchangeable (F2); carbonate-bound (F3); weakly organic-bound (F4); iron-manganese oxide-bound (F5); strongly organic-bound (F6); and residual (F7) forms of arsenic (As), cadmium (Cd), copper (Cu), mercury (Hg), nickel (Ni), lead (Pb), and zinc (Zn). The study found that the residual forms of heavy metals As, Cu, Hg, Ni, Pb, and Zn in the soil accounted for more than 50%, the effective components (F1-F3) accounted for less than 5%, and the potential biological effective components (F4-F6) were less than 45%, indicating low reactivity and low ecological risk. The effective and potentially bioavailable components of Cd accounted for 55.49% and 29.37%, respectively, which were much higher than those of other heavy metals. The ecological risk based on the speciation of heavy metals in the soil was much lower than that based on the total content of heavy metals. The stepwise regression equations could effectively establish the relationship between the bioavailable and potentially bioavailable fractions of Cd, Cu, and Pb and their influencing factors. Total heavy metal contents and pH value were important factors influencing the speciation of heavy metals in soils of carbonate rock with high geological background areas. The enrichment of heavy metal elements in the residual fraction was influenced by long-term zinc smelting activities and the weathering of carbonate rocks into soil. Soil organic matter (OM) and oxide content had a relatively small influence on the speciation of heavy metals in the soil.

Cyr61 delivery promotes angiogenesis during bone fracture repair.

Compromised vascular supply and insufficient neovascularization impede bone repair, increasing risk of non-union. Cyr61, Cysteine-rich angiogenic inducer of 61kD (also known as CCN1), is a matricellular growth factor that is regulated by mechanical cues during fracture repair. Here, we map the distribution of endogenous Cyr61 during bone repair and evaluate the effects of recombinant Cyr61 delivery on vascularized bone regeneration. In vitro, Cyr61 treatment did not alter chondrogenesis or osteogenic gene expression, but significantly enhanced angiogenesis. In a mouse femoral fracture model, Cyr61 delivery did not alter cartilage or bone formation, but accelerated neovascularization during fracture repair. Early initiation of ambulatory mechanical loading disrupted Cyr61-induced neovascularization. Together, these data indicate that Cyr61 delivery can enhance angiogenesis during bone repair, particularly for fractures with stable fixation, and may have therapeutic potential for fractures with limited blood vessel supply.

MiR-106a-5p by Targeting MAP3K2 Promotes Repair of Oxidative Stress Damage to the Intestinal Barrier in Prelaying Ducks.

Under caged stress conditions, severe disruptions in duck intestinal barrier function, which adversely affect economic performance, have been observed. MiRNAs play a crucial role in cellular processes, but the mechanisms underlying their involvement in repairing oxidative stress-induced damage to duck intestinal barriers have not been elucidated. We performed miRNA-seq and protein tandem mass tagging (TMT) sequencing and identified differentially expressed miRNAs and proteins in oxidative stress-treated ducks. Dual-luciferase reporter vector experiments, RT-qPCR, and Western blotting revealed the regulatory role of apla-miR-106a-5p/MAP3K2 in intestinal barrier damage repair. The results showed that oxidative stress led to shortened villi and deepened crypts, impairing intestinal immune function. Significant downregulation of apla-miR-106a-5p was revealed by miRNA-seq, and the inhibition of its expression not only enhanced cell viability but also improved intestinal barrier function. TMT protein sequencing revealed MAP3K2 upregulation in caged-stressed duck intestines, and software analysis confirmed MAP3K2 as the target gene of apla-miR-106a-5p. Dual-fluorescence reporter gene experiments demonstrated direct targeting of MAP3K2 by apla-miR-106a-5p. RT-qPCR showed no effect on MAP3K2 expression, while Western blot analysis indicated that MAP3K2 protein expression was suppressed. In summary, apla-miR-106a-5p targets MAP3K2, regulating gene expression at the transcriptional level and facilitating effective repair of intestinal barrier damage. This discovery provides new insights into the molecular mechanisms of physiological damage in ducks under caged stress, offering valuable guidance for related research.

Smoking timing, genetic susceptibility and the risk of incident type 2 diabetes: A cohort study from the UK Biobank.

AIM: To prospectively assess the association of smoking timing with the risk of type 2 diabetes (T2D) and examine whether smoking amount or genetic susceptibility might modify the relationship. MATERIALS AND METHODS: A total of 294 815 participants without diabetes from the UK Biobank, including non-smokers and smokers with data on the time from waking to first cigarette, were included. Cox proportional hazards models were used to evaluate the association between smoking timing and the risk of incident T2D. RESULTS: During a median follow-up time of 12 years, a total of 9937 incident cases of T2D were documented. Compared with non-smokers, a shorter time from waking to first cigarette was significantly associated with a higher risk of incident T2D (P for trend < .001). In the fully adjusted model, the hazard ratios (HRs) (95% confidence interval) associated with smoking timing were 1.46 (1.17-1.81) for more than 2 hours, 1.51 (1.21-1.87) for 1-2 hours, 1.58 (1.34-1.85) for 30-60 minutes, 1.86 (1.57-2.21) for 5-15 minutes and 2.01 (1.60-2.54) for less than 5 minutes. We found that even among those who reported being light smokers, those with the shortest time from waking to first cigarette had a 105% higher risk of T2D with an HR of 2.05 (1.52-2.76), which was comparable with heavy smokers. The genetic risk score for T2D did not modify this association (P-interaction = .51). CONCLUSIONS: Our findings indicate that shorter time from waking to first cigarette is significantly associated with a higher risk of incident T2D.

A Case of Epstein-Barr Virus Encephalitis and Orbital-Face Inflammation.

Epstein-Barr virus (EBV) can cause follicular conjunctivitis, keratitis, oculoglandular syndrome, meningitis, and encephalitis. We report a 54-year-old Hispanic male who presented with right pupil-involved complete ophthalmoplegia, orbital and masticatory muscle inflammation, trigeminal enhancement, and new corneal infiltrate highly suggestive of EBV. Labwork was negative except for positive EBV polymerase chain reaction (PCR) in serum. Magnetic resonance imaging (MRI) of his brain and orbits with contrast showed enhancement of the right ganglion of the trigeminal nerve, oculomotor nerve, all extraocular muscles in the right orbit, and right masticatory and temporalis muscles and a right subacute lacunar infarct. The patient was diagnosed with encephalitis and orbital-face inflammation secondary to EBV infection. The patient improved with systemic steroids.

HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development.

Regulating nuclear export precisely is essential for maintaining mRNA homeostasis and impacts tumor progression. However, the mechanisms governing nuclear mRNA export remain poorly elucidated. Herein, it is revealed that the enhanced hypoxic long no-ncoding RNA (lncRNA prostate cancer associated transcript 6 (PCAT6) in breast cancer (BC) promotes the nuclear export of m6A-modified mRNAs, bolstering breast cancer stem cells (BCSCs) stemness and doxorubicin resistance. Clinically, hypoxic PCAT6 correlates with malignant BC features and poor prognosis. Mechanically, PCAT6 functions as a scaffold between interferon-stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination-mediated proteasomal degradation. Interestingly, as an m6A reader, hnRNPA2B1 selectively mediates m6A-tagged mRNAs nuclear export via the Aly/REF export factor (ALYREF)/ nuclear RNA export factor 1 (NXF1) complex, which promotes stemness-related genes expression. HnRNPA2B1 knockdown or mRNA export inhibition can result in the retention of nuclear m6A-tagged mRNA associated with stemness maintenance, which suppresses BCSCs self-renewal and effectively improves the efficacy of doxorubicin therapy. These findings demonstrate the pivotal role of m6A-modified mRNA nuclear export in BC progression, highlighting that the inhibition of m6A-tagged mRNA and its nuclear export is a potential therapeutic strategy for the amelioration of cancer chemotherapy.

Comparison of the therapeutic effects of medication therapy, specific immunotherapy and anti-IgE (Omalizumab) in patients with hay fever.

Background: Hay fever, characterized by seasonal allergic reactions, poses a significant health challenge. Existing therapies encompass standard drug regimens, biological agents, and specific immunotherapy. This study aims to assess and compare the effectiveness of anti-IgE (omalizumab), medication therapy, and subcutaneous immunotherapy (SCIT) for hay fever. Methods: Conducted as a retrospective cohort study, this research involved 98 outpatient hay fever patients who underwent routine medication, omalizumab treatment, or SCIT before the onset of the spring pollen season. A follow-up was performed one month after the start of the pollen season. The comprehensive symptoms and drug scores were used to evaluate patients with different intervention methods, facilitating a comparative analysis of therapeutic outcomes. Results: Compared with before treatment, the symptoms of patients treated with the three methods were all significantly relieved, and the medication score were significantly reduced. Patients treated with omalizumab demonstrated higher symptoms and medication scores than SCIT group before treatment, but similar scores after treatment, which were both lower than medicine treatment group. After treatment with omalizumab or SCIT, patients in both groups had significantly lower medication scores than the medication group and were close to no longer using medication for symptom relief. The mountain juniper-sIgE was significantly higher after treatment than before treatment in both medicine treatment group and omalizumab treatment group. Conclusion: Omalizumab and SCIT offer superior effects than medication therapy in hay fever patients.

Study on the quality of Corydalis Rhizoma in Zhejiang based on multidimensional evaluation method.

ETHNOPHARMACOLOGICAL RELEVANCE: The quality requirements of Corydalis Rhizoma (CR) in different producing areas are uniform, resulting in uneven efficacy. As a genuine producing area, the effective quality control of CR in Zhejiang Province (ZJ) could provide a theoretical basis for the rational application of medicinal materials. AIM OF THE STUDY: The purpose of this study was to effectively distinguish the CR inside and outside ZJ, and provided a theoretical basis for the quality control and material basis research of ZJ CR. MATERIALS AND METHODS: The core components of ZJ CR could be identified by HPLC combined with chemometrics screening, and the quality of CR from different producing areas was evaluated by a genetic algorithm-back propagation (GA-BP) neural network. Chromaticity and near-infrared (NIR) spectroscopy were used to identify CR inside and outside ZJ, and rapid content prediction was realized. The analgesic effect of CR in different regions was compared by a zebrafish analgesic experiment. Analgesic experiments in rats and analysis of the research status of quality components were used to screen the quality control components of ZJ CR. RESULTS: The contents of palmatine hydrochloride (YSBMT), dehydrocorydaline (TQZJJ), tetrahydropalmatine (YHSYS), tetrahydroberberine (SQXBJ), corydaline (YHSJS), stylopine (SQHLJ), and isoimperatorin (YOQHS) in ZJ CR were higher than those in CR from outside ZJ, but the content of protopine (YAPJ) and berberine hydrochloride (YSXBJ) was lower than that in CR from outside ZJ. YHSJS and SQHLJ could be used as the core components to identify ZJ CR. The GA-BP neural network showed that the relative importance of ZJ CR was the strongest. Chroma-content correlation analysis and the NIR qualitative model could effectively distinguish CR from inside and outside of ZJ, and the NIR quantitative model could quickly predict the content of CR from inside and outside of ZJ. Zebrafish experiments showed that ZJ, Shaanxi (SX), Henan (HN), and Sichuan (SC) CR had significant analgesic effects, while Hebei (HB) CR had no significant analgesic effect. Overall comparison, the analgesic effect of ZJ CR was better than that of CR outside ZJ. The comprehensive score of the grey correlation degree between YAPJ, YSBMT, YSXBJ, TQZJJ, YHSYS, YHSJS, SQXBJ, and SQHLJ were higher than 0.9, and the research frequency were extremely high. CONCLUSIONS: The relative importance of the content and origin of most components of ZJ CR was higher than that of CR outside ZJ. The holistic analgesic effect of ZJ CR was better than that of CR outside ZJ, but slightly lower than that of SX CR. YHSJS and SQHLJ could be used as the core components to identify ZJ CR. YAPJ, YSBMT, YSXBJ, TQZJJ, YHSYS, SQXBJ, YHSJS, and SQHLJ could be used as the quality control components of ZJ CR. The multidimensional evaluation method used in this study provided a reference for the quality control and material basis research of ZJ CR.

WNT2B activates macrophages via NF-κB signaling pathway in inflammatory bowel disease.

Inflammation is a significant pathological manifestation of inflammatory bowel disease (IBD), yet its mechanism has remained unclear. Although WNT2B is enriched in the intestinal inflammatory tissue of IBD patients, the specific mechanism of WNT2B in the formation of intestinal inflammation remains unclear. This study was aimed to investigate whether macrophages expressing WNT2B can aggravate intestinal tissue inflammation. Samples were collected from both normal individuals and patients with IBD at multiple colon sites. Macrophages were identified using tissue immunofluorescence. IκB kinase (IKK)-interacting protein (IKIP), which interacts with WNT2B, was found by protein cross-linking and protein mass spectrometry. The expression of WNT2B, IKIP, the NF-κB pathway, and downstream molecules were analyzed. An acute colitis model of C57BL/6J mice was established using an adeno-associated virus (AAV)-mediated WNT2B knockdown system and 3% dextran sulfate sodium (DSS). The degree of intestinal inflammation in mice was assessed upon WNT2B knockdown in macrophages. Macrophages expressing WNT2B were found to be enriched in the colitis tissues of IBD patients. WNT2B in macrophages activated the NF-κB pathway and enhanced the expression of downstream inflammatory cytokines. By competitively binding IKIP, WNT2B reduced the binding of IKIP to IKKß and promoted the activation of the NF-κB pathway. Using an AAV-mediated WNT2B knockdown system, WNT2B expression in intestinal macrophages was suppressed, leading to a reduction in intestinal inflammation. WNT2B activated the NF-κB pathway and enhanced the expression of downstream inflammatory cytokines by competitively binding to IKIP, potentially contributing to colon inflammatory injury in IBD.

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Degree of joint risk factor control and hazard of mortality in diabetes patients: a matched cohort study in UK Biobank.

BACKGROUND: Diabetes patients are at higher risk for mortality than the general population; however, little is known about whether the excess mortality risk associated with diabetes could be mitigated or nullified via controlling for risk factors. METHODS: We included 18,535 diabetes patients and 91,745 matched individuals without diabetes without baseline cancer or cardiovascular disease (CVD), followed up from 2006 to 2021. The main exposure was the number of optimized risk factors including glycated hemoglobin < 53 mmol/mole, systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg, no albuminuria, non-current smoking and low-density lipoprotein cholesterol (LDL-C) < 2.5 mmol/L. We used Cox proportional hazards models to explore the association of the degree of risk factor control with all-cause mortality, cancer mortality, CVD mortality and other mortality. RESULTS: Each additional risk factor control was associated with a 16, 10, 21 and 15% lower risk of all-cause mortality, cancer mortality, CVD mortality and other mortality, respectively. Optimal risk factors control (controlling 5 risk factors) was associated with a 50% (HR 0.50, 95% CI 0.41-0.62), 74% (HR 0.26, 95% CI 0.16-0.43) and 38% (HR 0.62, 95% CI 0.44-0.87) lower risk of all-cause mortality, CVD mortality and other mortality, respectively. Diabetes patients with 4, 3 and 5 or more controlled risk factors, respectively, showed no excess risk of all-cause mortality, cancer mortality and CVD mortality compared to matched non-diabetes patients. CONCLUSIONS: The results from this study indicate that optimal risk factor control may eliminate diabetes-related excess risk of all-cause mortality, CVD mortality and other mortality.

Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

PURPOSE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. CONCLUSION: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in NASH remain largely unclear. We explored the anti-apoptotic effect of hepatocyte CD1d in NASH. METHODS: Hepatocyte CD1d expression was analyzed in patients with NASH and mouse models. Hepatocyte-specific gene overexpression or knockdown and anti-CD1d crosslinking were used to investigate the anti-apoptotic effect of hepatocyte CD1d on lipotoxicity-, Fas-, and concanavalin (ConA)-mediated liver injuries. A high-fat diet, a methionine-choline-deficient diet, a Fas agonist, and ConA were used to induce lipotoxic and/or apoptotic liver injuries. Palmitic acid was used to mimic lipotoxicity-induced apoptosis in vitro. RESULTS: We identified a dramatic decrease in CD1d expression in hepatocytes of patients with NASH and mouse models. Hepatocyte-specific CD1d overexpression and knockdown experiments collectively demonstrated that hepatocyte CD1d protected against hepatocyte apoptosis and alleviated hepatic inflammation and injuries in NASH mice. Furthermore, decreased JAK2-STAT3 signaling was observed in NASH patient livers. Mechanistically, anti-CD1d crosslinking on hepatocytes induced tyrosine phosphorylation of the CD1d cytoplasmic tail, leading to the recruitment and phosphorylation of JAK2. Phosphorylated JAK2 activated STAT3 and subsequently reduced apoptosis in hepatocytes, which was associated with an increase in anti-apoptotic effectors (Bcl-xL and Mcl-1) and a decrease in pro-apoptotic effectors (cleaved-caspase 3/7). Moreover, anti-CD1d crosslinking effectively protected against Fas- or ConA-mediated hepatocyte apoptosis and liver injury in mice. CONCLUSIONS: Our study uncovered a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 axis in hepatocytes that conferred hepatoprotection and highlighted the potential of hepatocyte CD1d-directed therapy for liver injury and fibrosis in NASH, as well as in other liver diseases associated with hepatocyte apoptosis. IMPACT AND IMPLICATIONS: Excessive and/or sustained hepatocyte apoptosis is critical in driving liver inflammation and injury. The mechanisms underlying the regulation of hepatocyte apoptosis in non-alcoholic steatohepatitis (NASH) remain largely unclear. Here, we found that CD1d expression in hepatocytes substantially decreases and negatively correlates with the severity of liver injury in patients with NASH. We further revealed a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 signaling axis in hepatocytes, which confers significant protection against liver injury in NASH and acute liver diseases. Thus, hepatocyte CD1d-targeted therapy could be a promising strategy to manipulate liver injury in both NASH and other hepatocyte apoptosis-related liver diseases.

TGF-ß1 induces PD-1 expression in macrophages through SMAD3/STAT3 cooperative signaling in chronic inflammation.

Programmed cell death protein 1 (PD-1), a coinhibitory T cell checkpoint, is also expressed on macrophages in pathogen- or tumor-driven chronic inflammation. Increasing evidence underscores the importance of PD-1 on macrophages for dampening immune responses. However, the mechanism governing PD-1 expression in macrophages in chronic inflammation remains largely unknown. TGF-ß1 is abundant within chronic inflammatory microenvironments. Here, based on public databases, significantly positive correlations between PDCD1 and TGFB1 gene expression were observed in most human tumors. Of note, among immune infiltrates, macrophages as the predominant infiltrate expressed higher PDCD1 and TGFBR1/TGFBR2 genes. MC38 colon cancer and Schistosoma japonicum infection were used as experimental models for chronic inflammation. PD-1hi macrophages from chronic inflammatory tissues displayed an immunoregulatory pattern and expressed a higher level of TGF-ß receptors. Either TGF-ß1-neutralizing antibody administration or macrophage-specific Tgfbr1 knockdown largely reduced PD-1 expression on macrophages in animal models. We further demonstrated that TGF-ß1 directly induced PD-1 expression on macrophages. Mechanistically, TGF-ß1-induced PD-1 expression on macrophages was dependent on SMAD3 and STAT3, which formed a complex at the Pdcd1 promoter. Collectively, our study shows that macrophages adapt to chronic inflammation through TGF-ß1-triggered cooperative SMAD3/STAT3 signaling that induces PD-1 expression and modulates macrophage function.

Development of New CD38 Targeted Peptides for Cancer Imaging.

PURPOSE: Multiple myeloma (MM) affects over 35,000 patients each year in the US. There remains a need for versatile Positron Emission Tomography (PET) tracers for the detection, accurate staging, and monitoring of treatment response of MM that have optimal specificity and translational attributes. CD38 is uniformly overexpressed in MM and thus represents an ideal target to develop CD38-targeted small molecule PET radiopharmaceuticals to address these challenges. PROCEDURES: Using phage display peptide libraries and pioneering algorithms, we identified novel CD38 specific peptides. Imaging bioconjugates were synthesized using solid phase peptide chemistry, and systematically analyzed in vitro and in vivo in relevant MM systems. RESULTS: The CD38-targeted bioconjugates were radiolabeled with copper-64 (64Cu) with100% radiochemical purity and an average specific activity of 3.3 - 6.6 MBq/nmol. The analog NODAGA-PEG4-SL022-GGS (SL022: Thr-His-Tyr-Pro-Ile-Val-Ile) had a Kd of 7.55 ± 0.291 nM and was chosen as the lead candidate. 64Cu-NODAGA-PEG4-SL022-GGS demonstrated high binding affinity to CD38 expressing human myeloma MM.1S-CBR-GFP-WT cells, which was blocked by the non-radiolabeled version of the peptide analog and anti-CD38 clinical antibodies, daratumumab and isatuximab, by 58%, 73%, and 78%, respectively. The CD38 positive MM.1S-CBR-GFP-WT cells had > 68% enhanced cellular binding when compared to MM.1S-CBR-GFP-KO cells devoid of CD38. Furthermore, our new CD38-targeted radiopharmaceutical allowed visualization of tumors located in marrow rich bones, remaining there for up to 4 h. Clearance from non-target organs occurred within 60 min. Quantitative PET data from a murine disseminated tumor model showed significantly higher accumulation in the bones of tumor-bearing animals compared to tumor-naïve animals (SUVmax 2.06 ± 0.4 versus 1.24 ± 0.4, P = 0.02). Independently, tumor uptake of the target compound was significantly higher (P = 0.003) compared to the scrambled peptide, 64Cu-NODAGA-PEG4-SL041-GGS (SL041: Thr-Tyr-His-Ile-Pro-Ile-Val). The subcutaneous MM model demonstrated significantly higher accumulation in tumors compared to muscle at 1 and 4 h after tracer administration (SUVmax 0.8 ± 0.2 and 0.14 ± 0.04, P = 0.04 at 1 h; SUVmax 0.89 ± 0.01 and 0.09 ± 0.01, P = 0.0002 at 4 h). CONCLUSIONS: The novel CD38-targeted, radiolabeled bioconjugates were specific and allowed visualization of MM, providing a starting point for the clinical translation of such tracers for the detection of MM.

Temperature prediction of Bragg grating sensing based on a one-dimensional convolutional neural network: retraction.

The referenced article [Opt. Express31, 40179 (2023)10.1364/OE.502875] has been retracted by the authors, following an anonymous complaint.