Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder.

Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.

Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

Clinical outcomes of clip-assisted endoscopic cyanoacrylate injection versus conventional endoscopic cyanoacrylate injection in treating gastric varices with a gastrorenal shunt.

BACKGROUND AND STUDY AIMS: The optimal treatment for gastric varices (GVs) is a topic that remains definite for this study. This study compared the clinical outcomes of clip-assisted endoscopic cyanoacrylate injection (clip-ECI) to conventional endoscopic cyanoacrylate injection (con-ECI) for the treatment of GVs with a gastrorenal shunt. PATIENTS AND METHODS: Data were collected retrospectively in five medical centers from 2015 to 2020. The patients were treated with con-ECI (n = 126) or clip-ECI (n = 148). Clinical characteristics and procedural outcomes were compared. Patients were followed until death, liver transplantation or 6 months after the treatment. The primary outcome was rebleeding, and the secondary outcome was survival. RESULTS: There were no significant differences in age, sex, etiology, shunt diameter and Child-Pugh classification between the two groups. Fewer GVs obliteration sessions were required in the clip-ECI group than in the con-ECI group (p = 0.015). The cumulative 6-month rebleeding-free rates were 88.6% in the clip-ECI group and 73.7% in the con-ECI group (p = 0.002). The cumulative 6-month survival rates were 97.1% in the clip-ECI group and 94.8% in the con-ECI group (p = 0.378). CONCLUSIONS: Compared with con-ECI, clip-ECI appears more effective for the treatment of GVs with a gastrorenal shunt, which required less sessions and achieved a higher 6-month rebleeding-free rate.

Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)-Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib.

Tyrosine kinase inhibitors represented by sorafenib are the first-line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain-point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib-sensitive and -insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib-insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction-responsive nanoplatform for systemic co-delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles-mediated co-delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC.

Dual role of PID1 in regulating apoptosis induced by distinct anticancer-agents through AKT/Raf-1-dependent pathway in hepatocellular carcinoma.

The treatment outcome of hepatocellular carcinoma (HCC) is severely hampered due to its etiology, and thus in depth understanding of the genetic mechanisms underlying response of HCC to various anticancer agents is needed. Here, we have identified Phosphotyrosine interaction domain-containing protein 1 (PID1) as a novel regulator involved in modulation of apoptosis induced by anticancer agents in a context-dependent manner. PID1 relieved chemotherapy-induced ROS production, mitochondrial outer membrane permeability and mitochondrial respiratory depression. In addition, PID1 restricted AKT-mediated inhibition on Raf-1 through interacting with PDPK1 at phosphorylated tyrosine sites, thus enhancing Raf-1-mediated BAD inhibition. Interestingly, AKT, Bcl2 inhibition or Raf-1 silencing abolished PID1-mediated anti-apoptotic effects. However, PID1 altered the rhythmicity of pharmacological activity of Sorafenib on various survival-related kinases, thus resulting in AKT blockade via Raf-1/BRAF/ERK/MEK pathway. BRAF inhibition or Raf-1 depletion disrupted PID1-mediated barrier in AKT activation in response to Sorafenib. Moreover, in vivo study indicated that PID1 deficiency led to increased survival rate upon Doxorubicin treatment but reduced efficacy of Sorafenib. Overall, we propose that PID1 can function as an underlying biomarker of resistance to conventional chemotherapeutic agents but sensitivity towards Sorafenib.

Survival prediction among pathologic T4 bladder cancer patients following cytoreductive cystectomy: A retrospective single-center study.

Objectives: This retrospective study aimed to describe our institutional experience with cytoreductive cystectomy (Cx) in patients with pathological T4 (pT4) bladder cancer (BCa) and to investigate the clinicopathologic factors that can predict patient survival outcomes. Methods: We reviewed the baseline demographics, clinicopathologic features, perioperative complications, and follow-up data of 44 patients who underwent Cx for pT4 BCa at our institution between 2013 and 2021. The Kaplan-Meier curve and the log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analyses were performed using the Cox regression model. Results: The median age of the patients was 68 years [95% confidence interval (CI) 49-81]. Overall, 21 patients (47.7%) were estimated to have a high age-adjusted Charlson comorbidity index (ACCI) score (>4), and nine patients (20.5%) had pT4b substage BCa. None of the patients died of complications within 30-90 days after surgery. Severe complications occurred in 16% (n = 7) of patients within 30-90 days. During a median follow-up of 51 months, disease progression was detected in 25 patients (56.8%), and 29 patients (65.9%) died of any cause. The median PFS and OS were 15.0 and 21.0 months, respectively. The Kaplan-Meier analysis indicated that patients with high ACCI scores or pT4b BCa had worse PFS (P = 0.003 and P = 0.002, respectively) and OS (P = 0.016 and P = 0.034, respectively) than those with low ACCI scores or pT4a BCa. On multivariate analysis, pT4b substage [hazard ratio (HR), 4.166; 95% CI, 1.549-11.206; P = 0.005] and ACCI score >4 (HR, 2.329; 95% CI, 1.105-4.908; P = 0.026) remained independent risk factors for PFS and OS, respectively. Conclusion: Our study revealed that the pT4b substage is associated with a poor prognosis and that the ACCI score is a relevant and practical method to evaluate survival outcomes in patients with pT4 BCa after Cx.

CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport.

Pancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to the prognosis of PC patients. CARD9-deficient PC mice exhibited rapider cancer progression and poorer survival rate. CARD9 knockout decreased dendritic cell (DC) maturation and impaired DC ability to activate T cells in vivo and in vitro. Adoptive DC transfer confirmed that the role of CARD9 deficiency in PC relied on DCs. Creatine was identified as the most significant differential metabolite between WT DCs and CARD9-/- DCs wherein it played an essential role in maintaining DC maturation and function. CARD9 deficiency led to decreased creatine levels in DCs by inhibiting the transcription of the creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, CARD9 deletion blocked p65 activation by abolishing the formation of CARD9-BCL10-MALT1 complex, which prevented the binding between p65 and SLC6A8 promoter. These events decreased the creatine transport into DCs, and led to DC immaturity and impairment in antitumor immunity, consequently promoting PC progression.

Nanoparticles (NPs)-mediated systemic mRNA delivery to reverse trastuzumab resistance for effective breast cancer therapy.

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy. The first monoclonal antibody authorized for treating human epidermal growth receptor 2 (HER2)-positive breast cancer is trastuzumab. However, resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes. To address this issue, tumor microenvironment (TME) pH-responsive nanoparticles (NPs) were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer (BCa). This nanoplatform is comprised of a methoxyl-poly (ethylene glycol)-b-poly (lactic-co-glycolic acid) copolymer with a TME pH-liable linker (Meo-PEG-Dlink m -PLGA) and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction. When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously, they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface. With the intracellular mRNA release to up-regulate PTEN expression, the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells, thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.

Concurrent silencing of TBCE and drug delivery to overcome platinum-based resistance in liver cancer.

Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E (TBCE) expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.

Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib alone for advanced hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: The combination of sorafenib and hepatic arterial infusion chemotherapy (HAIC) is expected to exert a synergistic anticancer effect. We conducted this systematic review to examine the efficacy and safety of sorafenib plus HAIC vs sorafenib alone for advanced hepatocellular carcinoma (HCC). METHODS: We systematically searched the PubMed, Embase, and Cochrane Library with the following search terms: "sorafenib," "hepatic arterial infusion chemotherapy," "HAIC," "advanced," "hepatocellular carcinoma," and "HCC." Pooled hazard ratios (HRs) and 95% CIs were calculated for overall survival (OS) and progression-free survival (PFS), and we calculated the pooled risk ratios (RRs) and 95% CIs for objective response rate (ORR) and adverse events (AEs). RESULTS: We found that sorafenib plus HAIC was associated with significantly better OS (HR, 0.56; 95% CI, 0.37-0.83; P < 0.01), PFS (HR, 0.44; 95% CI, 0.27-0.72; P < 0.01), and ORR (RR, 3.77; 95% CI, 1.87-7.58; P < 0.01) than sorafenib alone in advanced HCC. Grade 3/4 AEs were more frequent in the sorafenib plus HAIC group, including leukopenia (RR, 4.54; 95% CI, 1.77-11.64; P < 0.01), neutropenia (RR, 7.81; 95% CI, 3.36-18.16; P < 0.01), thrombocytopenia (RR, 2.97; 95% CI, 1.98-4.46; P < 0.01), anemia (RR, 2.24; 95% CI, 1.22-4.09; P < 0.01), anorexia (RR, 2.37; 95% CI, 1.07-5.27; P = 0.03), nausea (RR, 2.98; 95% CI, 1.19-7.42; P = 0.02), and vomiting (RR, 3.99; 95% CI, 1.14-14.01; P = 0.03). CONCLUSION: Sorafenib plus HAIC improved OS, PFS, and ORR compared with sorafenib alone in advanced HCC, with acceptable safety profile.

Lian-Qu formula treats metabolic syndrome via reducing fat synthesis, insulin resistance and inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic syndrome (MetS) is a pathological condition characterized by obesity, hyperglycemia, hypertension and hyperlipidemia that increases the risk of cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease. The traditional Chinese medicine Lian-Qu formula (LQF) is modified from Xiaoxianxiong decoction, which has been used for coronary heart disease or metabolic disease in clinical for a long time. However, the pharmacological mechanism of LQF on MetS is unclear. AIM OF THE STUDY: Here, we explored the actions of LQF on MetS via network pharmacology and validated the mechanism in the MetS mice. MATERIALS AND METHODS: The chemical components of LQF were searched in the traditional Chinese medicine systems pharmacology database and the natural product activity & species source database. The related targets of MetS disease were gathered from genes cluster with literature profiles database. The protein-protein interaction network was constructed to obtain the key target genes. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment of the key targets were performed to predict the potential mechanisms of LQF action on MetS. And then, the high-fat diet-induced MetS mice were used to validate its therapeutic effect and molecular targets. Insulin tolerance test and oral glucose tolerance test were used to assess insulin sensitivity. Body weight and visceral fat index were measured to assess obesity. Liver metabolism was detected by H&E section, oil red O staining and untargeted lipid metabolomics experiments. Finally, the key targets of LQF action on MetS were verified by PCR and ELISA kits. RESULTS: A total of 466 components in LQF were obtained, among which 71 were active. These components correspond to 74 targets associated with MetS. The predicted targets of LQF worked on MetS were AKT1, INSR, PPARs, FASN, LDLR, TNF, CRP, IL-6, IL-1ß and so on. Furthermore, these targets were related to pathways in cellular response to lipid, inflammatory response, glucose transmembrane transport and insulin resistance. Finally, the animal experiments validated that LQF inhibited lipids accumulation by inhibiting the gene expression of FASN and increasing ADPN, and it relieved insulin resistance by increasing GLUT-4 expression. Moreover, LQF alleviated inflammation by reducing IL-6 and CRP levels. CONCLUSION: LQF exerted anti-MetS effects through improving insulin sensitivity, ameliorating hyperlipidemia and obesity, reducing liver injury, and inhibiting inflammatory response.

The combination of gemcitabine and ginsenoside Rh2 enhances the immune function of dendritic cells against pancreatic cancer via the CARD9-BCL10-MALT1 / NF-κB pathway.

Cold tumor immune microenvironment (TIME) of pancreatic cancer (PC) with minimal dendritic cell (DC) and T cell infiltration can result in insufficient immunotherapy and chemotherapy. While gemcitabine (GEM) is a first-line chemotherapeutic drug for PC, its efficacy is reduced by immunosuppression and drug resistance. Ginsenoside Rh2 (Rh2) is known to have anti-cancer and immunomodulatory properties. Combining GEM with Rh2 may thus overcome immunosuppression and induce lasting anti-tumor immunity in PC. Here, we showed that after GEM-Rh2 therapy, there was significantly greater tumor infiltration by DCs. Caspase recruitment domain-containing protein 9 (CARD9), a central adaptor protein, was strongly up-regulated DCs with GEM-Rh2 therapy and promoted anti-tumor immune responses by DCs. CARD9 was found to be a critical target for Rh2 to enhance DC function. However, GEM-Rh2 treatment did not achieve the substantial anti-PC efficacy in CARD9-/- mice as in WT mice. The adoptive transfer of WT DCs to DC-depleted PC mice treated with GEM-Rh2 elicited strong anti-tumor immune responses, although CARD9-/- DCs were less effective than WT DCs. Our results showed that GEM-Rh2 may reverse cold TIME by enhancing tumor immunogenicity and decreasing the levels of immunosuppressive factors, reactivating DCs via the CARD9-BCL10-MALT1/ NF-κB pathway. Our findings suggest a potentially feasible and safe treatment strategy for PC, with a unique mechanism of action. Thus, Rh2 activation of DCs may remodel the cold TIME and optimize GEM chemotherapy for future therapeutic use.

Biological Effects of EGCG@MOF Zn(BTC)4 System Improves Wound Healing in Diabetes.

Tea contains high levels of the compound epigallocatechin gallate (EGCG). It is considered an important functional component in tea and has anti-cancer, antioxidant, and anti-inflammatory effects. The eight phenolic hydroxyl groups in EGCG's chemical structure are the basis for EGCG's multiple biological effects. At the same time, it also leads to poor chemical stability, rendering EGCG prone to oxidation and isomerization reactions that change its original structure and biological activity. Learning how to maintain the activity of EGCG has become an important goal in understanding the biological activity of EGCG and the research and development of tea-related products. Metal-organic frameworks (MOFs) are porous materials with a three-dimensional network structure that are composed of inorganic metals or metal clusters together with organic complexes. MOFs exploit the porous nature of the material itself. When a drug is an appropriate size, it can be wrapped into the pores by physical or chemical methods; this allows the drug to be released slowly, and MOFs can also reduce drug toxicity. In this study, we used MOF Zn(BTC)4 materials to load EGCG and investigated the sustained release effect of EGCG@MOF Zn(BTC)4 and the biological effects on wound healing in a diabetic mouse model.

Cytochalasin Q exerts anti-melanoma effect by inhibiting creatine kinase B.

Due to the pivotal role of microfilament in cancer cells, targeting microfilaments with cytochalasins is considered a promising anticancer strategy. Here, we obtained cytochalasin Q (CQ) from Xylaria sp. DO1801, the endophytic fungi from the root of plant Damnacanthus officinarum, and discovered its anti-melanoma activity in vivo and in vitro attributing to microfilament depolymerization. Mechanistically, CQ directly bound to and inactivated creatine kinase B (CKB), an enzyme phosphorylating creatine to phosphocreatine (PCr) and regenerating ATP to cope with high energy demand, and then inhibited the creatine metabolism as well as cytosolic glycolysis in melanoma cells. Preloading PCr recovered ATP generation, reversed microfilament depolymerization and blunted anti-melanoma efficacy of CQ. Knockdown of CKB resulted in reduced ATP level, perturbed microfilament, inhibited proliferation and induced apoptosis, and manifested lower sensitivity to CQ. Further, we found that either CQ or CKB depletion suppressed the PI3K/AKT/FoxO1 pathway, whereas 740Y-P, a PI3K agonist, elevated protein expression of CKB suppressed by CQ. Taken together, our study highlights the significant anti-melanoma effect and proposes a PI3K/AKT/FoxO1/ CKB feedback circuit for the activity of CQ, opening new opportunities for current chemotherapy.

Kinsenoside attenuates liver fibro-inflammation by suppressing dendritic cells via the PI3K-AKT-FoxO1 pathway.

Kinsenoside (KD) exhibits anti-inflammatory and immunosuppressive effects. Dendritic cells (DCs) are critical regulators of the pathologic inflammatory milieu in liver fibrosis (LF). Herein, we explored whether and how KD repressed development of LF via DC regulation and verified the pathway involved in the process. Given our analysis, both KD and adoptive transfer of KD-conditioned DCs conspicuously reduced hepatic histopathological damage, proinflammatory cytokine release and extracellular matrix deposition in CCl4-induced LF mice. Of note, KD restrained the LF-driven rise in CD86, MHC-II, and CCR7 levels and, simultaneously, upregulated PD-L1 expression on DCs specifically, which blocked CD8+T cell activation. Additionally, KD reduced DC glycolysis, maintained DCs immature, accompanied by IL-12 decrease in DCs. Inhibiting DC function by KD disturbed the communication of DCs and HSCs with the expression or secretion of α-SMA and Col-I declined in the liver. Mechanistically, KD suppressed the phosphorylation of PI3K-AKT driven by LF or PI3K agonist, followed by enhanced nuclear transport of FoxO1 and upregulated interaction of FoxO1 with the PD-L1 promoter in DCs. PI3K inhibitor or si-IL-12 acting on DC could relieve LF, HSC activation and diminish the effect of KD. In conclusion, KD suppressed DC maturation with promoted PD-L1 expression via PI3K-AKT-FoxO1 and decreased IL-12 secretion, which blocked activation of CD8+T cells and HSCs, thereby alleviating liver injury and fibro-inflammation in LF.

Regenerating islet-derived protein 3 gamma (Reg3g) ameliorates tacrolimus-induced pancreatic ß-cell dysfunction in mice by restoring mitochondrial function.

BACKGROUND AND PURPOSE: Tacrolimus a first-line medication used after transplantation can induce ß-cell dysfunction, causing new-onset diabetes mellitus (NODM). Regenerating islet-derived protein 3 gamma (Reg3g), a member of the pancreatic regenerative gene family, has been reported to improve type 1 diabetes by promoting ß-cell regeneration. We aim to investigate the role of Reg3g in reversing tacrolimus-induced ß-cell dysfunction and NODM in mice. EXPERIMENTAL APPROACH: Circulating REG3A (the human homologue of mouse Reg3g) in heart transplantation patients treated with tacrolimus was detected. The glucose-stimulated insulin secretion and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium, ATP production, oxygen consumption rate and mitochondrial morphology were investigated in ß-cells. Additionally, effects of Reg3g on tacrolimus-induced NODM in mice were analysed. KEY RESULTS: Circulating REG3A level in heart transplantation patients with NODM significantly decreased compared with those without diabetes. Tacrolimus down-regulated Reg3g via inhibiting STAT3-mediated transcription activation. Moreover, Reg3g restored glucose-stimulated insulin secretion suppressed by tacrolimus in ß-cells by improving mitochondrial functions, including increased MMP, mitochondria calcium uptake, ATP production, oxygen consumption rate and contributing to an intact mitochondrial morphology. Mechanistically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signalling pathway, leading to restoration of tacrolimus-induced mitochondrial impairment. Reg3g overexpression also effectively mitigated tacrolimus-induced NODM in mice. CONCLUSION AND IMPLICATIONS: Reg3g can significantly ameliorate tacrolimus-induced ß-cell dysfunction by restoring mitochondrial function in a pSTAT3(Ser727)-dependent manner. Our observations identify a novel Reg3g-mediated mechanism that is involved in tacrolimus-induced NODM and establish the novel role of Reg3g in reversing tacrolimus-induced ß-cell dysfunction.

Advances in organophosphorus pesticides pollution: Current status and challenges in ecotoxicological, sustainable agriculture, and degradation strategies.

Organophosphorus pesticides (OPPs) are one of the most widely used types of pesticide that play an important role in the production process due to their effects on preventing pathogen infection and increasing yield. However, in the early development and application of OPPs, their toxicological effects and the issue of environmental pollution were not considered. With the long-term overuse of OPPs, their hazards to the ecological environment (including soil and water) and animal health have attracted increasing attention. Therefore, this review first clarified the classification, characteristics, applications of various OPPs, and the government's restriction requirements on various OPPs. Second, the toxicological effects and metabolic mechanisms of OPPs and their metabolites were introduced in organisms. Finally, the existing methods of degrading OPPs were summarized, and the challenges and further addressing strategy of OPPs in the sustainable development of agriculture, the environment, and ecology were prospected. However, methods to solve the environmental and ecological problems caused by OPPs from the three aspects of use source, use process, and degradation methods were proposed, which provided a theoretical basis for addressing the stability of the ecological environment and improving the structure of the pesticide industry in the future.

A siRNA-Assisted Assembly Strategy to Simultaneously Suppress "Self" and Upregulate "Eat-Me" Signals for Nanoenabled Chemo-Immunotherapy.

Effectively activating macrophages that can engulf cancer cells is a promising immunotherapeutic strategy but remains a major challenge due to the expression of "self" signals (e.g., CD47 molecules) by tumor cells to prevent phagocytosis. Herein, we explored a siRNA-assisted assembly strategy for the simultaneous delivery of siRNA and mitoxantrone hydrochloride (MTO·2HCl) via PLGA-based nanoparticles. The siRNA suppressed a "self" signal by silencing the CD47 gene, while the MTO induced surface exposure of calreticulin (CRT) to provide an "eat-me" signal. The siRNA-assisted assembly strategy synergistically increased the phagocytosis of tumor cells by macrophages, promoted effective antigen presentation, and initiated T cell-mediated immune responses in two aggressive tumor animal models of melanoma and colon cancer, eventually achieving significantly improved antitumor activity. This study provides a straightforward codelivery strategy to simultaneously suppress "self" and upregulate "eat-me" signals to potentiate macrophage-mediated immunotherapy.

STING inhibitors target the cyclic dinucleotide binding pocket.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1-/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.