Nrf2 induces angiogenesis in spinal cystic echinococcosis by activating autophagy via regulating oxidative stress.

Spinal cystic echinococcosis (CE) is a rare but malignant zoonosis that can cause disability or even death in more than half of patients. Due to the complex pathological features, it is not curable by conventional drugs and surgery, so new therapeutic targets urgently need to be discovered. In this study, we clarify the occurrence of the phenomenon of spinal encapsulation angiogenesis and explore its underlying molecular mechanisms. A co-culture system was established by protoscoleces (PSCs) with human umbilical vein endothelial cells (HUVECs) which showed a high expression level of Nrf2. A short hairpin RNA (shRNA) and Sulforaphane (SFN) affecting the expression of Nrf2 were used to treat HUVECs. The results showed that Nrf2 could promote the tube formation of HUVECs. Nrf2 also exerts a protective effect against HUVECs, which is achieved by promoting NQO1 expression to stabilize ROS levels. Furthermore, autophagy activation significantly promotes angiogenesis in the spinal echinococcosis model (SEM) as a result of Nrf2 regulation of oxidative stress. These results suggest that the ROS/Nrf2/autophagy axis can induce angiogenesis and may be a potential target for the treatment of spinal cystic echinococcosis.

Generation of an iPSC line from a 79-year-old female patient diagnosed with sporadic Parkinson's disease.

Parkinson's disease is a common neurodegenerative disorder. Here we present a human induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) of a 79-year-old female patient diagnosed with sporadic Parkinson's disease using the sendai virus. Generated iPSCs maintain normal karyotype, exhibit pluripotent stem cell markers, and possess differentiation potential. The iPSCs allows for differentiation into various cell subtypes, providing conditions for the research of the pathogenesis and drug development of Parkinson's disease.

Lactate metabolism and acute kidney injury.

ABSTRACT: Acute kidney injury (AKI) is a common clinically critical syndrome in hospitalized patients with high morbidity and mortality. At present, the mechanism of AKI has not been fully elucidated, and no therapeutic drugs exist. As known, glycolytic product lactate is a key metabolite in physiological and pathological processes. The kidney is an important gluconeogenic organ, where lactate is the primary substrate of renal gluconeogenesis in physiological conditions. During AKI, altered glycolysis and gluconeogenesis in kidneys significantly disturb the lactate metabolic balance, which exert impacts on the severity and prognosis of AKI. Additionally, lactate-derived posttranslational modification, namely lactylation, is novel to AKI as it could regulate gene transcription of metabolic enzymes involved in glycolysis or Warburg effect. Protein lactylation widely exists in human tissues and may severely affect non-histone functions. Moreover, the strategies of intervening lactate metabolic pathways are expected to bring a new dawn for the treatment of AKI. This review focused on renal lactate metabolism, especially in proximal renal tubules after AKI, and updated recent advances of lactylation modification, which may help to explore potential therapeutic targets against AKI.

Supercritical CO2 extrusion foaming of highly open-cell poly(lactic acid) foam with superior oil adsorption performance.

Addressing marine oil spills and industrial water pollution necessitates the development of eco-efficient oil-absorbing materials. With increasing concern for the environment, there is a consensus to decrease the use of petroleum-based polymers. Herein, lightweight poly(lactic acid) (PLA) blend foams with varying thermoplastic polyurethane (TPU) content were fabricated via a solvent-free, eco-friendly supercritical carbon dioxide (scCO2) extrusion foaming technology. The incorporation of TPU significantly enhanced the crystallization rate of PLA, with the semi-crystallization time of PT30 and PT50 blends at 105 °C exhibiting a reduction of 77.2 % and 47.9 %, respectively, compared to neat PLA. The resulting foams exhibited an open-cell structure with excellent selective oil adsorption capabilities. Notably, the PT30 foam achieved a remarkable maximum expansion ratio of 36.0, while the PT50 foam attained the highest open-cell content of 96.2 %. The PT50 foam demonstrated an outstanding adsorption capacity, spanning from 4.7 to 18.8 g/g for diverse oils and solvents, with rapid adsorption kinetics, reaching 94.9 % of the equilibrium adsorption capacity for CCl4 within just 1 min. Furthermore, the PT50 foam retained 95.2 % of its adsorption capacity for CCl4 over 10 adsorption-desorption cycles. This study presents a scalable and sustainable approach for large-scale production of high-performance, bio-based foams, facilitating efficient oil-water separation.

Hypoglycemic Response to Dorzagliatin in a Patient With GCK-MODY.

OBJECTIVE: Metformin, insulin, and insulin secretagogues do not alter HbA1c levels in glucokinase-maturity-onset diabetes of the young (GCK-MODY). However, the efficacy of the new hypoglycemic drugs on GCK-MODY remains unclear. RESEARCH DESIGN AND METHODS: We describe a case of GCK-MODY with unchanged blood glucose under different therapies during an 8 years' follow-up. His HbA1c and biochemical indices under different hypoglycemic treatments were recorded. RESULTS: Oral antidiabetic drugs, including thiazolidinediones, dipeptidyl peptidase IV inhibitor, α-glucosidase inhibitor, and sodium-glucose cotransporter 2 inhibitor that had not been evaluated previously, did not improve the HbA1c level in this patient. However, the glucokinase activator dorzagliatin effectively and safely lowered his HbA1c level. CONCLUSIONS: Dorzagliatin was effective and safe in this patient with GCK-MODY, providing potential application prospects for precise treatment of GCK-MODY with dorzagliatin.

Zinc peroxide-based nanotheranostic platform with endogenous hydrogen peroxide/oxygen generation for enhanced photodynamic-chemo therapy of tumors.

Nanotheranostic platforms, which can respond to tumor microenvironments (TME, such as low pH and hypoxia), are immensely appealing for photodynamic therapy (PDT). However, hypoxia in solid tumors harms the treatment outcome of PDT which depends on oxygen molecules to generate cytotoxic singlet oxygen (1O2). Herein, we report the design of TME-responsive smart nanotheranostic platform (DOX/ZnO2@Zr-Ce6/Pt/PEG) which can generate endogenously hydrogen peroxide (H2O2) and oxygen (O2) to alleviate hypoxia for improving photodynamic-chemo combination therapy of tumors. DOX/ZnO2@Zr-Ce6/Pt/PEG nanocomposite was prepared by the synthesis of ZnO2 nanoparticles, in-situ assembly of Zr-Ce6 as typical metal-organic framework (MOF) on ZnO2 surface, in-situ reduction of Pt nanozymes, amphiphilic lipids surface coating and then doxorubicin (DOX) loading. DOX/ZnO2@Zr-Ce6/Pt/PEG nanocomposite exhibits average sizes of ∼78 nm and possesses a good loading capacity (48.8 %) for DOX. When DOX/ZnO2@Zr-Ce6/Pt/PEG dispersions are intratumorally injected into mice, the weak acidic TEM induces the decomposition of ZnO2 core to generate endogenously H2O2, then Pt nanozymes catalyze H2O2 to produce O2 for alleviating tumor hypoxia. Upon laser (630 nm) irradiation, the Zr-Ce6 component in DOX/ZnO2@Zr-Ce6/Pt/PEG can produce cytotoxic 1O2, and 1O2 generation rate can be enhanced by 2.94 times due to the cascaded generation of endogenous H2O2/O2. Furthermore, the generated O2 can suppress the expression of hypoxia-inducible factor α, and further enable tumor cells to become more sensitive to chemotherapy, thereby leading to an increased effectiveness of chemotherapy treatment. The photodynamic-chemo combination therapy from DOX/ZnO2@Zr-Ce6/Pt/PEG nanoplatform exhibits remarkable tumor growth inhibition compared to chemotherapy or PDT. Thus, the present study is a good demonstration of a TME-responsive nanoplatform in a multimodal approach for cancer therapy.

Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms.

Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.

Myeloid-derived Wnts play an indispensible role in macrophage and fibroblast activation and kidney fibrosis.

Wnt/ß-catenin signaling plays a pivotal role in the pathogenesis of chronic kidney diseases (CKD), which is associated with macrophage activation and polarization. However, the relative contribution of macrophage-derived Wnts in the evolution of CKD is poorly understood. Here we demonstrate a critical role of Wnts secreted by macrophages in regulating renal inflammation and fibrosis after various injuries. In mouse model of kidney fibrosis induced by unilateral ureteral obstruction (UUO), macrophages were activated and polarized to M1 and M2 subtypes, which coincided with the activation of Wnt/ß-catenin signaling. In vitro, multiple Wnts were induced in primary cultured bone marrow-derived macrophages (BMDMs) after polarization. Conversely, Wnt proteins also stimulated the activation and polarization of BMDMs to M1 and M2 subtype. Blockade of Wnt secretion from macrophages in mice with myeloid-specific ablation of Wntless (Wls), a cargo receptor that is obligatory for Wnt trafficking and secretion, blunted macrophage infiltration and activation and inhibited the expression of inflammatory cytokines. Inhibition of Wnt secretion by macrophages also abolished ß-catenin activation in tubular epithelium, repressed myofibroblast activation and reduced kidney fibrosis after either obstructive or ischemic injury. Furthermore, conditioned medium from Wls-deficient BMDMs exhibited less potency to stimulate fibroblast proliferation and activation, compared to the controls. These results underscore an indispensable role of macrophage-derived Wnts in promoting renal inflammation, fibroblasts activation and kidney fibrosis.

Taurine attenuates activation of hepatic stellate cells by inhibiting autophagy and inducing ferroptosis.

BACKGROUND: Liver fibrosis is a compensatory response during the tissue repair process in chronic liver injury, and finally leads to liver cirrhosis or even hepatocellular carcinoma. The pathogenesis of hepatic fibrosis is associated with the progressive accumulation of activated hepatic stellate cells (HSCs), which can transdifferentiate into myofibroblasts to produce an excess of the extracellular matrix (ECM). Myofibroblasts are the main source of the excessive ECM responsible for hepatic fibrosis. Therefore, activated hepatic stellate cells (aHSCs), the principal ECM producing cells in the injured liver, are a promising therapeutic target for the treatment of hepatic fibrosis. AIM: To explore the effect of taurine on aHSC proliferation and the mechanisms involved. METHODS: Human HSCs (LX-2) were randomly divided into five groups: Normal control group, platelet-derived growth factor-BB (PDGF-BB) (20 ng/mL) treated group, and low, medium, and high dosage of taurine (10 mmol/L, 50 mmol/L, and 100 mmol/L, respectively) with PDGF-BB (20 ng/mL) treated group. Cell Counting Kit-8 method was performed to evaluate the effect of taurine on the viability of aHSCs. Enzyme-linked immunosorbent assay was used to estimate the effect of taurine on the levels of reactive oxygen species (ROS), malondialdehyde, glutathione, and iron concentration. Transmission electron microscopy was applied to observe the effect of taurine on the autophagosomes and ferroptosis features in aHSCs. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the effect of taurine on the expression of α-SMA, Collagen I, Fibronectin 1, LC3B, ATG5, Beclin 1, PTGS2, SLC7A11, and p62. RESULTS: Taurine promoted the death of aHSCs and reduced the deposition of the ECM. Treatment with taurine could alleviate autophagy in HSCs to inhibit their activation, by decreasing autophagosome formation, downregulating LC3B and Beclin 1 protein expression, and upregulating p62 protein expression. Meanwhile, treatment with taurine triggered ferroptosis and ferritinophagy to eliminate aHSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Furthermore, bioinformatics analysis demonstrated that taurine had a direct targeting effect on nuclear receptor coactivator 4, exhibiting the best average binding affinity of -20.99 kcal/mol. CONCLUSION: Taurine exerts therapeutic effects on liver fibrosis via mechanisms that involve inhibition of autophagy and trigger of ferroptosis and ferritinophagy in HSCs to eliminate aHSCs.

Partially knocking out NtPDK1a/1b/1c/1d simultaneously in Nicotiana tabacum using CRISPR/CAS9 technology results in auxin-related developmental defects.

The eukaryotic AGC protein kinase subfamily (protein kinase A/ protein kinase G/ protein kinase C-family) is involved in regulating numerous biological processes across kingdoms, including growth and development, and apoptosis. PDK1(3-phosphoinositide-dependent protein kinase 1) is a conserved serine/threonine kinase in eukaryotes, which is both a member of AGC kinase and a major regulator of many other downstream AGC protein kinase family members. Although extensively investigated in model plant Arabidopsis, detailed reports for tobacco PDK1s have been limited. To better understand the functions of PDK1s in tobacco, CRISPR/CAS9 transgenic lines were generated in tetraploid N. tabacum, cv. Samsun (NN) with 5-7 of the 8 copies of 4 homologous PDK1 genes in tobacco genome (NtPDK1a/1b/1c/1d homologs) simultaneously knocked out. Numerous developmental defects were observed in these NtPDK1a/1b/1c/1d CRISPR/CAS9 lines, including cotyledon fusion leaf shrinkage, uneven distribution of leaf veins, convex veins, root growth retardation, and reduced fertility, all of which reminiscence of impaired polar auxin transport. The severity of these defects was correlated with the number of knocked out alleles of NtPDK1a/1b/1c/1d. Consistent with the observation in Arabidopsis, it was found that the polar auxin transport, and not auxin biosynthesis, was significantly compromised in these knockout lines compared with the wild type tobacco plants. The fact that no homozygous plant with all 8 NtPDK1a/1b/1c/1d alleles being knocked out suggested that knocking out 8 alleles of NtPDK1a/1b/1c/1d could be lethal. In conclusion, our results indicated that NtPDK1s are versatile AGC kinases that participate in regulation of tobacco growth and development via modulating polar auxin transport. Our results also indicated that CRISPR/CAS9 technology is a powerful tool in resolving gene redundancy in polyploidy plants.

Overburden of rare ALMS1 deleterious variants in Chinese early-onset type 2 diabetes with severe insulin resistance.

AIMS: Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early-onset type 2 diabetes (age at diagnosis ≤40 years; EOD). MATERIALS AND METHODS: ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants. RESULTS: Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR. CONCLUSIONS: ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.

Generation of KCNH2 heterozygous knockout induced pluripotent stem cell (iPSC) line (Long and Short QT Syndrome).

KCNH2 (Potassium Voltage-Gated Channel Subfamily H Member) encodes a voltage-activated potassium channel role as rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of the ventricular action potential. Mutations in this gene can cause long QT syndrome and short QT syndrome. Transcript variants encoding distinct isoforms were also identified. In this study, we generated induced pluripotent stem cells (iPSC) from a healthy individual by electroporation of peripheral blood mononuclear cells and generated a KCNH2 heterozygous knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had a normal karyotype, were free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.

Varenicline solution nasal spray for dry eye disease in Chinese patients: a randomized phase 3 trial.

Background: Dry eye disease has a high prevalence and exerts a significant negative effect on quality of life. In China, there are currently no available nasal sprays to promote natural tear production in patients with dry eye disease. We therefore evaluated the efficacy and safety of OC-01 (varenicline solution) nasal spray versus vehicle in Chinese patients with dry eye disease. Methods: This was a randomized, multicenter, double-masked, vehicle-controlled, phase 3 clinical trial conducted at ophthalmology departments in 20 hospitals across China (NCT05378945). Eligible patients had a diagnosis of dry eye disease based on patient symptoms, Eye Dryness Score (EDS), Schirmer's Test (with topical anesthesia) Score (STS), and corneal fluorescein staining (CFS) score. Participants were randomly assigned 1:1 using an Interactive Web Response System (IWRS) to receive OC-01 0.6 mg/mL twice daily (BID) or vehicle nasal spray. Participants, investigators, and sponsor were all masked to treatment assignment. The primary endpoint was the percentage of subjects in the intention-to-treat population achieving ≥10 mm improvement in STS from baseline at week 4. Findings: In total, 340 patients were randomized from 21 July 2022 to 04 April 2023, 78.8% were female. Patients in the OC-01 group (n = 176) had significantly higher achievement of ≥10 mm improvement in STS (35.8% [n = 63] versus 17.7% [n = 29], stratified odds ratio: 2.67, 95% CI: 1.570-4.533, p = 0.0002) and a significantly greater increase from baseline STS (least-squares mean difference [SE]: 3.87 [0.794], p < 0.0001) at week 4 versus the vehicle group (n = 164). In addition, OC-01 led to a numerically greater reduction in mean EDS from baseline at week 4 compared to the vehicle group (LS mean [SE] difference: -1.3 [2.20]; 95% CI: -5.64 to 2.99, p = 0.5467). The most common adverse event was mild, transient sneezing (78% of OC-01 administrations). No serious adverse events related to nasal administration occurred. Interpretation: OC-01 (varenicline solution) nasal spray BID has clinically meaningful efficacy for reducing the signs (as measured by STS) and may improve the symptoms (as measured by EDS) of dry eye disease, with an excellent safety and tolerability profile, in the Chinese population. Funding: Jixing Pharmaceutical Co. Ltd.

Prevalence and risk factors of fatigue and its association with quality of life among patients with chronic pancreatitis: A cross-sectional study.

BACKGROUND: Fatigue is a debilitating symptom found in various chronic diseases and is associated with more severe symptoms and worse quality of life (QoL). However, this symptom has not been adequately addressed in chronic pancreatitis (CP), and there have been no studies on fatigue in patients with CP. METHODS: This cross-sectional study was conducted at the Changhai Hospital in Shanghai, China. Data on the patients' sociodemographic, disease, and therapeutic characteristics were collected. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. QoL was assessed utilizing the European Organization for the Research and Treatment of Cancer of QoL questionnaire (EORTC-QLQ-C30). Sleep quality, anxiety and depression, and pain was assessed using Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and the Brief Pain Inventory, respectively. RESULTS: The prevalence of fatigue among Chinese patients with CP was 35.51 % (87/245). Multivariate analysis showed that steatorrhea (OR = 2.638, 95 % CI: 1.117-6.234), history of smoking (OR = 4.627, 95 % CI: 1.202-17.802), history of endoscopic treatment (OR = 0.419, 95 % CI: 0.185-0.950), depression (OR = 5.924, 95 % CI: 2.462-14.255), and sleep disorder (OR = 6.184, 95 % CI: 2.543-15.034) were influencing factors for the presence of fatigue. The scores for global health and all functional dimensions in the EORTC-QLQ-C30 significantly decreased, whereas the scores for all symptom dimensions significantly increased in patients with fatigue. CONCLUSIONS: This study indicated that Fatigue is a common symptom and has a negative impact on the QoL of patients with CP. Steatorrhea, smoking history, endoscopic treatment, depression, and sleep disorders were associated with fatigue.

Dressing and undressing MOF nanophotosensitizers to manipulate phototoxicity for precise therapy of tumors.

Photodynamic therapy (PDT) is a clinically approved treatment for tumors, and it relies on the phototoxicity of photosensitizers by producing reactive oxygen species (ROS) to destroy cancer cells under light irradiation. However, such phototoxicity is a double-edged sword, which is also harmful to normal tissues. To manipulate phototoxicity and improve the therapy effect, herein we have proposed a dressing-undressing strategy for de-activating and re-activating therapy functions of photosensitizer nanoparticles. One kind of metal organic framework (PCN-224), which is composed of Zr(IV) cation and tetrakis (4-carboxyphenyl) porphyrin (TCPP), has been prepared as a model of photosensitizer, and it has size of ∼70 nm. These PCN-224 nanoparticles are subsequently coated with a mesoporous organic silica (MOS) shell containing tetrasulfide bonds (-S-S-S-S-), realizing the dressing of PCN-224. MOS shell has the thickness of ∼20 nm and thus can block 1O2 (diffusion distance: <10 nm), deactivating the phototoxicity and preventing the damage to skin and eyes. Furthermore, PCN-224@MOS can be used to load chemotherapy drug (DOX·HCl). When PCN-224@MOS-DOX are mixed with glutathione (GSH), MOS shell with -S-S-S-S- bonds can be reduced by GSH and then be decomposed, which results in the undressing and then confers the exposure of PCN-224 with good PDT function as well as the release of DOX. When PCN-224@MOS-DOX dispersion is injected into the mice and accumulated in the tumor, endogenous GSH also confers the undressing of PCN-224@MOS-DOX, realizing the in-situ activation of PDT and chemotherapy for tumor. Therefore, the present study not only demonstrates a general dressing-undressing strategy for manipulating phototoxicity of photosensitizers, but also provide some insights for precise therapy of tumors without side-effects. STATEMENT OF SIGNIFICANCE: Photosensitizers can generate reactive oxygen species (ROS) under light radiation to destroy cancer cells. However, this phototoxicity is a double-edged sword and also harmful to normal tissues such as the skin and eyes. To control phototoxicity and improve therapeutic efficacy, we prepared a PCN-224@MOS-DOX nanoplatform and proposed a dressing and undressing strategy to deactivate and reactivate the therapeutic function of the photosensitizer nanoparticles. The MOS shell can block the diffusion of 1O2, eliminate phototoxicity, and prevent damage to the skin and eyes. When injected into mice and accumulated in tumors, PCN-224@MOS-DOX dispersions are endowed with an endogenous GSH-driven undressing effect, achieving in situ activation of PDT and tumor chemotherapy.

The crosstalk between Toll and AMPK signaling pathways mediates growth inhibition of Eriocheir sinensis under deltamethrin stress.

Hepatopancreatic necrosis disease (HPND) broke out in 2015 in the Eriocheir sinensis aquaculture region of Xinghua, Jiangsu Province; however, the specific cause of HPND remains unclear. A correlation was found between HPND outbreak and the use of deltamethrin by farmers. In this study, E. sinensis specimens developed the clinical symptoms of HPND after 93 days of deltamethrin stress. The growth of E. sinensis with HPND was inhibited. Adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of energy homeostasis, and its expression was up-regulated in the intestine of E. sinensis with HPND. Growth inhibitory genes (EsCabut, Es4E-BP, and EsCG6770) were also up-regulated in the intestine of E. sinensis with HPND. The expression levels of EsCabut, Es4E-BP, and EsCG6770 decreased after EsAMPK knockdown. Therefore, AMPK mediated the growth inhibition of E. sinensis with HPND. Further analysis indicated the presence of a crosstalk between the Toll and AMPK signaling pathways in E. sinensis with HPND. Multiple genes in the Toll signaling pathway were upregulated in E. sinensis under 93 days of deltamethrin stress. EsAMPK and its regulated growth inhibition genes were down-regulated after the knockdown of genes in the Toll pathway. In summary, the crosstalk between the Toll and AMPK signaling pathways mediates the growth inhibition of E. sinensis under deltamethrin stress.

Exosomal secreted SCIMP regulates communication between macrophages and neutrophils in pneumonia.

In pneumonia, the deficient or delayed pathogen clearance can lead to pathogen proliferation and subsequent overactive immune responses, inducing acute lung injury (ALI). While screening human genome coding genes using our peripheral blood cell chemotactic platform, we unexpectedly find SLP adaptor and CSK interacting membrane protein (SCIMP), a protein with neutrophil chemotactic activity secreted during ALI. However, the specific role of SCIMP in ALI remains unclear. In this study, we investigate the secretion of SCIMP in exosomes (SCIMPexo) by macrophages after bacterial stimulation, both in vitro and in vivo. We observe a significant increase in the levels of SCIMPexo in bronchoalveolar lavage fluid and serum of pneumonia patients. We also find that bronchial perfusion with SCIMPexo or SCIMP N-terminal peptides increases the survival rate of the ALI model. This occurs due to the chemoattraction and activation of peripheral neutrophils dependent on formyl peptide receptor 1/2 (FPR1/2). Conversely, exosome suppressors and FPR1/2 antagonists decrease the survival rate in the lethal ALI model. Scimp-deficient and Fpr1/2-deficient mice also have lower survival rates and shorter survival times than wild-type mice. However, bronchial perfusion of SCIMP rescues Scimp-deficient mice but not Fpr1/2-deficient mice. Collectively, our findings suggest that the macrophage-SCIMP-FPRs-neutrophil axis plays a vital role in the innate immune process underlying ALI.

Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma.

The androgen receptor (AR) plays an important role in male-dominant hepatocellular carcinoma, and specific acquired somatic mutations of AR have been observed in HCC patients. Our previous research have established the role of AR wild type as one of the key oncogenes in hepatocarcinogenesis. However, the role of hepatic acquired somatic mutations of AR remains unknown. In this study, we identify two crucial acquired somatic mutations, Q62L and E81Q, situated close to the N-terminal activation function domain-1 of AR. These mutations lead to constitutive activation of AR, both independently and synergistically with androgens, making them potent driver oncogene mutations. Mechanistically, these N-terminal AR somatic mutations enhance de novo lipogenesis by activating sterol regulatory element-binding protein-1 and promote glycogen accumulation through glycogen phosphorylase, brain form, thereby disrupting the AMPK pathway and contributing to tumorigenesis. Moreover, the AR mutations show sensitivity to the AMPK activator A769662. Overall, this study establishes the role of these N- terminal hepatic mutations of AR as highly malignant oncogenic drivers in hepatocarcinogenesis and highlights their potential as therapeutic targets for patients harboring these somatic mutations.

Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death.

Both lytic and apoptotic cell death remove senescent and damaged cells in living organisms. However, they elicit contrasting pro- and anti-inflammatory responses, respectively. The precise cellular mechanism that governs the choice between these two modes of death remains incompletely understood. Here we identify Gasdermin E (GSDME) as a master switch for neutrophil lytic pyroptotic death. The tightly regulated GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival rate; instead, it specifically precludes pyroptosis and skews neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, by controlling the mode of neutrophil death, GSDME dictates host inflammatory outcomes, providing a potential therapeutic target for infectious and inflammatory diseases.

Predictive Value of Nutritional Risk for All-Cause Death and Functional Outcomes in Chinese Elderly Patients with Acute Stroke: A 3-Year Follow-Up Study.

Purpose: To explore the predictive value of nutritional risk for all-cause death and functional outcomes among elderly acute stroke patients. Patients and Methods: A total of 479 elderly acute stroke patients were enrolled in this study. The nutritional risk of patients was screened by the GNRI and NRS-2002. The primary outcome was all-cause death, and the secondary outcome was poor prognosis defined as a modified Rankin Scale (mRS) score ≥3. Results: Based on the NRS-2002, patients with nutritional risk had a higher risk of all-cause death at 3 months (adjusted OR: 3.642, 95% CI 1.046~12.689) and at 3 years (adjusted OR: 2.266, 95% CI 1.259~4.076) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.748, 95% CI 1.518~4.972. Based on the GNRI, compared to those without nutritional risk, patients with mild malnutrition also had a higher risk of all-cause death at 3 months (adjusted OR: 7.186, 95% CI 1.550~33.315) and at 3 years (adjusted OR: 2.255, 95% CI 1.211~4.199) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 1.947, 95% CI 1.030~3.680), so patients with moderate and severe malnutrition had a higher risk of all-cause death at 3 months (adjusted OR: 6.535, 95% CI 1.380~30.945) and at 3 years (adjusted OR: 2.498, 95% CI 1.301~4.799) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.213, 95% CI 1.144~4.279). Conclusion: Nutritional risk increases the risk of poor short-term and long-term outcomes in elderly patients with acute stroke. For elderly stroke patients, we should pay attention to early nutritional risk screening, and effective intervention should be provided to improve the prognosis of such patients.