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1.
Small ; : e2403804, 2024 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-38973112

RESUMEN

In the pursuit of efficient singlet oxygen generation in Fenton-like catalysis, the utilization of single-atom catalysts (SACs) emerges as a highly desired strategy. Here, a discovery is reported that the single-atom Fe coordinated with five N-atoms on N-doped porous carbon, denoted as Fe-N5/NC, outperform its counterparts, those coordinated with four (Fe-N4/NC) or six N-atoms (Fe-N6/NC), as well as state-of-the-art SACs comprising other transition metals. Thus, Fe-N5/NC exhibits exceptional efficacy in activating peroxymonosulfate for the degradation of organic pollutants. The coordination number of N-atoms can be readily adjusted by pyrolysis of pre-assembly structures consisting of Fe3+ and various isomers of phenylenediamine. Fe-N5/NC displayed outstanding tolerance to environmental disturbances and minimal iron leaching when incorporated into a membrane reactor. A mechanistic study reveals that the axial ligand N reduces the contribution of Fe-3d orbitals in LUMO and increases the LUMO energy of Fe-N5/NC. This, in turn, reduces the oxophilicity of the Fe center, promoting the reactivity of *OO intermediate-a pivotal step for yielding singlet oxygen and the rate-determining step. These findings unveil the significance of manipulating the oxophilicity of metal atoms in single-atom catalysis and highlight the potential to augment Fenton-like catalysis performance using Fe-SACs.

2.
J Clin Invest ; 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38916955

RESUMEN

Neutrophil infiltration occurs in a variety of liver diseases, but it is unclear how neutrophils and hepatocytes interact. Neutrophils generally use granule proteases to digest phagocytosed bacteria and foreign substances or neutralize them in neutrophil extracellular traps. In certain pathological states, granule proteases play a destructive role against the host as well. More recently, non-destructive actions of neutrophil granule proteins have been reported, such as modulation of tissue remodeling and metabolism. Here we report a completely different mechanism by which neutrophils act non-destructively, by inserting granules directly into hepatocytes. Specifically, elastase-containing granules were transferred to hepatocytes where elastase selectively degraded intracellular calcium channels to reduce cell proliferation without cytotoxicity. In response, hepatocytes increased expression of serpin E2 and A3, which inhibited elastase activity. Elastase insertion was seen in patient specimens of alcohol-associated hepatitis, and the relationship between elastase-mediated ITPR2 degradation and reduced cell proliferation was confirmed in mouse models. Moreover, neutrophils from patients with alcohol-associated hepatitis were more prone to degranulation and more potent in reducing calcium channel expression than neutrophils from healthy subjects. This non-destructive and reversible action on hepatocytes defines a previously unrecognized role for neutrophils in the transient regulation of epithelial calcium signaling mechanisms.

3.
Surg Endosc ; 38(7): 3948-3956, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38844730

RESUMEN

INTRODUCTION: Total pancreatectomy with islet autotransplantation (TPIAT) treats refractory pain in chronic pancreatitis, prevents episodes of acute exacerbation, and mitigates postoperative brittle diabetes. The minimally invasive (MIS) approach offers a decreased surgical access trauma and enhanced recovery. Having established a laparoscopic TPIAT program, we adopted a robotic approach (R-TPIAT) and studied patient outcomes compared to open TPIAT. METHODS: Between 2013 and 2021, 61 adult patients underwent TPIAT after a comprehensive evaluation (97% chronic pancreatitis). Pancreatic islets were isolated on-site during the procedure. We analyzed and compared intraoperative surgical and islet characteristics, postoperative morbidity and mortality, and 1-year glycemic outcomes. RESULTS: MIS-TPIAT was performed in 41 patients (67%, 15 robotic and 26 laparoscopic), and was associated with a shorter mean length of intensive care unit stay compared to open TPIAT (2.9 vs 4.5 days, p = 0.002). R-TPIAT replaced laparoscopic TPIAT in 2017 as the MIS approach of choice and demonstrated decreased blood loss compared to open TPIAT (324 vs 843 mL, p = 0.004), similar operative time (609 vs 562 min), 30-day readmission rate (7% vs 15%), and 90-day complication rate (13% vs 20%). The glycemic outcomes including C-peptide detection at 1-year (73% vs 88%) and insulin dependence at 1-year (75% vs 92%) did not differ. The mean length of hospital stay after R-TPIAT was 8.6 days, shorter than for laparoscopic (11.5 days, p = 0.031) and open TPIAT (12.6 days, p = 0.017). Both MIS approaches had a 1-year mortality rate of 0%. CONCLUSIONS: R-TPIAT was associated with a 33% reduction in length of hospital stay (4-day benefit) compared to open TPIAT. R-TPIAT was similar to open TPIAT on measures of feasibility, safety, pain control, and 1-year glycemic outcomes. Our data suggest that robotic technology, a new component in the multidisciplinary therapy of TPIAT, is poised to develop into the primary surgical approach for experienced pancreatic surgeons.


Asunto(s)
Trasplante de Islotes Pancreáticos , Pancreatectomía , Pancreatitis Crónica , Procedimientos Quirúrgicos Robotizados , Trasplante Autólogo , Humanos , Pancreatitis Crónica/cirugía , Procedimientos Quirúrgicos Robotizados/métodos , Trasplante de Islotes Pancreáticos/métodos , Masculino , Femenino , Pancreatectomía/métodos , Persona de Mediana Edad , Adulto , Laparoscopía/métodos , Tiempo de Internación/estadística & datos numéricos , Estudios Retrospectivos , Tempo Operativo , Resultado del Tratamiento , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología
4.
Front Immunol ; 15: 1351717, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38476227

RESUMEN

Combined islet and kidney xenotransplantation for the treatment of diabetic nephropathy represents a compelling and increasingly relevant therapeutic possibility for an ever-growing number of patients who would benefit from both durable renal replacement and cure of the underlying cause of their renal insufficiency: diabetes. Here we briefly review immune barriers to islet transplantation, highlight preclinical progress in the field, and summarize our experience with combined islet and kidney xenotransplantation, including both challenges with islet-kidney composite grafts as well as our recent success with sequential kidney followed by islet xenotransplantation in a pig-to-baboon model.


Asunto(s)
Diabetes Mellitus Tipo 1 , Nefropatías Diabéticas , Trasplante de Islotes Pancreáticos , Humanos , Porcinos , Animales , Trasplante Heterólogo , Riñón
6.
Metabolism ; 151: 155740, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37995805

RESUMEN

BACKGROUND & AIMS: Dysbiosis contributes to alcohol-associated liver disease (ALD); however, the precise mechanisms remain elusive. Given the critical role of the gut microbiota in ammonia production, we herein aim to investigate whether and how gut-derived ammonia contributes to ALD. METHODS: Blood samples were collected from human subjects with/without alcohol drinking. Mice were exposed to the Lieber-DeCarli isocaloric control or ethanol-containing diets with and without rifaximin (a nonabsorbable antibiotic clinically used for lowering gut ammonia production) supplementation for five weeks. Both in vitro (NH4Cl exposure of AML12 hepatocytes) and in vivo (urease administration for 5 days in mice) hyperammonemia models were employed. RNA sequencing and fecal amplicon sequencing were performed. Ammonia and triglyceride concentrations were measured. The gene and protein expression of enzymes involved in multiple pathways were measured. RESULTS: Chronic alcohol consumption causes hyperammonemia in both mice and human subjects. In healthy livers and hepatocytes, ammonia exposure upregulates the expression of urea cycle genes, elevates hepatic de novo lipogenesis (DNL), and increases fat accumulation. Intriguingly, ammonia promotes ethanol catabolism and acetyl-CoA formation, which, together with ammonia, synergistically facilitates intracellular fat accumulation in hepatocytes. Mechanistic investigations uncovered that ATF4 activation, as a result of ER stress induction and general control nonderepressible 2 activation, plays a central role in ammonia-provoked DNL elevation. Rifaximin ameliorates ALD pathologies in mice, concomitant with blunted hepatic ER stress induction, ATF4 activation, and DNL activation. CONCLUSIONS: An overproduction of ammonia by gut microbiota, synergistically interacting with ethanol, is a significant contributor to ALD pathologies.


Asunto(s)
Amoníaco , Hígado Graso , Hiperamonemia , Hepatopatías Alcohólicas , Animales , Humanos , Ratones , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Amoníaco/efectos adversos , Amoníaco/metabolismo , Etanol/efectos adversos , Etanol/metabolismo , Hígado Graso/inducido químicamente , Hígado Graso/metabolismo , Hiperamonemia/complicaciones , Hiperamonemia/metabolismo , Hiperamonemia/patología , Lipogénesis , Hígado/metabolismo , Hepatopatías Alcohólicas/metabolismo , Ratones Endogámicos C57BL , Rifaximina/farmacología
7.
J Burn Care Res ; 45(1): 234-241, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37801462

RESUMEN

Skin substitutes including allografts remain a standard therapeutic approach to promote healing of both acute and chronic large wounds. However, none have resulted in the regrowth of lost and damaged tissues and scarless wound healing. Here, we demonstrate skin allograft chimerism and repair through the mobilization of endogenous bone marrow-derived stem and immune cells in rats and swine. We show that pharmacological mobilization of bone marrow stem cells and immune cells into the circulation promotes host repopulation of skin allografts and restoration of the skin's normal architecture without scarring and minimal contracture. When skin allografts from DA rats are transplanted into GFP transgenic Lewis recipients with a combination of AMD3100 and low-dose FK506 (AF) therapy, host-derived GFP-positive cells repopulate and/or regenerate cellular components of skin grafts including epidermis and hair follicles and the grafts become donor-host chimeric skin. Using AF combination therapy, burn wounds with skin allografts were healed by newly regenerated chimeric skin with epidermal appendages and pigmentation and without contracture in swine.


Asunto(s)
Quemaduras , Contractura , Ratas , Animales , Porcinos , Trasplante de Médula Ósea , Médula Ósea , Quimerismo , Ratas Endogámicas Lew , Quemaduras/cirugía , Trasplante de Piel , Aloinjertos , Células Madre , Supervivencia de Injerto
8.
Adv Mater ; 36(9): e2307006, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37924225

RESUMEN

The ferroptosis pathway is recognized as an essential strategy for tumor treatment. However, killing tumor cells in deep tumor regions with ferroptosis agents is still challenging because of distinct size requirements for intratumoral accumulation and deep tumor penetration. Herein, intelligent nanocapsules with size-switchable capability that responds to acid/hyperthermia stimulation to achieve deep tumor ferroptosis are developed. These nanocapsules are constructed using poly(lactic-co-glycolic) acid and Pluronic F127 as carrier materials, with Au-Fe2 C Janus nanoparticles serving as photothermal and ferroptosis agents, and sorafenib (SRF) as the ferroptosis enhancer. The PFP@Au-Fe2 C-SRF nanocapsules, designed with an appropriate size, exhibit superior intratumoral accumulation compared to free Au-Fe2 C nanoparticles, as evidenced by photoacoustic and magnetic resonance imaging. These nanocapsules can degrade within the acidic tumor microenvironment when subjected to laser irradiation, releasing free Au-Fe2 C nanoparticles. This enables them to penetrate deep into tumor regions and disrupt intracellular redox balance. Under the guidance of imaging, these PFP@Au-Fe2 C-SRF nanocapsules effectively inhibit tumor growth when exposed to laser irradiation, capitalizing on the synergistic photothermal and ferroptosis effects. This study presents an intelligent formulation based on iron carbide for achieving deep tumor ferroptosis through size-switchable cascade delivery, thereby advancing the comprehension of ferroptosis in the context of tumor theranostics.


Asunto(s)
Compuestos Inorgánicos de Carbono , Ferroptosis , Hipertermia Inducida , Compuestos de Hierro , Nanocápsulas , Nanopartículas , Neoplasias , Humanos , Línea Celular Tumoral , Neoplasias/terapia , Sorafenib , Hipertermia/terapia , Hipertermia Inducida/métodos , Microambiente Tumoral
9.
J Hazard Mater ; 465: 133124, 2024 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-38142658

RESUMEN

In actual lakes, the "unstable components" of macrophyte-derived DOM (MDOM) are always degraded and cannot exist abidingly, but the environmental impact brought by it is ignored. In this study, MDOM from Potamogeton crispus was extracted to carry out microbial combined photodegradation (M-Photodegradation) and fluorescence titration experiments. Then the traits and metal binding reaction of MDOM under M-Photodegradation were analysed and compared with the features of lake-derived DOM (LDOM) from point monitoring of Dongping Lake through EEM-PARAFAC, 2D-SF-COS, and 2D-FTIR-COS. The results showed that the features of MDOM after M-Photodegradation were closer to those of LDOM. The degradation amplitudes were 93.53% ± 0.53% for C4 in microbial degradation and 78.31% ± 0.74% for C3 in photodegradation. Correspondingly, both were hardly detected in LDOM. Protein-like substances and aliphatic C-OH were preferentially selected by Cu2+, while humic-like matter and phenolic hydroxyl O-H responded faster to Pb2+. Although the binding sequences remained unchanged after M-Photodegradation, the LogKCu and LogKPb of components decreased overall, indicating increased environmental risks. This study proves that the refractory MDOM retained after degradation was more consistent with the actual state of macrophytic lakes and provides more information for the treatment of heavy metal pollution in lakes.


Asunto(s)
Lagos , Plomo , Espectrometría de Fluorescencia/métodos , Lagos/química , Plomo/análisis , Fotólisis , Sustancias Húmicas/análisis , Análisis Factorial
10.
Elife ; 122023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-38055614

RESUMEN

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.


Asunto(s)
Hepatitis Alcohólica , Humanos , Escherichia coli , Inmunoglobulina A , Autoanticuerpos , Inmunoglobulina G , Inmunoglobulina M
11.
Environ Sci Technol ; 57(49): 20822-20829, 2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-38014909

RESUMEN

Silver (Ag) undergoes a complex and dynamic Ag+/Ag0 cycle under environmental conditions. The Ag+ → Ag nanoparticles (AgNPs) transformation due to the combined actions of sunlight, O2, and dissolved organic matter has been a well-known environmental phenomenon. In this study, we indicate that this process may be accompanied by a pronounced accumulation of Ag(0) single atoms (Ag-SAs) on the minerals' surfaces. According to spherical aberration-corrected scanning transmission electron microscopy and high-energy-resolution X-ray adsorption fine structure analyses, humic acid (HA) and phenol (PhOH) can induce Ag-SAs accumulation, whereas oxalic acid causes only AgNPs deposition. Ag-SAs account for more than 20 wt % of total Ag(0) on the γ-Al2O3 surfaces during HA- and PhOH-mediated photolysis processes. HA also causes Ag-SAs to accumulate on two other prevalent soil minerals, SiO2 and Fe2O3, and the fractions of Ag-SAs are about 15 wt %. Our mechanism studies suggest that a phenolic molecule acts as a reducing agent of Ag+ and a stabilizer of Ag-SAs, protecting Ag-SAs against autocatalytic nucleation.


Asunto(s)
Nanopartículas del Metal , Agua , Nanopartículas del Metal/química , Dióxido de Silicio , Plata , Sustancias Húmicas/análisis , Minerales , Luz Solar , Iones/química
12.
Cell Rep Med ; 4(9): 101169, 2023 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-37633275

RESUMEN

Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).


Asunto(s)
Leucocitos Mononucleares , Células Madre , Humanos , Voluntarios Sanos , Trasplante Homólogo
13.
Cell Mol Gastroenterol Hepatol ; 16(5): 685-709, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37460041

RESUMEN

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) represents a spectrum of alcohol use-related liver diseases. Outside of alcohol abstinence, there are currently no Food and Drug Administration-approved treatments for advanced ALD, necessitating a greater understanding of ALD pathogenesis and potential molecular targets for therapeutic intervention. The ABL-family proteins, including ABL1 and ABL2, are non-receptor tyrosine kinases that participate in a diverse set of cellular functions. We investigated the role of the ABL kinases in alcohol-associated liver disease. METHODS: We used samples from patients with ALD compared with healthy controls to elucidate a clinical phenotype. We established strains of liver-specific Abl1 and Abl2 knockout mice and subjected them to the National Institute on Alcohol Abuse and Alcoholism acute-on-chronic alcohol feeding regimen. Murine samples were subjected to RNA sequencing, AST, Oil Red O staining, H&E staining, Western blotting, and quantitative polymerase chain reaction to assess phenotypic changes after alcohol feeding. In vitro modeling in HepG2 cells as well as primary hepatocytes from C57BL6/J mice was used to establish this mechanistic link of ALD pathogenesis. RESULTS: We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well as in liver tissues from mice subjected to an alcohol feeding regimen. We found that the liver-specific knockout of Abl2, but not Abl1, attenuated alcohol-induced steatosis, liver injury, and inflammation. Subsequent RNA sequencing and gene set enrichment analyses of mouse liver tissues revealed that relative to wild-type alcohol-fed mice, Abl2 knockout alcohol-fed mice exhibited numerous pathway changes, including significantly decreased peroxisome proliferator activated receptor (PPAR) signaling. Further examination revealed that PPARγ, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in Abl2 knockout mice. In vitro analyses revealed that shRNA-mediated knockdown of ABL2 abolished the alcohol-induced accumulation of PPARγ as well as subsequent lipid accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARγ protein expression. Furthermore, we demonstrated that the regulation of hypoxia inducible factor 1 subunit alpha (HIF1α) by ABL2 is required for alcohol-induced PPARγ expression. Furthermore, treatment with ABL kinase inhibitors attenuated alcohol-induced PPARγ expression, lipid droplet formation, and liver injury. CONCLUSIONS: On the basis of our current evidence, we propose that alcohol-induced ABL2 activation promotes ALD through increasing HIF1α and the subsequent PPARγ expression, and ABL2 inhibition may serve as a promising target for the treatment of ALD.


Asunto(s)
Hepatopatías Alcohólicas , PPAR gamma , Humanos , Animales , Ratones , Hepatopatías Alcohólicas/patología , Etanol/toxicidad , Ratones Noqueados , Tirosina
14.
J Am Chem Soc ; 145(20): 11019-11032, 2023 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-37190936

RESUMEN

Biomedical micro/nanorobots as active delivery systems with the features of self-propulsion and controllable navigation have made tremendous progress in disease therapy and diagnosis, detection, and biodetoxification. However, existing micro/nanorobots are still suffering from complex drug loading, physiological drug stability, and uncontrollable drug release. To solve these problems, micro/nanorobots and nanocatalytic medicine as two independent research fields were integrated in this study to achieve self-propulsion-induced deeper tumor penetration and catalytic reaction-initiated tumor therapy in vivo. We presented self-propelled Janus nanocatalytic robots (JNCRs) guided by magnetic resonance imaging (MRI) for in vivo enhanced tumor therapy. These JNCRs exhibited active movement in H2O2 solution, and their migration in the tumor tissue could be tracked by non-invasive MRI in real time. Both increased temperature and reactive oxygen species production were induced by near-infrared light irradiation and iron-mediated Fenton reaction, showing great potential for tumor photothermal and chemodynamic therapy. In comparison with passive nanoparticles, these self-propelled JNCRs enabled deeper tumor penetration and enhanced tumor therapy after intratumoral injection. Importantly, these robots with biocompatible components and byproducts exhibited biosecurity in the mouse model. It is expected that our work could promote the combination of micro/nanorobots and nanocatalytic medicine, resulting in improved tumor therapy and potential clinical transformations.


Asunto(s)
Hipertermia Inducida , Nanopartículas , Neoplasias , Robótica , Animales , Ratones , Peróxido de Hidrógeno , Hipertermia Inducida/métodos , Línea Celular Tumoral , Neoplasias/terapia , Nanopartículas/uso terapéutico , Imagen por Resonancia Magnética/métodos
15.
Environ Sci Technol ; 57(15): 6150-6158, 2023 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-37010425

RESUMEN

Silver is among the most essential antimicrobial agents. Increasing the efficacy of silver-based antimicrobial materials will reduce operating costs. Herein, we show that mechanical abrading causes atomization of Ag nanoparticles (AgNPs) into atomically dispersed Ag (AgSAs) on the surfaces of an oxide-mineral support, which eventually boosts the antibacterial efficacy considerably. This approach is straightforward, scalable, and applicable to a wide range of oxide-mineral supports; additionally, it does not require any chemical additives and operates under ambient conditions. The obtained AgSAs-loaded γ-Al2O3 inactivated Escherichia coli (E. coli) five times as fast as the original AgNPs-loaded γ-Al2O3. It can be utilized over 10 runs with minimal efficiency loss. The structural characterizations indicate that AgSAs exhibit a nominal charge of 0 and are anchored at the doubly bridging OH on the γ-Al2O3 surfaces. Mechanism studies demonstrate that AgSAs, like AgNPs, damage bacterial cell wall integrity, but they release Ag+ and superoxide substantially faster. This work not only provides a simple method for manufacturing AgSAs-based materials but also shows that AgSAs have better antibacterial properties than the AgNPs counterpart.


Asunto(s)
Antiinfecciosos , Nanopartículas del Metal , Nanopartículas del Metal/química , Plata , Escherichia coli , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antibacterianos/farmacología , Antibacterianos/química , Óxidos
16.
bioRxiv ; 2023 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-36865259

RESUMEN

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We sought to determine if there was antibody deposition in SAH livers and whether antibodies extracted from SAH livers were cross-reactive against both bacterial antigens and human proteins. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissue from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. Employing human proteome arrays, we profiled the antibodies extracted from explanted SAH, alcoholic cirrhosis (AC), nonalcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), hepatitis B virus (HBV), hepatitis C virus (HCV) and HD livers and found that antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins as autoantigens. The use of an E. coli K12 proteome array revealed the presence of unique anti- E. coli antibodies in SAH, AC or PBC livers. Further, both Ig and E. coli captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion and focal adhesion (IgG). Except IgM from PBC livers, no common autoantigen was recognized by Ig and E. coli captured Ig from AC, HBV, HCV, NASH or AIH suggesting no cross-reacting anti- E. coli autoantibodies. The presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in the liver may participate in the pathogenesis of SAH.

17.
Hepatology ; 78(2): 503-517, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36999531

RESUMEN

BACKGROUND AND AIMS: The aim of the study was to investigate the role and mechanisms of tuberous sclerosis complex 1 (TSC1) and mechanistic target of rapamycin complex 1 (mTORC1) in alcohol-associated liver disease. APPROACH AND RESULTS: Liver-specific Tsc1 knockout (L- Tsc1 KO) mice and their matched wild-type mice were subjected to Gao-binge alcohol. Human alcoholic hepatitis (AH) samples were also used for immunohistochemistry staining, western blot, and quantitative real-time PCR (q-PCR) analysis. Human AH and Gao-binge alcohol-fed mice had decreased hepatic TSC1 and increased mTORC1 activation. Gao-binge alcohol markedly increased liver/body weight ratio and serum alanine aminotransferase levels in L- Tsc1 KO mice compared with Gao-binge alcohol-fed wild-type mice. Results from immunohistochemistry staining, western blot, and q-PCR analysis revealed that human AH and Gao-binge alcohol-fed L- Tsc1 KO mouse livers had significantly increased hepatic progenitor cells, macrophages, and neutrophils but decreased HNF4α-positive cells. Gao-binge alcohol-fed L- Tsc1 KO mice also developed severe inflammation and liver fibrosis. Deleting Tsc1 in cholangiocytes but not in hepatocytes promoted cholangiocyte proliferation and aggravated alcohol-induced ductular reactions, fibrosis, inflammation, and liver injury. Pharmacological inhibition of mTORC1 partially reversed hepatomegaly, ductular reaction, fibrosis, inflammatory cell infiltration, and liver injury in alcohol-fed L- Tsc1 KO mice. CONCLUSIONS: Our findings indicate that persistent activation of mTORC1 due to the loss of cholangiocyte TSC1 promotes liver cell repopulation, ductular reaction, inflammation, fibrosis, and liver injury in Gao-binge alcohol-fed L- Tsc1 KO mice, which phenocopy the pathogenesis of human AH.


Asunto(s)
Hepatitis Alcohólica , Hepatopatías Alcohólicas , Diana Mecanicista del Complejo 1 de la Rapamicina , Proteína 1 del Complejo de la Esclerosis Tuberosa , Animales , Humanos , Ratones , Etanol , Fibrosis , Hepatitis Alcohólica/patología , Inflamación/patología , Hígado/patología , Hepatopatías Alcohólicas/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Noqueados , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismo
18.
Cell Mol Gastroenterol Hepatol ; 15(5): 1027-1049, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36754207

RESUMEN

BACKGROUND: Alcohol-associated liver disease (ALD) is a worldwide health problem, of which the effective treatment is still lacking. Both detrimental and protective roles of adipose tissue have been implicated in ALD. Although alcohol increases adipose tissue lipolysis to promote alcohol-induced liver injury, alcohol also activates brown adipose tissue (BAT) thermogenesis as an adaptive response in protecting against alcohol-induced liver injury. Moreover, aging and obesity are also risk factors for ALD. In the present study, we investigated the effects of autophagy receptor protein SQSTM1/p62 on adipose tissue and obesity in alcohol-induced liver injury in both young and aged mice. METHODS: Young and aged whole-body SQSTM1/p62 knockout (KO) and their age-matched wild-type (WT) mice were subjected to chronic plus binge (Gao-binge) alcohol feeding. Blood, adipose and liver tissues were collected for biochemical and histologic analysis. RESULTS: Aged but not young SQSTM1/p62 KO mice had significantly increased body weight and fat mass compared with the matched WT mice. Gao-binge alcohol feeding induced white adipose atrophy and decreased levels of SQSTM1/p62 levels in adipose tissue in aged WT mice. SQSTM1/p62 KO aged mice were resistant to Gao-binge alcohol-induced white adipose atrophy. Alcohol feeding increased the expression of thermogenic genes in WT mouse BAT, which was significantly blunted in SQSTM1/p62 KO aged mice. Alcohol-fed aged SQSTM1/p62 KO mice showed significantly higher levels of serum alanine aminotransferase, hepatic triglyceride, and inflammation compared with young and aged WT mice fed with alcohol. Alcohol-fed SQSTM1/p62 KO mice also increased secretion of proinflammatory and angiogenic adipokines that may promote alcohol-induced liver injury. CONCLUSIONS: Loss of SQSTM1/p62 in aged mice leads to obesity and impairs alcohol-induced BAT adaptation, resulting in exacerbated alcohol-induced liver injury in mice.


Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Hepatopatías Alcohólicas , Animales , Ratones , Proteína Sequestosoma-1 , Etanol/toxicidad , Hepatopatías Alcohólicas/patología , Ratones Noqueados , Obesidad/complicaciones , Atrofia
19.
Water Res ; 231: 119605, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36680825

RESUMEN

The nature of sediment dissolved organic matter (SDOM) can reflect the environmental background, nutritional status and human activities and is an important part of lakes. The differences in the binding capacity of heavy metals and organic matter in lake sediments with different trophic states at the catchment scale and the mechanism of the differences in binding are still unclear. To solve this problem, we collected bulk SDOMs (< 0.7 µm) from 6 respective lakes (from upstream to downstream) in the Yangtze River Basin (YRB) to qualitatively and quantitatively characterize their properties and metal binding behaviors using excitation-emission matrix spectroscopy combined with parallel factor analysis (EEM-FARAFAC) and two-dimensional correlation spectroscopy of synchronous fluorescence spectroscopy and Fourier transform infrared spectroscopy (2D-SF-COS and 2D-FTIR-COS). The results showed that sediment dissolved organic carbon (SDOC) was mainly enriched in low molecular weight (LMW: < 1 kDa) fractions. The total fluorescence intensity (Fmax) of SDOM from upstream was larger than that from downstream (p = 0.033), and humic-like fluorophores were dominant in these lakes. The Fmax of sediment humic-like components (C1+C2) was closely related to the trophic levels of the lakes. Protein-like substances and oxygen-containing functional groups (C-OH, C=O, and C-O) were preferred in the reaction between SDOM and copper (Cu2+) or cadmium (Cd2+), while a unique binding path was exhibited in the moderately eutrophic DCL. In terms of fluorophore types, higher Cu2+-binding abilities (LogKCu) were observed in the humic-like matter for the lakes in the upper reaches and tryptophan-like matter for the lakes from the midstream and downstream areas of the YRB. Although Cd2+ complexed only with humic-like matter, LogKCd was higher than LogKCu. In terms of molecular weight (MW), the LogKCu/Cd of components were enhanced after MW fractionation. The HMW (0.7 µm - 1 kDa) components possessed higher LogKCu in most lakes (except for CHL and C4). The different fluorophores and molecular weight fractions in SDOM make an important contribution to reducing the ecological risks of heavy metals in lakes.


Asunto(s)
Materia Orgánica Disuelta , Metales Pesados , Cadmio/análisis , Sustancias Húmicas/análisis , Lagos/química , Metales Pesados/análisis , Estado Nutricional , Espectrometría de Fluorescencia
20.
Hepatology ; 77(1): 159-175, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-35698731

RESUMEN

BACKGROUND AND AIMS: Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study aims to determine the mechanisms by which alcohol consumption increases megamitochondria formation in the pathogenesis of ALD. APPROACH AND RESULTS: Human alcoholic hepatitis (AH) liver samples were used for electron microscopy, histology, and biochemical analysis. Liver-specific dynamin-related protein 1 (DRP1; gene name DNM1L, an essential gene regulating mitochondria fission ) knockout (L-DRP1 KO) mice and wild-type mice were subjected to chronic plus binge alcohol feeding. Both human AH and alcohol-fed mice had decreased hepatic DRP1 with increased accumulation of hepatic megamitochondria. Mechanistic studies revealed that alcohol feeding decreased DRP1 by impairing transcription factor EB-mediated induction of DNM1L . L-DRP1 KO mice had increased megamitochondria and decreased mitophagy with increased liver injury and inflammation, which were further exacerbated by alcohol feeding. Seahorse flux and unbiased metabolomics analysis showed alcohol intake increased mitochondria oxygen consumption and hepatic nicotinamide adenine dinucleotide (NAD + ), acylcarnitine, and ketone levels, which were attenuated in L-DRP1 KO mice, suggesting that loss of hepatic DRP1 leads to maladaptation to alcohol-induced metabolic stress. RNA-sequencing and real-time quantitative PCR analysis revealed increased gene expression of the cGAS-stimulator of interferon genes (STING)-interferon pathway in L-DRP1 KO mice regardless of alcohol feeding. Alcohol-fed L-DRP1 KO mice had increased cytosolic mtDNA and mitochondrial dysfunction leading to increased activation of cGAS-STING-interferon signaling pathways and liver injury. CONCLUSION: Alcohol consumption decreases hepatic DRP1 resulting in increased megamitochondria and mitochondrial maladaptation that promotes AH by mitochondria-mediated inflammation and cell injury.


Asunto(s)
Hepatitis Alcohólica , Hepatopatías Alcohólicas , Ratones , Humanos , Animales , Dilatación Mitocondrial , Hepatopatías Alcohólicas/metabolismo , Mitocondrias/metabolismo , Etanol/toxicidad , Nucleotidiltransferasas , Inflamación , Interferones , Dinámicas Mitocondriales
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