Cellular Trojan Horse initiates bimetallic Fe-Cu MOF-mediated synergistic cuproptosis and ferroptosis against malignancies.

Disruptions in metal balance can trigger a synergistic interplay of cuproptosis and ferroptosis, offering promising solutions to enduring challenges in oncology. Here, we have engineered a Cellular Trojan Horse, named MetaCell, which uses live neutrophils to stably internalize thermosensitive liposomal bimetallic Fe-Cu MOFs (Lip@Fe-Cu-MOFs). MetaCell can instigate cuproptosis and ferroptosis, thereby enhancing treatment efficacy. Mirroring the characteristics of neutrophils, MetaCell can evade the immune system and not only infiltrate tumors but also respond to inflammation by releasing therapeutic components, thereby surmounting traditional treatment barriers. Notably, Lip@Fe-Cu-MOFs demonstrate notable photothermal effects, inciting a targeted release of Fe-Cu-MOFs within cancer cells and amplifying the synergistic action of cuproptosis and ferroptosis. MetaCell has demonstrated promising treatment outcomes in tumor-bearing mice, effectively eliminating solid tumors and forestalling recurrence, leading to extended survival. This research provides great insights into the complex interplay between copper and iron homeostasis in malignancies, potentially paving the way for innovative approaches in cancer treatment.

Smart Metabolism Nanovalve Reprograms Cancer Energy Homeostasis for Maximizing Photometabolism Therapy.

Better understanding of important roles of metabolic reprogramming in therapeutic resistance provides insights into advancing cancer treatment. Herein, we present a photoactive metabolic reprogramming strategy (termed as photometabolism therapy, PMT), in which photoregulation of mitochondria leads to cancer cell metabolic crisis, and consequently overcomes therapeutic resistance while improving treatment efficacy. In specific, a stimuli-responsive metabolism NanoValve is developed for improving cascade cancer therapy through blocking mitochondrial energy supply. NanoValve is composed of an onion-like architecture with a gold nanorod core, a mesoporous silica shell encapsulating photosensitizer chlorin e6 and oxygen-saturated perfluorocarbon, and cationic liposomal coating with MMP2-cleavable polyethylene glycol corona, which together initiate mitochondria-specific PMT. NanoValve selectively responds to tumor-overexpressed MMP2 and achieves size decrease and charge reversal, which consequently enhances tumor penetration, cancer cell uptake, endosome escape, and most critically, mitochondrial accumulation. Importantly, NanoValve-mediated phototherapy can strongly destruct mitochondrial energy metabolism, thereby minimizing therapy resistance. Particularly, perfluorocarbon supplies oxygen to further overcome the tumor hypoxia-associated therapeutic barrier and maximizes synergistic anticancer effects. In vivo studies show that NanoValve can effectively eliminate tumors without side effects, thereby dramatically prolonging the survival of tumor-bearing mice. Thus, NanoValve provides a modular PMT approach and has the potential of advancing the treatment of malignancy.

Orthogonal Chemical Reporter Strategy Enables Sensitive and Specific SERS Detection of Hydrazine Derivatives.

Hydrazine and its derivatives are well-known environmental hazards and biological carcinogens; therefore, there is a great need for a powerful workflow solution for protecting the public from unexpected exposure to toxic contaminants. Recently, functional surface-enhanced Raman scattering (SERS) exhibits enormous benefits in sensing trace biochemical substances due to its fingerprint-like identification of individual molecules, making it an ideal method for detecting and quantifying hydrazine. Herein, for the first time, we integrated the orthogonal chemical reporter strategy with SERS to build an intelligent hydrazine detection platform (orthogonal chemical SERS, ocSERS), in which 4-mercaptobenzaldehyde was incorporated on a nanoimprinted gold nanopillar array, which acted as an orthogonal coupling partner of hydrazine to form Raman active benzaldehyde hydrazone, allowing for sensitively detecting hydrazine with a detection limit of 10-13 M in complex circumstances. Particularly, ocSERS could effectively identify the carcinogen N-nitrosodimethylamine (NDMA) after its reduction to dimethylhydrazine (UDMH), enabling ultrasensitive detection of UDMH (10-13 M). Importantly, ocSERS could not only monitor elevated levels of NDMA in ranitidine due to improper storage but also quantify NDMA in urine and blood after oral administration of NDMA-containing drugs, thereby preventing NDMA overexposure. Therefore, ocSERS represents the first click SERS sensor and may open up a new analytical field.

Peripheral Administration of NMU Promotes White Adipose Tissue Beiging and Improves Glucose Tolerance.

PURPOSE: Targeting white adipose tissue (WAT) beiging has been proposed as an effective way to increase thermogenesis and improve glucose metabolism. Neuromedin U (NMU) is a neuropeptide that could increase energy expenditure, while its effects on WAT beiging and glucose homeostasis remain to be investigated. METHODS: Male C57BL/6 mice were fed with high fat diet (HFD) to induce obesity and hyperglycemia and then treated with chronic subcutaneous injection of NMU. Body weight and food intake were recorded daily. After 14 days of injection, intraperitoneal glucose tolerance tests and 18F-fluorodeoxyglucose micro-positron emission tomography/computed tomography (18F-FDG micro-PET/CT) scans were conducted. Subcutaneous WAT (sWAT) and interscapular brown adipose tissue were collected for the evaluation of adipocyte size, expression of uncoupling protein 1 (Ucp1), and other thermogenic-related genes. Stromal vascular fraction of subcutaneous WAT was extracted for the measurement of type 2 innate lymphocytes (ILC2s) proportions. RESULTS: Glucose tolerance was markedly improved by peripherally administered NMU. Micro-PET/CT suggested that NMU promoted WAT beiging, which was further confirmed by haematoxylin and eosin (H&E) staining and immunohistochemistry. In diet-induced-obese (DIO) mice, NMU activated thermogenic-related genes in WAT. In addition, NMU stimulated ILC2s in the stromal vascular fraction of WAT. CONCLUSION: Taken together, our study indicates that peripheral administration of NMU is a potential therapeutic strategy for the promotion of WAT beiging and the improvement of impaired glucose tolerance.

Body Adiposity Index Is Predictive of Weight Loss after Roux-en-Y Gastric Bypass.

BACKGROUND/AIMS: Roux-en-Y gastric bypass (RYGB) is one of the most effective therapies for morbid obesity, yet some patients who have taken the surgery still undergo insufficient weight loss. Visceral adiposity index (VAI), lipid accumulation product (LAP), body adiposity index (BAI), and cardiometabolic index (CMI) have been regarded as clinical indicators of adiposity phenotypes that associated closely with obesity-related metabolic diseases. However, no studies have evaluated the relationship between these indexes and weight loss after bariatric surgery. In this prospective study, we aimed to evaluate whether VAI, LAP, BAI, and CMI would predict postoperative weight loss outcomes after RYGB. METHODS: This study included 38 men and 67 women who have undergone RYGB between January 2017 and May 2018 and recorded their %TWL (percent of total weight loss), %EBMIL (percent of excess body mass index loss), %EWL (percent of excess weight loss), anthropometric indices, and biochemical parameters before and 12 months after the surgery. In addition, VAI, LAP, BAI, and CMI were measured with anthropometric measures or lipid profiles using related equations and analyzed with metabolic characteristics. RESULTS: Subjects with lower BAI (<32.54 in men and 37.39 in women) displayed higher %EBMIL and %EWL 12 months after surgery. BAI was independently associated with %EWL 12 months after surgery in both men and women (both p < 0.05). The area under the receiver operating characteristic curve for BAI was significantly higher (0.773 in men and 0.818 in women) than VAI, LAP, and CMI. CONCLUSIONS: BAI serves as a reliable surrogate marker of the weight loss outcome after RYGB. The predictivity of adiposity indexes in beneficial outcomes after weight loss therapies is of important referential value for the implementation and optimization of individualized and refined weight loss treatments for obese patients.

Association of Omental Adipocyte Hypertrophy and Fibrosis with Human Obesity and Type 2 Diabetes.

OBJECTIVE: Morphological alterations including adipocyte hypertrophy and fibrosis deposition are important surrogate markers of visceral adipose tissue function, but the relationships between these morphological changes and type 2 diabetes mellitus (T2DM) and impaired insulin sensitivity are poorly defined. METHODS: Omental adipose tissue was obtained from 66 individuals with obesity but without T2DM (OB group), 93 individuals with both obesity and T2DM (T2DM group), and 15 individuals with normal BMI and normal glucose tolerance (NGT group). Adipocyte diameter and volume were measured through pathological section analysis. Pericellular and perilobular fibrosis was determined through picrosirius red staining and immunochemistry, while fibrosis-related genes were tested through gene expression and hydroxyproline content. RESULTS: Compared with the NGT and OB groups, individuals from the T2DM group displayed increased adipocyte diameter and volume levels. Increased adipocyte size (diameter and volume) was positively associated with hyperglycemia and insulin resistance and inversely correlated with insulin sensitivity (using the Matsuda whole-body insulin sensitivity index assessment of insulin sensitivity) and ß-cell function (disposition index 30 and disposition index 120). The fibrosis levels of the OB group were the highest out of the three groups, whereas the fibrosis levels of T2DM individuals were lower than the OB group but higher than the NGT group. Although fibrosis was negatively correlated with T2DM, fibrosis deposition was not remarkably associated with impaired systemic insulin sensitivity and glucose metabolism. CONCLUSIONS: Compared with fibrosis deposition, adipocyte hypertrophy is more closely associated with T2DM and impaired systemic insulin sensitivity.

Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction.

Emerging evidence highlights that dysfunction of adipose tissue contributes to impaired insulin sensitivity and systemic metabolic deterioration in obese state. Of note, adipocyte hypertrophy serves as a critical event which associates closely with adipose dysfunction. An increase in cell size exacerbates hypoxia and inflammation as well as excessive collagen deposition, finally leading to metabolic dysregulation. Specific mechanisms of adipocyte hypertrophy include dysregulated differentiation and maturation of preadipocytes, enlargement of lipid droplets, and abnormal adipocyte osmolarity sensors. Also, weight loss therapies exert profound influence on adipocyte size. Here, we summarize the critical role of adipocyte hypertrophy in the development of metabolic disturbances. Future studies are required to establish a standard criterion of size measurement to better clarify the impact of adipocyte hypertrophy on changes in metabolic homeostasis.

Modulation of gut microbiota contributes to effects of intensive insulin therapy on intestinal morphological alteration in high-fat-diet-treated mice.

AIMS: Disturbance of intestinal homeostasis promotes the development of type 2 diabetes. Although intensive insulin therapy has been shown to promote extended glycemic remission in newly diagnosed type 2 diabetic patients through multiple mechanisms, its effect on intestinal homeostasis remains unknown. METHODS: This study evaluated the effects of intensive insulin therapy on intestinal morphometric parameters in a hyperglycemic mice model induced by high-fat diet (HFD). 16S rRNA V4 region sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota. RESULTS: HFD-induced increases in the lengths of villus, microvillus and crypt depth were significantly reversed after intensive insulin therapy. Moreover, intestinal proliferation was notably decreased after intensive insulin therapy, whereas intestinal apoptosis was further increased. Importantly, intensive insulin therapy significantly shifted the overall structure of the HFD-disrupted gut microbiota toward that of mice fed a normal diet and changed the gut microbial composition. The abundances of 54 operational taxonomic units (OTUs) were changed by intensive insulin therapy. Thirty altered OTUs correlated with two or more intestinal morphometric parameters and were designated 'functionally relevant phylotypes.' CONCLUSIONS: For the first time, our data indicate that intensive insulin therapy recovers diabetes-associated gut structural abnormalities and restores the microbiome landscape. Moreover, specific altered 'functionally relevant phylotypes' correlates with improvement in diabetes-associated gut structural alterations.