IRX3 promotes adipose tissue browning and inhibits fibrosis in obesity-resistant mice.

Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated obesity resistance (OR) on a high-fat diet (HFD) and the role of the Iroquois homeobox 3 (IRX3) gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.

Adipocyte-specific FAK deletion promotes pancreatic ß-cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus.

BACKGROUND: White adipose tissue (WAT) has a key role in maintaining energy balance throughout the body, and their dysfunction take part in the regulation of diabetes mellitus. However, the internal regulatory mechanisms underlying are still unknown. METHODS AND RESULTS: We generated adipocyte-specific FAK KO (FAK-AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic ß-cells were proposed in FAK-AKO mice and validated by cell line studies using 3T3-L1, Raw264.7 and Min6. The FAK-AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases ß cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ-induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic ß cell area. Moreover, serum pro-inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3-L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS-treated RAW264.7 macrophages with knockdown FAK of 3T3-L1 adipocytes increased macrophage pro-inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF-κB signaling, which exacerbates inflammation of adipocytes themselves. CONCLUSION: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro-inflammatory factors released by the FAK-null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK-mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized.

Ulinastatin in combination with aprotinin improves systemic inflammation in patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: To investigate the impact of ulinastatin combined with protease inhibitors on serum inflammatory factors in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: A retrospective analysis was conducted on 86 patients who underwent cardiac surgery with cardiopulmonary bypass at Xi'an Gaoxin Hospital from May 2019 to June 2021. Based on the administration of drugs by a micro-infusion pump after anesthesia induction and before skin incision, the patients were divided into an observation group (receiving ulinastatin at a dose of 12,000 U/kg and protease inhibitors at a dose of 4 million units) with 46 cases and a control group (receiving protease inhibitors at a dose of 2 million units) with 40 cases. Peripheral blood leukocyte count, neutrophil percentage, interleukin (IL)-6, tumor necrosis factor (TNF)-α, serum creatine kinase isoenzyme (CK-MB), and serum cardiac troponin I (cTnI) levels were measured and compared between the two groups before surgery, 1 hour after surgery, and 24 hours after surgery. The positive inotropic drug usage, duration of postoperative mechanical ventilation, and incidence of complications were also compared between the two groups. Finally, an analysis was conducted to identify independent risk factors affecting patient prognosis. RESULTS: The peripheral blood white blood cell (WBC) count, neutrophil percentage, serum inflammatory factor level, CK-MB, and cTnI of the two groups of patients at 1 h and 24 h after the operation were significantly higher than those before the operation. However, the observation group had significantly lower levels of peripheral blood WBC count, neutrophil percentage, serum inflammatory factors, CK-MB, and cTnI compared to the control group (all P<0.05). Additionally, the observation group had significantly lower dopamine dosage and a shorter duration of mechanical ventilation compared to the control group (all P<0.05). The incidence of complications was lower in the observation group compared to the control group (P<0.05). TNF-α, cTnI, and treatment regimen were identified as independent risk factors associated with adverse patient prognosis. CONCLUSION: The perioperative use of ulinastatin combined with protease inhibitors in patients undergoing cardiac surgery with cardiopulmonary bypass is beneficial in suppressing systemic inflammatory response, improving cardiopulmonary function, and reducing the incidence of complications. These findings suggest its clinical utility.

A Comprehensive Review of the Current Knowledge of Chlorfenapyr: Synthesis, Mode of Action, Resistance, and Environmental Toxicology.

Creating new insecticide lead compounds based on the design and modification of natural products is a novel process, of which chlorfenapyr is a typical successful example. Chlorfenapyr is an arylpyrrole derivative that has high biological activity, a wide insecticidal spectrum, and a unique mode of action. For decades, a series of chlorfenapyr derivatives were designed and synthesized continuously, of which many highly active insecticidal compounds were discovered sequentially. However, due to the widespread application of chlorfenapyr and its degradation properties, some adverse effects, including pest resistance and environmental toxicity, occurred. In this review, a brief history of the discovery and development of chlorfenapyr is first introduced. Then, the synthesis, structural modification, structure activity relationship, and action mechanism of arylpyrroles are summarized. However, challenges and limitations still exist, especially in regard to the connection with pest resistance and environmental toxicology, which is discussed at the end of this review. This comprehensive summary of chlorfenapyr further promotes its progress and sensible application for pest management.

A Rare B-Myeloid Conversion of Follicular Lymphoma into Clonally Related Acute Myeloid Leukemia: A Case Report.

Follicular lymphoma (FL) is a highly prevalent indolent lymphoma, and the risk of histological transformation is approximately 2-3% per year. Transformation of FL generally occurs in the same lineage (B cell lineage). Another rare form of disease progression is the transformation of neoplastic B-cells to another cell lineage such as acute myeloid leukemia (AML). The low incidence of B-myeloid transformation associated with poor prognosis hinders the establishment of model systems to identify molecular mechanisms. A 64-year-old woman was diagnosed with FL and achieved a satisfactory response after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Approximately one month after treatment terminated, the disease progressed to AML with an increased white blood cell count and abnormal coagulation. Interestingly, nucleotide sequence analysis of the genomic region encoding the immunoglobulin heavy-chain variable domain showed the possibility of homologous transformation from lymphoma to leukemia cells. Although the patient experienced transient improvement after undergoing treatment with one cycle of idarubicin and cytarabine combined with etoposide, she relapsed and died 8 days after venetoclax salvage therapy. Patient with B-myeloid transformation was associated with an aggressive clinical course and poor prognosis. Conventional strategies for treating histologically transformed AML were ineffective. However, treatment with a Bcl-2 inhibitor could serve as an option. Here we review the literature relevant to this rare histological transformation of FL.

Adipose extracellular matrix deposition is an indicator of obesity and metabolic disorders.

Obesity and metabolic disorders are threats to human health. Extracellular matrix (ECM) is an important member of adipose microenvironment. ECM remodeling contributes to obesity and insulin resistance, but the roles of every single ECM component is still not fully understood. We observed glucose and lipids metabolic disorders in high-fat diet (HFD)-fed mice and humans with obesity. Higher levels of inflammatory factors and hormones existed in serum of HFD-fed mice. Multiple collagens, laminins, fibronectin, nidogen, and Hspg2 were upregulated in obese white adipose tissue (WAT) from mice and humans. These effects were stronger in subcutaneous WAT than visceral WAT in mice, but the fat depot difference was reversed in humans. The ECM structure and the morphology of adipocytes seeded on ECM were changed in the HFD group. In human visceral WAT, ECM genes showed positive correlations with blood lipids and glucose. In vitro, collagen I/IV and LAMA4 proteins showed similar changes with C/EBPα during the differentiation of adipocytes. Macromolecular crowders (MMC) promoted partial collagen and non-collagen gene expression. Oleic acid (OA) and MMC upregulated collagen I/IV and LAMA4 proteins, and the effects of MMC were stronger than that of OA. Moreover, MMC promoted the differentiation of adipocytes, but OA increased the size of lipid droplets. Positive correlations were observed between ECM genes and adipogenesis-related genes in adipocytes. In conclusion, some obesogens (such as HFD) induce ECM remodeling, and the upregulation of ECM components is closely related to adipogenesis, suggesting that adipose ECM deposition is an indicator of obesity and metabolic disorders.

Unravelling the Polytoxicology of Chlorfenapyr on Non-Target HepG2 Cells: The Involvement of Mitochondria-Mediated Programmed Cell Death and DNA Damage.

Chlorfenapyr (CHL) is a type of insecticide with a wide range of insecticidal activities and unique targets. The extensive use of pesticides has caused an increase in potential risks to the environment and human health. However, the potential toxicity of CHL and its mechanisms of action on humans remain unclear. Therefore, human liver cells (HepG2) were used to investigate the cytotoxic effect and mechanism of toxicity of CHL at the cellular level. The results showed that CHL induced cellular toxicity in HepG2 cells and induced mitochondrial damage associated with reactive oxygen species (ROS) accumulation and mitochondrial calcium overload, ultimately leading to apoptosis and autophagy in HepG2 cells. Typical apoptotic changes occurred, including a decline in the mitochondrial membrane potential, the promotion of Bax/Bcl-2 expression causing the release of cyt-c into the cytosol, the activation of cas-9/-3, and the cleavage of PARP. The autophagic effects included the formation of autophagic vacuoles, accumulation of Beclin-1, transformation of LC3-II, and downregulation of p62. Additionally, DNA damage and cell cycle arrest were detected in CHL-treated cells. These results show that CHL induced cytotoxicity associated with mitochondria-mediated programmed cell death (PCD) and DNA damage in HepG2 cells.

Saponins from Panax japonicus alleviate adipose tissue fibrosis and metabolic dysfunction in high-fat-diet-induced obese mice.

INTRODUCTION: Adipose tissue fibrosis is a typical feature of adipose tissue dysfunction in obese individuals, which is closely related to metabolic diseases. OBJECTIVE: To explore the effect and mechanism of Saponins from Panax japonicus (SPJ) on adipose tissue fibrosis in obese mice induced by high fat diet (HFD). MATERIALS AND METHODS: We established a HFD induced obese mice model. Then the obese mice were treated with 90 mg/kg SPJ by oral gavage for 10 weeks. The levels of adipose tissue fibrosis and molecules related to signalling pathways were measured. Then the effects of SPJ on TGFß1-induced fibrosis in 3T3-L1 differentiated adipocytes were evaluated. RESULTS: SPJ reduced body weight, fat accumulation, and improved glucose and lipid metabolism in obese mice. SPJ decreased collagen deposition and expressions of fibrotic genes in epididymal white adipose tissue (eWAT) of obese mice. SPJ decreased the levels of TGFß1 protein and pSmad2, and increased the expression of PPARγ and PGC1α, thus alleviating oxidative stress in eWAT. Consistently, SPJ inhibited TGFß1-induced fibrosis in 3T3-L1 differentiated adipocytes. CONCLUSIONS: SPJ may alleviate adipose tissue fibrosis and improve obesity by inhibiting TGFß1/Smad2 and activating PPARγ/PGC1α pathway. SPJ is expected to become an efficient medicine for treatment of obesity.

High-Fat-Diet-Induced Extracellular Matrix Deposition Regulates Integrin-FAK Signals in Adipose Tissue to Promote Obesity.

SCOPE: High-fat-diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown. METHODS AND RESULTS: This study uses three models-HFD-fed mice, human with obesity, and 3T3-L1 adipocytes with oleic acid (OA)/macromolecular crowders (MMC) treatment. Glucose and lipids metabolic disorders, increased collagen I/IV and laminin α2/4 (LAMA2/4), and upregulated integrins (ITGA1/ITGA7) - focal adhesion kinase (FAK) - c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinase 1/2 (ERK1/2) signals in obese WAT from mice and human are observed. The upregulation of ECM - integrin - FAK signals is stronger in subcutaneous WAT than that in visceral WAT of mice, but these results are reversed in human. In vitro, oleic acid (OA) promotes lipid accumulation and upregulates collagen IV, LAMA4, and p-JNK. MMC is used to induce ECM deposition in adipocytes. MMC promotes adipocyte differentiation and integrins - FAK - JNK/ERK1/2 signals. When FAK phosphorylation is inhibited, downstream p-JNK is decreased. Inhibition of FAK phosphorylation reduces adipocyte differentiation, but MMC partially reverses this effect. CONCLUSION: HFD-induced ECM deposition, whose signals are transmitted into adipocytes through upregulating ITGA1/ITGA7, activates the phosphorylation of intracellular FAK - JNK/ERK1/2 signals, and promotes adipogenesis in WAT. This mechanism provides novel therapeutic targets to treat obesity.

Syndecan-2, negatively regulated by miR-20b-5p, contributes to 5-fluorouracil resistance of colorectal cancer cells via the JNK/ERK signaling pathway.

5-Fluorouracil (5-FU) resistance has been long considered as an obstacle to the efficacy of chemotherapy in colorectal cancer (CRC). In this study, we demonstrated the role of miR-20b-5p-regulated syndecan-2 (SDC2) in 5-FU resistance of CRC cells. 5-FU-resistant SW480 CRC cells were established by treatment of SW480 cells with stepwise increase of 5-FU concentration. The results showed that SDC2 was expressed significantly higher in SW480/5-FU cells than in SW480/WT cells as revealed by quantitative real-time polymerase chain reaction and western blot analysis. MTT assay and BrdU assay showed that SDC2 overexpression led to increased cell survival rate, while SDC2 knockdown reversed the drug resistance of SW480/5-FU cells. Wound healing and transwell invasion assays revealed that knockdown of SDC2 inhibited the migratory and invasive ability of SW480/5-FU cells. Moreover, animal experiments indicated that si-SDC2 plays a suppressive role in tumor growth in vivo. We also confirmed that miR-20b-5p interacted with SDC2, which reversed the effect of SDC2 in SW480/5-FU cells via the c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinases (ERK) signaling pathway. These findings showed that JNK/ERK signaling pathway is involved in miR-20b-5p/SDC2 axis-mediated 5-FU resistance in SW480/5-FU cells, indicating that the miR-20b-5p/SDC2 axis is a potential target for reversing 5-FU resistance in CRC.

Mechanism of total glucosides of paeony in hypoxia/reoxygenation-induced cardiomyocyte pyroptosis.

Inflammasome-mediated pyroptosis can aggravate myocardial ischemia/reperfusion injury. Total glucosides of paeony (TGP) is widely used in anti-inflammation. This study investigated the effect of TGP on pyroptosis of hypoxia/reoxygenation (H/R)-induced cardiomyocytes. HL-1 cells were subjected to H/R treatment. H/R-induced cardiomyocytes were treated with TGP at different concentrations (50, 100, and 200 mg/kg). The viability of H/R-induced cardiomyocytes was measured. The levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were determined. The activity of caspase-1, the expressions of NLRP3 and GSDMD-N, and the concentrations of IL-1ß and IL-18 were examined. miR-181a-5p expression in H/R cardiomyocytes was determined. The targeting relationship between miR-181a-5p and adenylate cyclase 1 (ADCY1) was verified. Functional rescue experiments were performed to verify the effect of miR-181a-5p or ADCY1 on the pyroptosis of H/R cardiomyocytes. TGP enhanced H/R-induced cardiomyocyte viability in a dose-dependent manner, reduced LDH, MDA, and ROS levels, increased SOD level, decreased caspase-1 activity, reduced NLRP3 and GSDMD-N expressions, and inhibited IL-1ß and IL-18 concentrations. TGP suppressed miR-181a-5p expression in H/R cardiomyocytes. miR-181a-5p targeted ADCY1. miR-181a-5p overexpression or ADCY1 inhibition reversed the inhibitory effect of TGP on the pyroptosis of H/R cardiomyocytes. Collectively, TGP alleviated the pyroptosis of H/R cardiomyocytes via the miR-181a-5p/ADCY1 axis.

Ursolic acid induces white adipose tissue beiging in high-fat-diet obese male mice.

Ursolic acid (UA) shows an effect on obesity and related metabolic diseases, but its mechanism of action remains unclear. We found that UA clearly reduced the body weight and adipose tissue mass and improved the glucose tolerance and insulin sensitivity in obese male mice. UA treatment significantly reduced the volume and weights of the epididymal white adipose tissue (eWAT) and inguinal subcutaneous white adipose tissue (igSWAT) of HFD-fed mice, respectively. UA also decreased the expression of genes involved in adipocyte differentiation and lipogenesis in igSWAT. Real-time PCR and immunohistochemistry showed that the expression of beiging-related genes 4-1BB factor (CD137), T-box transcription factor 1 (TBX1), and transmembrane protein 26 (TMEM26) were significantly increased in the UA treatment group. UA treatment significantly reduced the weight of gastrocnemius muscle (GM) and lipid droplets in the GM. UA treatment significantly upregulated the expression of PR domain-containing 16 (PRDM16), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and fibronectin type 3 domain-containing protein 5 (FNDC5) in GM and igSWAT. UA also stimulated irisin secretion in the serum. In conclusion, these results indicate that UA plays an anti-obesogenic role by increasing the secretion of irisin and promoting the beiging of WAT.

Promising Response to Lenalidomide-Combination Therapy in a Discordant Lymphoma Consisting of EBV-Positive Diffuse Large B-Cell Lymphoma and Angioimmunoblastic T-Cell Lymphoma: A Case Report.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) complicated with angioimmunoblastic T-cell lymphoma (AITL) is extremely rare and typically shows an aggressive clinical course and unsatisfactory prognosis. Here, we describe the case of a 77-year-old man who was referred to the hospital because of repeated fever, night sweats, and weight loss. He was finally diagnosed with a discordant lymphoma consisting of AITL and DLBCL, with significantly different maximum standardized uptake values on positron emission tomography/computed tomography. Based on his complex illness and poor performance status, the patient received six cycles of lenalidomide combined with R-miniCHOP regimen and achieved complete remission with tolerable and controlled toxicity. He subsequently received lenalidomide maintenance therapy and achieved sustained remission. We consider the possible causes of this discordance involved AITL and EBV-positive DLBCL, and the possible mechanism of lenalidomide action in both T-cell and B-cell non-Hodgkin lymphomas. Lenalidomide-combination therapy may be a preferable choice in patients with an EBV-associated discordant lymphoma.

Ibrutinib in Chronic Lymphocytic Leukemia: Clinical Applications, Drug Resistance, and Prospects.

Bruton's tyrosine kinase (BTK), a pivotal component of B-cell receptor (BCR) signaling, has been recognized as an important driver of the pathogenesis of chronic lymphocytic leukemia. Ibrutinib is a highly active and selectively irreversible inhibitor of BTK, which has been approved to be effective in both frontline and recurrent therapy of CLL. Acquired resistance has become a greater problem than initially anticipated with the widespread use of ibrutinib. An ongoing exploration of the mechanisms of ibrutinib resistance (IR) in CLL has revealed potentially useful therapeutic targets. New drugs expected to overcome IR in CLL are in the early stages of clinical development. This study aimed to summarize the possible mechanisms of IR and retrospectively analyze promising therapies that might have superior efficacy in overcoming IR.

Syndecan-2 in colorectal cancer plays oncogenic role via epithelial-mesenchymal transition and MAPK pathway.

PURPOSE: In this study, we aimed to elucidate the biological roles of Syndecan-2 (SDC2) in colorectal cancer (CRC), thereby further understanding its clinical role. METHODS: The expression of SDC2 was assessed by qRT-PCR and Western blot analysis. To understand the potential biological role of SDC2, we also explored the correlation between its expression level and clinicopathologic parameters. By using MTT, plate colony formation assay, Transwell invasion assays, and flow cytometry in vitro, the biological impact of SDC2 on CRC cell proliferation, migration, invasion, and apoptosis. In addition, the related signaling pathways were investigated. RESULTS: SDC2 expression was significantly upregulated in CRC tissues. The expression of SDC2 was highly associated with four parameters, i.e., stage (P < 0.01), vascular invasion (P = 0.0045), lymph node metastasis (P=0.0018), and distant metastasis (P = 0.0019). Knockdown of SDC2 significantly reduced proliferation, migration, and invasion of HCT116 and SW480 cells, and induced cell apoptosis. Moreover, SDC2 promoted epithelial-mesenchymal transition (EMT) in CRC cells, whereas the ratio of p-MEK/MEK and p-ERK/ERK markedly reduced after depleting SDC2. CONCLUSION: During CRC development, overexpression of SDC2 plays a carcinogenic role in CRC. Therapeutic solutions targeting SDC2 may provide potential insights into CRC prevention and treatment.