Rabeprazole mitigates obesity-induced chronic inflammation and insulin resistance associated with increased M2-type macrophage polarization.

Macrophage polarization is closely associated with obesity-induced chronic inflammation and insulin resistance. Proton pump inhibitor Rabeprazole has long been used to treat gastritis and gastric ulcers. However, whether Rabeprazole plays a role in macrophage polarization during obesity is unknown. Here, we show that Rabeprazole suppresses M1-type macrophage-mediated inflammation, leads to increased M2-type macrophages and alters the polarization status from M1 to M2 in vitro. Mechanistically, Rabe-regulated macrophage polarization is associated with inhibition of NF-κB and activation of STAT6 signaling pathways. Furthermore, Rabeprazole induces M2-type adipose tissue macrophages and alleviates chronic inflammation, improving glucose tolerance and insulin sensitivity in high-fat diet-fed mice. In addition, Rabeprazole increases CD206+ M2-type liver macrophages and relieves liver inflammation, alleviating liver injury and lipid accumulation. Thus, our findings show that Rabeprazole effectively regulates macrophage polarization and controls obesity-associated chronic inflammation and insulin resistance, thus providing a potential therapeutic strategy against obesity-associated metabolic diseases.

Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

Adipose tissue­derived extracellular vesicles: Systemic messengers in health and disease (Review).

Adipose tissue (AT) is a complicated metabolic organ consisting of a heterogeneous population of cells that exert wide­ranging effects on the regulation of systemic metabolism and in maintaining metabolic homeostasis. Various obesity­related complications are associated with the development of dysfunctional AT. As an essential transmitter of intercellular information, extracellular vesicles (EVs) have recently been recognized as crucial in regulating multiple physiological functions. AT­derived extracellular vesicles (ADEVs) have been shown to facilitate cellular communication both inside and between ATs and other peripheral organs. Here, the role of EVs released from ATs in the homeostasis of metabolic and cardiovascular diseases, cancer, and neurological disorders by delivering lipids, proteins, and nucleic acids between different cells is summarized. Furthermore, the differences in the sources of ADEVs, such as adipocytes, AT macrophages, AT­derived stem cells, and AT­derived mesenchymal stem cells, are also discussed. This review may provide valuable information for the potential application of ADEVs in metabolic syndrome, cardiovascular diseases, cancer, and neurological disorders.

UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders.

Inflammation is closely associated with obesity and related metabolic disorders. However, its origin during obesity is largely unknown. Here, we report that ubiquitin-conjugating enzyme E2M (UBE2M) is critical to obesity-related inflammation induced by macrophages. In mice with UBE2M-deficient macrophages, obesity, insulin resistance, and hepatic steatosis induced by a high-fat diet are greatly alleviated, an effect related to the decreased proinflammatory activity of macrophages due to reduced IL-1ß production. Mechanistically, UBE2M deficiency inhibits the neddylation of E3 ubiquitin ligase TRIM21 on K129/134, leading to reduced recruitment and ubiquitination-mediated degradation of E3 ubiquitin ligase VHL. Subsequently, VHL reduces HIF-1α-induced IL-1ß production by degrading HIF-1α. Targeting macrophage TRIM21 with Trim21 antisense oligonucleotide-loaded red blood cell extracellular vesicles effectively inhibits obesity-induced inflammation and related metabolic disorders. Thus, our results demonstrate that macrophage UBE2M is essential for obesity-induced inflammation and that TRIM21 is a proof-of-concept target for treating obesity and associated metabolic diseases.

Type I interferon/STAT1 signaling regulates UBE2M-mediated antiviral innate immunity in a negative feedback manner.

Type I interferon (IFN-I) signaling is central to inducing antiviral innate immunity. However, the mechanisms for IFN-I signaling self-regulation are still largely unknown. Here, we report that RNA virus-infected macrophages with UBE2M deficiency produced decreased IFN-I expression in a RIG-I-dependent manner, causing an aggravated viral infection. Mechanistically, UBE2M inhibits RIG-I degradation by preventing the interaction of RIG-I and E3 ligase STUB1, resulting in antiviral IFN-I signaling activation. Simultaneously, IFN-I signaling-activated STAT1 facilitates the transcription of Trim21, leading to increased UBE2M degradation and blunted antiviral immunity. Translationally, oral administration of milk-derived extracellular vesicles containing RING domain-truncated TRIM21 (TRIM21-ΔRING) lacking E3 ligase activity efficiently transfers TRIM21-ΔRING into macrophages. TRIM21-ΔRING suppresses UBE2M degradation by competitively binding to UBE2M with TRIM21, thereby enhancing antiviral immunity. Overall, we reveal a negative feedback loop of IFN-I signaling and develop a reagent to improve innate immunity against RNA viruses.

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.

PD-L1+ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1+ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1+ Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.

Clinical Practice Guidelines for the Management of Behavioral and Psychological Symptoms of Dementia: A Systematic Review With AGREE II.

Background: High-quality clinical practice guidelines (CPGs) are important for the effective treatment of behavioral and psychological symptoms of dementia (BPSD). However, recommendations provided by different quality guidelines may lead to varied clinical practice outcomes. Objective: To assess the quality of available CPGs for the management of BPSD and summarize the best recommendations for treating BPSD. Methods: This was a systematic review of CPGs for the management of BPSD with data obtained from electronic databases and evaluated using the Appraisal of Guidelines for Research and Evaluation II instrument, consisting of six domains: "Scope and purpose", "Stakeholder involvement", "Rigor of development", "Clarity of presentation", "Applicability", and "Editorial independence". The criteria for high-quality guidelines were set as: the score of high-quality guidelines in the "Rigor of development" domain should be ≥60% and as well as a score of >60% in at least three other domains. High-quality guidelines were selected for recommendation extraction, and the final recommendations were formed in combination with the latest meta-analysis and randomized clinical-trial results. Results: In term of median scores in each domain for the six included CPGs, "Scope and purpose" (87.5%) scored better than all others, whereas "Applicability" (46.5%) was the domain with the lowest score. Four CPGs (2015 APA, 2018 NICE, 2018 CANADA, 2020 EAN) met the criteria of high-quality guidelines and were used to extract recommendations. From these four CPGs, nine specific recommendations related to the management of BPSD were summarized, of which seven were related to pharmacological treatment and two to non-pharmacological treatment. These recommendations covered the applicability of antipsychotic drugs, medication recommendations, withdrawal times, and several suitable non-pharmacological therapies. Conclusion: The quality of CPGs for the management of BPSD requires improvement, especially for the "Applicability" domain. For psychotic-like symptoms in dementia, the use of antipsychotics should be based on the individual's risk-benefit ratio, and the use of atypical antipsychotics seems to be a better choice. Non-pharmacological treatments may be suitable for emotional symptoms and sleep disorders. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020209204.

Association between family history and prognosis of patients with colorectal cancer: a systematic review and meta-analysis.

Background: A family history of colorectal cancer (CRC) increases the risk of developing CRC, and numerous studies have assessed the influence of family history on survival among CRC patients. However, the prognostic effect of a family history of CRC remains uncertain. The aim of this meta-analysis was to systematically assess the association between family history and CRC prognosis. Methods: A comprehensive literature search was performed in the PubMed, Embase, Medline, Web of Science and Scopus databases up to October 2021, based on the Population, Intervention, Comparator, Outcomes and Study designs framework. Two reviewers independently extracted data on baseline characteristics and outcomes from the included studies. The Newcastle-Ottawa Scale was used for quality assessment of each study. Either a fixed- or a random-effects model was used to calculate the pooled hazard ratio (HR). Results: Eighteen studies comprising 80,093 CRC patients were finally included in this meta-analysis. The Newcastle-Ottawa Scale scores of the included studies ranged from 4 to 8, and 12 studies were of high quality. A significant association between family history and improved overall survival was determined in the CRC patients (HR =0.89, 95% CI: 0.81-0.99) with significant heterogeneity (I2=65.7%, P<0.001). This effect was found in male CRC patients (HR 0.70, 95% CI: 0.56-0.88) but not females (HR =0.77, 95% CI: 0.54-1.09). The association between family history and disease-free survival was not significant (HR =0.94, 95% CI: 0.88-1.01) (I2=21.0%, P=0.263). However, a subgroup analysis supported the prognostic value of disease-free survival in patients with stage III CRC (pooled HR =0.78, 95% CI: 0.67-0.92). Discussion: In conclusion, a positive family history was associated with improved overall survival in CRC patients. It was also a favorable predictor of disease-free survival in patients with stage III CRC. These findings should be interpreted with caution because of limitations related to study quality and differences in the adjusted factors across studies.

A rare gastric lesion: diminutive, well-differentiated, Grade 3, type 3 gastric neuroendocrine tumor with extremely high ki-67 index removed en bloc under endoscopy.

Grade 3, type 3 gastric neuroendocrine tumor (g-NET) shows specific features of clinical interest and the therapeutic management of the lesion is not yet completely standardized. We present the unusual case of a 34-year-old male patient with a diminutive (less than 0.5 cm), well-differentiated, G3, type 3g-NET with extremely high Ki-67 index (higher than 80%). The lesion was subsequently removed en bloc via endoscopic submucosal dissection. Regarding the proliferation rate, Ki-67 index values usually range from 21 to 50%, and less commonly above 55%, in G3 NET. To our knowledge, this lesion represents a small size with the highest Ki-67 index diagnosed with G3 g-NET. However, as g-NET might recur even after a long duration, we recommend a long-term follow-up, such as 10 years after complete resection in patients to evaluate the endoscopic resection approach.

Generation and characterization of a human induced pluripotent stem cell line (XWHNi001-A) derived from an Alzheimer's disease patient with mutation in the APP gene.

Mutations in the APP gene are popularly known as the second cause trigger the familial Alzheimer's disease (AD). We generated a human induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells isolated from an AD patient using non-integrative Sendai virus. The iPSC line highly expresses pluripotency markers, has the capacity to differentiate into the normal teratoma tissue, retains the APP mutation, and displays the normal karyotype. The iPSC line will provide a useful resource to study the pathogenesis and drugs screening of AD.

Computed tomography in the size measurement of gastric gastrointestinal stromal tumors: Implication to risk stratification and "wait-and-see" tactics.

INTRODUCTION: This study aimed to compare the radiologic size of gastric gastrointestinal stromal tumors (GISTs) on computed tomography (CT) with the pathologic size in a Chinese population, and elucidate the potential significance of the CT size in the preoperative risk stratification. MATERIALS AND METHODS: The study enrolled 314 patients treated by endoscopic/surgical resection of gastric lesions that proved postoperatively to be GISTs. Bland-Altman analysis and intraclass correlation coefficient (ICC) were adopted to assess the size agreement between CT and pathology. Independent predictors of risk category underestimation and the optimal cut-off value of CT size were determined by logistic regression analysis and the receiver operating characteristic (ROC) curve. RESULTS: CT underestimated gastric GISTs size by 0.30 cm [95% confidence interval (CI): (-0.42, - 0.19); p < 0.001]. In the subgroup analysis, the size underestimation was 0.10 cm in GISTs ≤ 5 cm [95% CI: (-0.19, -0.01); p = 0.024]; and 0.75 cm in GISTs >5 cm [95% CI: (-1.05, 0.45), p < 0.001]. Though ICC values showed well reliability for the corresponding pathologic size, with 0.95 in all size, 0.86 in size ≤ 5 cm, and 0.92 in size >5 cm respectively. Risk underestimation by CT imaging mainly occurred in gastric GISTs with smaller size (≤5 cm; p = 0.010) and lower mitotic index (≤5 per 50 high-power fields; p = 0.011). CT size of 3.65 cm was defined as an absolute cut-off to differentiate intermediate/high-risk patients from low-risk group, with 87.5% sensitivity at a specificity of 57.8%. CONCLUSION: Preoperative CT underestimated the mean size by 0.30 cm in gastric GISTs. A CT size of 3.65 cm would facilitate the selection of potential intermediate/high-risk patients, instant intervention should be encouraged in the absence of contraindications.

A Comparative Study of Structural and Metabolic Brain Networks in Patients With Mild Cognitive Impairment.

Background: Changes in the metabolic and structural brain networks in mild cognitive impairment (MCI) have been widely researched. However, few studies have compared the differences in the topological properties of the metabolic and structural brain networks in patients with MCI. Methods: We analyzedmagnetic resonance imaging (MRI) and fluoro-deoxyglucose positron emission tomography (FDG-PET) data of 137 patients with MCI and 80 healthy controls (HCs). The HC group data comes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The permutation test was used to compare the network parameters (characteristic path length, clustering coefficient, local efficiency, and global efficiency) between the two groups. Partial Pearson's correlation analysis was used to calculate the correlations of the changes in gray matter volume and glucose intake in the key brain regions in MCI with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) sub-item scores. Results: Significant changes in the brain network parameters (longer characteristic path length, larger clustering coefficient, and lower local efficiency and global efficiency) were greater in the structural network than in the metabolic network (longer characteristic path length) in MCI patients than in HCs. We obtained the key brain regions (left globus pallidus, right calcarine fissure and its surrounding cortex, left lingual gyrus) by scanning the hubs. The volume of gray matter atrophy in the left globus pallidus was significantly positively correlated with comprehension of spoken language (p = 0.024) and word-finding difficulty in spontaneous speech item scores (p = 0.007) in the ADAS-cog. Glucose intake in the three key brain regions was significantly negatively correlated with remembering test instructions items in ADAS-cog (p = 0.020, p = 0.014, and p = 0.008, respectively). Conclusion: Structural brain networks showed more changes than metabolic brain networks in patients with MCI. Some brain regions with significant changes in betweenness centrality in both structural and metabolic networks were associated with MCI.

Neddylation of Coro1a determines the fate of multivesicular bodies and biogenesis of extracellular vesicles.

Multivesicular bodies (MVBs) fuse with not only the plasma membranes to release extracellular vesicles (EVs) but also lysosomes for degradation. Rab7 participates in the lysosomal targeting of MVBs. However, the proteins on MVB that directly bind Rab7, causing MVB recruitment of Rab7 remain unidentified. Here, we show that Coro1a undergoes neddylation modification at K233 by TRIM4. Neddylated Coro1a is associated with the MVB membrane and facilitates MVB recruitment and activation of Rab7 by directly binding Rab7. Subsequently, MVBs are targeted to lysosomes for degradation in a Rab7-dependent manner, leading to reduced EV secretion. Furthermore, a decrease in neddylated Coro1a enhances the production of tumour EVs, thereby promoting tumour progression, indicating that neddylated Coro1a is an ideal target for the regulation of EV biogenesis. Altogether, our data identify a novel substrate of neddylation and reveal an unknown mechanism for MVB recruitment of Rab7, thus providing new insight into the regulation of EV biogenesis.

Mesenchymal Stem Cells in Gastric Cancer: Vicious but Hopeful.

Tumor progression depends on the collaborative interactions between tumor cells and the surrounding stroma. First-line therapies direct against cancer cells may not reach a satisfactory outcome, such as gastric cancer (GC), with high risk of recurrence and metastasis. Therefore, novel treatments and drugs target the effects of stroma components are to be promising alternatives. Mesenchymal stem cells (MSC) represent the decisive components of tumor stroma that are found to strongly affect GC development and progression. MSC from bone marrow or adjacent normal tissues express homing profiles in timely response to GC-related inflammation signals and anchor into tumor bulks. Then the newly recruited "naïve" MSC would achieve phenotype and functional alternations and adopt the greater tumor-supporting potential under the reprogramming of GC cells. Conversely, both new-comers and tumor-resident MSC are able to modulate the tumor biology via aberrant activation of oncogenic signals, metabolic reprogramming and epithelial-to-mesenchymal transition. And they also engage in remodeling the stroma better suited for tumor progression through immunosuppression, pro-angiogenesis, as well as extracellular matrix reshaping. On the account of tumor tropism, MSC could be engineered to assist earlier diagnosis of GC and deliver tumor-killing agents precisely to the tumor microenvironment. Meanwhile, intercepting and abrogating vicious signals derived from MSC are of certain significance for the combat of GC. In this review, we mainly summarize current advances concerning the reciprocal metabolic interactions between MSC and GC and their underlying therapeutic implications in the future.

Risk for gastric cancer in patients with gastric atrophy: a systematic review and meta-analysis.

BACKGROUND: The risk for gastric cancer among patients with gastric atrophy is unclear. We investigated the association between the risk for gastric cancer and gastric atrophy. METHODS: We performed a comprehensive literature search in the PubMed and Embase databases and extracted relevant data from eligible studies. A fixed- or random-effects model was applied to pool study-specific risk according to heterogeneity across studies. RESULTS: Thirteen cohort or nested case-control studies with 655,937 participants and 2,794 patients with gastric cancer were analyzed. The pooled results suggested that gastric atrophy was associated with an elevated risk for gastric cancer [pooled risk ratio (RR) =2.91, 95% confidence interval (CI): 2.58-3.27]. The pooled RR (3.10, 95% CI: 2.58-3.73) of studies that used serum levels of pepsinogen for diagnosis of gastric atrophy was similar to that of those that used (pooled RR =2.79, 95% CI: 2.37-3.27) (for endoscopy). Gastric atrophy was positively associated with the risk for gastric cancer in both prospective and retrospective studies. Moreover, the pooled RRs did not significantly vary by country of origin (Asia and Europe) or gastric cancer subtype (cardia and non-cardia). CONCLUSIONS: Gastric atrophy is associated with an elevated risk for gastric cancer, and endoscopy and serum levels of pepsinogens can be used to predict the risk.

Diagnosis and Treatment of Esophageal Candidiasis: Current Updates.

Esophageal candidiasis (EC) is the most common type of infectious esophagitis. In the gastrointestinal tract, the esophagus is the second most susceptible to candida infection, only after the oropharynx. Immunocompromised patients are most at risk, including patients with HIV/AIDS, leukemia, diabetics, and those who are receiving corticosteroids, radiation, and chemotherapy. Another group includes those who used antibiotics frequently and those who have esophageal motility disorder (cardiac achalasia and scleroderma). Patients complained of pain on swallowing, difficulty swallowing, and pain behind the sternum. On physical examination, there is a plaque that often occurs together with oral thrush. Endoscopic examination is the best approach to diagnose this disease by directly observing the white mucosal plaque-like lesions and exudates adherent to the mucosa. These adherent lesions cannot be washed off with water from irrigation. This disease is confirmed histologically by taking the biopsy or brushings of yeast and pseudohyphae invading mucosal cells. The treatment is by systemic antifungal drugs given orally in a defined course. It is important to differentiate esophageal candidiasis from other forms of infectious esophagitis such as cytomegalovirus, herpes simplex virus, gastroesophageal reflux disease, medication-induced esophagitis, radiation-induced esophageal injury, and inflammatory conditions such as eosinophilic esophagitis. Except for a few complications such as necrotizing esophageal candidiasis, fistula, and sepsis, the prognosis of esophageal candidiasis has been good.