Specific Knockout of Notch-1 in Macrophages Modulate the Progression of Hepatic Insulin Resistance in HFD Fed Mice via Regulating IRE1α-XBP1 Signals.

OBJECTIVE: To develop an intervention based on Notch-1 signalling pathway blockade by investigating the potential application of the neurogenic locus notch homologue protein 1(Notch-1) signalling pathway as a key regulator of chronic inflammation and adipogenesis in the treatment of hepatic insulin resistance (HIR). STUDY DESIGN: Experimental study. Place and Duration of the Study: Animal Laboratory of the Fourth Hospital of Hebei Medical University, Shijiazhuang, China, from April 2021 to June 2022. METHODOLOGY: HIR models were established in Notch-1WT and Notch-1MAC-KO mice by high fat diet (HFD) for 16 weeks. Haematoxylin and eosin (HE) staining and oil red O (ORO) staining were used to detect inflammatory infiltration and lipid accumulation in each group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of TNF-α and IL-6. Free fatty acid (FFA) and total cholesterol (TC) were measured with relevant kits. Moreover, real-time quantitative polymerase chain reaction (PCR) was performed to detect the relative expressions of F4/80, Mcp1, and CD11b in hepatic tissues. Mass spectrometry was used to analyse the levels of triglyceride (TG), diacylglycerol (DAG) and conformite europeenne (CE) in liver tissue. Western blotting was used to detect the expression of related proteins. RESULTS: Specific knockdown of Notch-1 in macrophages decreases the relative fluorescence intensity of CD68 and attenuates inflammatory infiltration and lipid degeneration. There was no difference in plasma levels of FFA and TG. Specific knockdown of Notch-1 in macrophages decreases the expression of F4/80, Mcp1, and CD11b, as well as the levels of TG, DAG, CE, IL-6, and TNF-α. CONCLUSION: Specific knockout of Notch-1 in macrophages may reduce HIR by inhibiting the IRE1α-XBP1 signalling pathway. KEY WORDS: Hepatic insulin resistance, Macrophages, Notch-1, IRE1α, XBP1.

Specific knockout of notch-1 attenuates non-alcoholic fatty liver disease by promoting SHP2 phosphorylation.

OBJECTIVE: To investigate the effect of Notch-1 signaling on NAFLD and its molecular mechanism. METHODS: The lipid deposition in liver tissues was detected by oil red O staining. Western blotting was performed to detect the expressions of SREBP1C, SREBP2, LXR, IL-1ß, IL-18, NLRP3, Notch-1, NOX2, NOX4, p-PI3K and p-SHP2 in macrophages, and the expressions of ALIX, CD9, IL-1ß and SREBP1C in exosomes. Macrophages in the Notch-1MAC-KO group and Notch-1WT group were treated with FFA, and those in the Notch-1WT+FFA group and Notch-1MAC-KO+FFA group were treated with SHP2 inhibitors PHPS1 and Relaxin. RESULTS: It was observed by oil red O staining that lipid deposition in mice with NAFLD was reduced in the Notch-1MAC-KO group. The results of Western blotting showed that the expressions of ALIX, CD9, IL-1ß and SREBP1C in macrophage exosomes were significantly lower in the Notch-1MAC-KO group than in the Notch-1WT group. In macrophages, the expressions of SREBP1C, SREBP2, LXR, IL-1ß, IL-18, Notch-1, NOX2, NOX4 and p-PI3K significantly decreased, while the expression of p-SHP2 significantly increased in the Notch-1MAC-KO group compared with the Notch-1WT group. The Notch-1MAC-KO+FFA group had significantly decreased expressions of SREBP1C, NLRP3, IL-1ß, IL-18, SREBP2, NOX2, NOX4 and p-PI3K and a significantly increased expression of p-SHP2 compared with the Notch-1WT+FFA group. However, the differences in the above proteins were all eliminated after PHPS1 and Relaxin were added. CONCLUSION: Specific knockout of Notch-1 attenuates NAFLD, and reduces inflammation and lipid deposition in the liver by promoting SHP2 phosphorylation.

Association Between Polymorphism in Diabetes Susceptibility Gene Insulin-Like Growth Factor 2mRNA-Binding Protein 2 and Risk of Diffuse Large B-Cell Lymphoma.

Background: Numerous studies have shown that polymorphisms in the diabetes susceptibility gene, insulin-like growth factor 2mRNA-binding protein 2 (IGF2BP2), are associated with the occurrence and development of various malignant tumors; however, their correlation with the onset of diffuse large B-cell lymphoma (DLBCL) is still unknown. Therefore, this study aimed to explore whether IGF2BP2 polymorphisms increase the risk of developing DLBCL. Methods: This study included 295 DLBCL patients and 331 healthy individuals. Peripheral blood was collected, and polymerase chain reaction-ligase detection reaction (PCR-LDR) was used to detect IGF2BP2 gene polymorphisms. Logistic regression was used to assess the association between IGF2BP2 polymorphism and the risk of DLBCL, adjusted for age, sex, and body mass index (BMI). P < .05 indicated statistical significance. Results: The rs4402960 polymorphism in the IGF2BP2 gene was associated with the occurrence and development of DLBCL. After adjusting for age, sex, and BMI, GT (odd ratio [OR] = 1.54; 95% confidence interval [CI] = 1.08-2.19; P = .016), TT (OR = 2.00; 95% CI = 1.09-3.68; P = .026), and T genotype carrying (GT + TT) (OR = 1.62; 95% CI = 1.17-2.25; P = .004) significantly increased the risk of DLBCL. This study also found that the polymorphism rs1470579 was related to the development of DLBCL. After adjusting for age, sex, and BMI, AC (OR = 1.55; 95% CI = 1.11-2.17; P = .010), CC (OR = 2.18; 95% CI = 1.17-4.06; P = .014), and C genotype carrying (AC + CC) (OR = 1.64; 95% CI = 1.19-2.26; P = .002) significantly increased the risk of DLBCL. Conclusions: Our study found that polymorphism in the IGF2BP2 gene was associated with an increased risk of developing DLBCL.

Synergistic effect of berberine hydrochloride and dehydrocostus lactone in the treatment of ulcerative colitis: Take gut microbiota as the target.

Ulcerative colitis (UC) is a difficult-to-cure and recurrent inflammatory bowel disease, and it is difficult to maintain long-term results with a single drug. Inspired by clinical medication in traditional Chinese medicine, we used berberine hydrochloride (BBH) and dehydrocostus lactone (DEH) in combination for the first time and focused on studying their mechanism of treating UC based on gut microbiota. Therefore, we evaluated the therapeutic effects of BBH and DEH on DSS-induced UC mice using ELISA, HE and AB-PAS staining, 16s rDNA amplicon sequencing technology, and fecal transplantation experiments (FMT). In this study, the combination of BBH and DEH significantly relieved symptoms, colonic inflammation, and intestinal barrier damage of DSS-induced UC mice, and they did not show antagonism. In addition, the co-administration of BBH and DEH altered the composition and function of gut microbiota, with BBH increasing the abundance of key beneficial bacterial genus Akkermansia and DEH aiming to enhance species diversity and supplying intestinal proteins to prevent overconsumption. Furthermore, our data showed that BBH and DEH improve the levels of short-chain fatty acids, which also proved the positive regulation of gut microbiota by BBH and DEH. Finally, the FMT confirmed the strong correlation between BBH, DEH, and the gut microbiota. In conclusion, the co-administration of BBH and DEH protected the intestinal barrier and reduced inflammatory damage by regulating gut microbiota, targeting the key beneficial bacterial genus Akkermansia, and maintaining a normal supply of intestinal proteins.

The Treatment of Diffuse Large B-Cell Lymphoma (Triple Expression) Involving the Breast, Spleen, and Bone in a Male Patient with Viral Hepatitis B: A Rare Case Report.

Background: Diffuse large B-cell lymphoma (DLBCL) involving the breast, spleen, and bone in a male patient with hepatitis B virus (HBV) infection is extremely rare in clinical practice. Case Presentation: We report a case of DLBCL involving the breast, spleen, and bone (triple expression of Bcl-2+, Bcl-6+, and 70% positive C-mcy) in a male patient with HBV admitted to our hospital. The patient was treated with EPOCH×4, lenalidomide+EPOCH×2 chemotherapy, intermittent methotrexate intrathecal injections to prevent central invasion, and autologous stem cell transplantation (ASCT). The patient is currently in complete remission, and the follow-up time was 43 months. Conclusion: A patient with DLBCL involving the breast, spleen, and bone can be treated with a combination of multiple regimens. If the patient's economic conditions permit it, ASCT can be considered.

Non-Traditional Blood Lipid Indices for Metabolism Dysfunction-Associated Fatty Liver Disease Prediction in Non-Obese Type 2 Diabetes Mellitus.

Objective: This study aims to investigate the predictive value of non-traditional blood lipid indices for metabolism dysfunction-associated fatty liver disease (MAFLD) in non-overweight/obese patients with type 2 diabetes mellitus (T2DM). Methods: A retrospective observational study was conducted, including non-overweight/obese patients with T2DM who visited the Fourth Hospital of Hebei Medical University between August 2018 and August 2022. The low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, the triacylglycerol-glucose index (TyG) multiplied by body mass index (BMI), and TyG/HDL-C ratio were calculated. Results: The study involved 190 participants, of whom 34 were diagnosed with MAFLD (24 males and 10 females), while 156 did not have MAFLD (64 males and 92 females). Multivariable analysis revealed that aspartate transaminase (AST) (OR=1.216, 95% CI: 1.059-1.374, P=0.006), blood uric acid (BUA) (OR=1.017, 95% CI: 1.002-1.032, P=0.022), TyG*BMI (OR=1.231, 95% CI: 1.051-1.442, P=0.010), and TyG/HDL-C (OR=3.162, 95% CI: 1.228-8.141, P=0.017) were independently associated with MAFLD. The TyG*BMI index exhibited an area under the ROC curve (AUC) of 0.812, with 91.2% sensitivity and 69.2% specificity for MAFLD. The TyG/HDL-C index had an AUC of 0.929, with 85.3% sensitivity and 88.5% specificity for MAFLD. Conclusion: The results indicate that TyG*BMI and TyG/HDL-C are independently associated with MAFLD in non-overweight/obese patients with T2DM.

Comprehensive quality evaluation of two different geography originated Angelica sinensis Radix based on potential production area development and resource protection.

Angelica sinensis Radix (ASR) is mainly produced in the southern region of Gansu, China, and is a famous edible and medicinal herb. Noticeably, Aba region in Sichuan, China has similar geographical and climatic conditions to the southern region of Gansu, China, and has the potential to further develop the ASR planting industry chain. This study was the first to use an innovative method that combines GC-MS, HPLC-DAD fingerprints, and stoichiometric analysis to compare and explore the feasibility of using the Aba region as a source of high-quality ASR supplements. GC-MS analysis showed that the composition of ASR essential oil(AEO) in these two regions was highly similar (>99%). The HPLC data showed that the main sources of differences in ASR components between the two regions were coniferyl ferulate, E-ligustilide, Z-ligustilide, and Butylidenephthalide, which have great potential in anti-depression, regulating gut microbiota, and other aspects. The ASR in Aba region was rich in these components, and its biological activity might be higher to some extent than that in southern Gansu. This study confirmed the potential of the Aba region in Sichuan to become a high-quality production area for ASR, which was conducive to the expansion of ASR resources and the development of related industrial chains.

Insulin Resistance and the Prognosis in Diffuse Large B-cell Lymphoma.

OBJECTIVE:  To investigate whether insulin resistance (IR) affects the prognosis in patients with diffuse large B-cell lymphoma (DLBCL). Place and Duration of the Study: The Fourth Hospital of Hebei Medical University, Shijiazhuang, China, from September 2017 to December 2021. METHODOLOGY: This study retrospectively analysed 324 patients with DLBCL who were divided into a non-IR group (251 cases) and IR group (73 cases) according to IR. The authors collected clinical data of the study population and calculated the overall survival (OS) of patients through inpatient case data or follow-up. The Cox regression method was used to assess the prognostic factors of the patients. The Kaplan-Meier method was used for drawing the survival curve of IR on OS of the DLBCL patients. RESULTS: The IR group had older age, higher international prognostic index (IPI), later stage, and higher insulin levels. The five-year OS rate was 46% in the IR group and 66% in the non-IR group. Compared with the non-IR group, the IR group showed a poor prognosis (OS: adjusted HR 1.23, 95% CI: 1.02-1.41, p = 0.031). CONCLUSION: IR was one of the factors leading to poor prognosis in patients with DLBCL, and attention should be paid to this risk factor. KEY WORDS: Insulin resistance, Diffuse large B-cell lymphoma, Overall survival, Prognosis.

Polygonati Rhizoma with the homology of medicine and food: A review of ethnopharmacology, botany, phytochemistry, pharmacology and applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonati Rhizoma (PR), which contains rich national cultural connotations, is a traditional Chinese medicine with homology of medicine and food. It has been used for a long time as a tonic in China's multi-ethnic medical system, and is also used to treat diseases such as premature graying hair, deficiency of blood and essence, diabetes, hypertension, etc. Meanwhile, PR is often used as food in China, India, South Korea and other Asian countries, which can satisfy hunger and provide many health benefits. AIM OF THE REVIEW: This paper systematically reviewed the ethnopharmacology, botany, phytochemistry, pharmacology and related applications research of PR, and provided a reference for the comprehensive applications of PR, including basic research, product development and clinical applications. This paper also refined the national application characteristics of PR, such as rich plant resources, special chemical components and anti-hidden hungry, which laid a foundation for its high value and high connotation development in the future. MATERIALS AND METHODS: The literature information was collected systematically from the electronic scientific databases, including PubMed, Science Direct, Google Scholar, Web of Science, Geen Medical, China National Knowledge Infrastructure, as well as other literature sources, such as classic books of herbal medicine. RESULTS: A comprehensive analysis of the above literature confirmed that PR has been used in the ethnic medicine system of Asian countries such as China for thousands of years. In this paper, 12 species including official species that can be used as PR are summarized, which provide rich plant resources for PR. The chemical components in PR are divided into nutritional components and active components. The former not only contains non-starch polysaccharides and fructo-oligosaccharides, which account for about 50% in PR and are recognized as high-quality diet in the world, but also contains inorganic elements and mineral elements. And a total of 199 kinds active ingredients, including saponins, flavonoids, alkaloids, etc., were sorted out by us. The above ingredients make PR have a special property of anti-hidden hunger. Studies have shown that PR has a wide range of pharmacological activities, such as immune regulation, blood glucose regulation, lipid-lowering, antioxidant, anti-tumor, antibacterial, etc. It has been widely used in medicine, food, cosmetics, gardens and other fields. CONCLUSIONS: PR, as a classic medicinal material of the same origin, is widely used in the traditional ethnic medicine system. It contains abundant potential plant resources, chemical components and pharmacological activities. This paper also suggests that PR with high application value in food industry, has the potential to become a high-quality coarse grain. Exploring the way of grain and industrialization of PR is beneficial to fully develop the economic value of PR.

Primary diffuse large B-cell lymphoma of the breast: A retrospective study of outcomes and insulin resistance.

OBJECTIVES: To investigate the clinicopathological features, insulin resistance (IR) status, and the outcomes of populations with diffuse large B-cell lymphoma (DLBCL) of the breast. METHODS: This study was carried out at Department of Haematology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China, that included 32 patients treated form January 2009 to June 2020. The primary endpoints of the study were their survival time. RESULTS: There were 32 patients in the study. A total of 18 (56.2%) patients had IR. In terms of treatment, 31.2% were treated with surgery, most (93.8%) received chemotherapy, and 25% received radiotherapy and intrathecal therapy. Univariate analysis indicated the patients with stages III-IV, B symptoms, tumour recurrence, PAX5 positivity, and c-MYC positivity showed a shorter survival time (p<0.05). The overall survival and progression-free survival (PFS) rates in IR group were shorter than those without IR, but there was no statistical difference (p>0.05). Multivariate analysis indicated that tumour recurrence shortened the 5-year PFS of the patients (p=0.037). CONCLUSION: Primary DLBCL of the breast was very rare; more than half of the cases had IR, but IR did not affect their survival.

Influence of Hyperglycemia on the Prognosis of Patients with Diffuse Large B-Cell Lymphoma.

Purpose: To explore the effects of primary and secondary hyperglycemia and the application of the hypoglycemic drug metformin on the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). Methods: We performed a retrospective analysis of 1767 DLBCL patients.Cox regression method was used for analysis to evaluate the prognostic factors, and the Kaplan-Meier method was used to draw a survival curve to analyze the effect of hyperglycemia and the hypoglycemic drug metformin on the progression-free survival (PFS) and overall survival (OS) of DLBCL patients. Results: Our study showed that patients with hyperglycemia tend to have higher age (age>60 years), high body mass index (BMI)(≥24kg/m2), late Ann Arbor stage (III-IV), high international prognostic index (IPI) (3-5 score), high lactic dehydrogenase (LDH) level (>250U/L), bulky disease and comorbidity. Hyperglycemia affects the survival time of the DLBCL population (PFS: adjusted HR 1.41, 95% CI: 1.16-1.70, P <0.001, OS: adjusted HR 1.33, 95% CI:1.09-1.61, P=0.004).Compared with the non-hyperglycemia group, the secondary hyperglycemia increase affects the prognosis of the DLBCL population (P<0.001). Compared with the secondary hyperglycemia group, the primary hyperglycemia group has a poor prognosis (P<0.05). For patients with DLBCL and hyperglycemia (732 patients in total), the use of metformin can improve their PFS and OS (PFS: adjusted HR 0.69, 95% CI: 0.49-0.96, P=0.028, OS: adjusted HR 0.68, 95% CI: 0.49-0.95, P=0.024). Conclusion: Hyperglycemia and secondary hyperglycemia are related to the poor prognosis of DLBCL population.For patients with DLBCL combined with hyperglycemia, the application of metformin can improve survival rate.

Quercetin protects against the Aß(25-35)-induced amnesic injury: involvement of inactivation of rage-mediated pathway and conservation of the NVU.

Quercetin has demonstrated protective effects against Aß-induced toxicity on both neurons and endothelial cells. However, whether or not quercetin has an effect on the neurovascular coupling is unclear. In the present study, we aim to investigate the anti-amnesic effects of quercetin and to explore the underlying mechanisms. Aß(25-35) (10 nmol) was administrated to mice i.c.v. Quercetin was administrated orally for 8 days after injection. Learning and memory behaviors were evaluated by measuring spontaneous alternation in Morris Water Maze test and the step-through positive avoidance test. The regional cerebral blood flow was monitored before the Aß(25-35) injection and on seven consecutive days after injection. Mice were sacrificed and cerebral cortices were isolated on the last day. The effects of quercetin on the neurovascular unit (NVU) integrity, microvascular function and cholinergic neuronal changes, and the modification of signaling pathways were tested. Our results demonstrate that quercetin treatment for Aß(25-35)-induced amnesic mice improved the learning and memory capabilities and conferred robust neurovascular coupling protection, involving maintenance of the NVU integrity, reduction of neurovascular oxidation, modulation of microvascular function, improvement of cholinergic system, and regulation of neurovascular RAGE signaling pathway and ERK/CREB/BDNF pathway. In conclusion, in Aß(25-35)-induced amnesic mice, optimal doses of quercetin administration were beneficial. Quercetin protected the NVU likely through reduction of oxidative damage, inactivation of RAGE-mediated pathway and preservation of cholinergic neurons, offering an alternative medication for Alzheimer's disease.

The protective effect of 3-deoxysappanchalcone on in vitro influenza virus-induced apoptosis and inflammation.

Influenza virus is one of the most important causes of acute respiratory disease. Viral infection and viral replication activate multiple cell signalling pathways. Apoptosis of infected cells and immune response against viral replication, which are generally considered to be protective mechanisms, are also probably mediated by viruses, which lead to severe health problems. We previously reported that 3-deoxysappanchalcone (3-DSC), a compound that is isolated from Caesalpinia sappan, exhibited in vitro anti-influenza activity. In the present study, we further identified that 3-DSC inhibited viral genomic replication and transcription only at a relatively high concentration. We then evaluated the effect of 3-DSC on the regulation of virus-induced cellular apoptosis. 3-DSC ameliorated virus-induced DNA fragmentation in a concentration-dependent manner, which tends to be a consequence of its inhibition of upstream caspase activation. 3-DSC also protected host cells against influenza-induced inflammation by suppressing CCL5 and CXCL10 secretions in endothelial cells and reducing the production of IL-6 and IL-1ß in monocytes/macrophages. In conclusion, our results demonstrate that anti-influenza virus mechanisms of 3-DSC involved anti-apoptosis and anti-inflammation activities in vitro. Moreover, 3-DSC could be a promising drug candidate for influenza treatment.

In vitro anti-influenza virus and anti-inflammatory activities of theaflavin derivatives.

The theaflavins fraction (TF80%, with a purity of 80%) and three theaflavin (TF) derivatives from black tea have been found to exhibit potent inhibitory effects against influenza virus in vitro. They were evaluated with a neuraminidase (NA) activity assay, a hemagglutination (HA) inhibition assay, a real-time quantitative PCR (qPCR) assay for gene expression of hemagglutinin (HA) and a cytopathic effect (CPE) reduction assay. The experimental results showed that they all exerted significant inhibitory effects on the NA of three different subtypes of influenza virus strains [A/PR/8/34(H1N1), A/Sydney/5/97(H3N2) and B/Jiangsu/10/2003] with 50% inhibitory concentration (IC(50)) values ranging from 9.27 to 36.55 µg/mL, and they also displayed an inhibitory effect on HA; these inhibitory effects might constitute two major mechanisms of their antiviral activity. Time-of-addition studies demonstrated that TF derivatives might have a direct effect on viral particle infectivity, which was consistent with the inhibitory effect on HA. Subsequently, the inhibitory effect of TF derivatives on the replication of the viral HA gene as assayed by qPCR and on the nuclear localization of the influenza virus vRNP further demonstrated that they may primarily act during the early stage of infection. Interestingly, besides the activity against functional viral proteins, TF derivatives also decreased the expression level of the inflammatory cytokine IL-6 during viral infection, expression of which may result in serious tissue injury and apoptosis. Our results indicated that TF derivatives are potential compounds with anti-influenza viral replication and anti-inflammatory properties. These findings will provide important information for new drug design and development for the treatment of influenza virus infection.

[Active neuraminidase constituents of Polygonum cuspidatum against influenza A(H1N1) influenza virus].

OBJECTIVE: To isolate and identify active neuraminidase constituents of Polygonum cuspidatum against influenza A (H1N1) influenza virus. METHOD: On the basis of the bioassay-guided fractionation,such chromatographic methods as silica gel, sephadex LH-20 and HPLC were adopted to isolate active constituents of extracts from Polygonum cuspidatum, and their molecular structures were identifiied on the basis of their spectral data such as NMR and MS and physico-chemical properties. RESULT: Seven compounds were isolated from the ethyl acetate extract of P. cuspidatum and identified as 2-methoxystypandrone (1), emodin (2), resveratrol (3), polydatin (4), emodin-8-O-beta-D-glucopyranoside (5), (E)-3, 5, 12-trihydroxystilbene-3-O-beta-D-glucopyranoside-2'-(3", 4", 5"-trihydroxybenzoate) (6) and catechin-3-O-gallate (7), respectively. Among them, the NA test showed that compounds 3, 6 and 7 had inhibitory effect against NAs activity, with IC50 values of 129.8, 44.8 and 21.3 micromol x L(-1), respectively. Moreover, the further CPE test showed compounds 6 and 7 had significant inhibitory effect against H1N influenza virus (EC50 = 5.9, 0.9 micromol x L(-1), respectively), with very low cytotoxicity to the host cells, their therapeutic selective index(SI) in MDCK cells ranged from 56 to 269. CONCLUSION: The neuraminidase inhibitors against H1N1 anti-influenza virus isolated from extracts of P. cuspidatum on the basis of the bioassay-guided fractionation are significant in specifying their therapeutic material basis and drug R&D against influenza.