Objective To investigate the effects of Osteoking on hyperglycemia and regulating gut microbiota in db/db mice.Methods Wildtype mice were used as the control group,and db/db mice were randomly divided into model and Osteoking groups.After intragastric administration for 12 weeks,fasting blood glucose and serum glycosylated hemoglobin and insulin levels were measured,changes in intestinal microflora were determined,and functional pathways related to intestinal microflora in mice were predicted by 16S rDNA sequencing.Results Compared with the model group,Osteoking decreased fasting blood glucose(P<0.01),serum glycosylated hemoglobin(P<0.01),and the insulin resistance index(P<0.01),and increased insulin content(P<0.01)in db/db mice.Osteoking increased the abundance of beneficial intestinal microflora and decreased the abundance of harmful bacteria.Moreover,the abundance of Marvinbryantia was increased.Osteoking alleviated the decrease in metabolism of D-arginine and D-ornithine,sphingolipid,and galactose metabolism(P<0.05)and inhibited lysine degradation,the sulfur relay system,and propanoate metabolism(P<0.05).Conclusions Osteoking has hypoglycemic properties and improves the intestinal microflora imbalance in db/db mice.

Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1β, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.

OBJECTIVE To evaluate the efficacy and safety of PD-1/PD-L1 inhibitors for neoadjuvant treatment of bladder cancer， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from PubMed， Cochrane Library， Embase， American Society of Clinical Oncology Meeting Library， CNKI， VIP and Wanfang database， etc.， the randomized controlled trials （RCTs）， non-RCT， case-control studies， cohort studies， etc. about PD-1/PD-L1 inhibitors for neoadjuvant treatment of bladder cancer were collected from the inception to Jan 31st， 2023. After literature screening， data extraction and quality evaluation， RevMan 5.3 software was used to perform meta-analysis of single-group rates； sensitivity analysis and publication bias analysis were conducted using Stata12 software. RESULTS A total of 25 studies were included in this discussion， involving 940 patients. The results of meta-analysis showed that the pathologic complete response （pCR） rate was 32% [OR＝0.32， 95%CI （0.22， 0.45）， P＝0.006]， downstaging rate was 52% [OR＝0.52， 95%CI （0.45， 0.60）， P＝0.55]， and the incidence of ≥grade 3 immune-related adverse events （irAEs） was 16% [OR＝0.16， 95%CI （0.11， 0.22）， P＜0.000 01]. Subgroup analysis showed that the patients receiving PD-1/PD-L1 inhibitors alone had a pCR rate of 25% and a incidence of Grade≥3 irAEs of 9%； the patients receiving combined immunotherapy had a pCR rate of 29% and a incidence of Grade≥3 irAEs of 28%； the patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a pCR rate of 43% and a incidence of Grade≥3 irAEs of 12%； PD-L1 positive patients had a pCR rate of 44%， and PD-L1 negative patients had a pCR rate of 25%. The results of the sensitivity analysis showed that the study was robust. The results of the publication bias analysis showed that there was no significant publication bias. CONCLUSIONS PD-1/PD-L1 inhibitors are effective and safe for adjuvant treatment of bladder cancer.

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structure-activity relationship analysis indicated: (i) 12-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound exhibited the most potent potency against EBOV with an IC value of 5.29 μmol/L and an SI value of over 37.8. Further anti-EBOV assay of identified its high effectiveness, and anti-MARV assay of suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.

Objective To study the effect of Shenlingbaizhu Pills on hyperlipidemia and gut microbiota in guinea pigs, providing data support for the treatment of hyperlipidemia from the " spleen" . Methods Guinea pigs were randomly divided into control group, model group, ezetimibe group, Shenlingbaizhu Pills high and low dose groups, with 12 guinea pigs for each group. Guinea pig models of hyperlipidemia were established with high fat diet for 8 weeks. Oral administration of the drug began at the fifth week and continued for 4 weeks. The serum lipid levels of guinea pigs were determined after final administration. The pathological changes of liver tissue were observed by HE staining. The mRNA expression levels of ATP binding cassette ( ABC ) A1 in liver, Niemann Pick C1 like 1 ( NPC1L1) and ABCG5/8 in small intestine were detected by realtime PCR. 16S rDNA sequencing was used to detect changes of gut microbiotas in guinea pigs. Results Shenlingbaizhu Pills significantly reduced the serum triglyceride, total cholesterol, and low density lipoprotein-cholesterol levels in guinea pigs with hyperlipidemia ( P＜0. 01 or P＜0.05). The pathological degree of fatty liver was improved obviously by Shenlingbaizhu Pills. Shenlingbaizhu Pills could reduce the mRNA expression level of NPC1L1 of small intestine and increase the level of liver ABCA1 and small intestine ABCG5/8 (P＜0.01 or P＜0.05). At the phylum level, Shenlingbaizhu Pills could reduce the proportion of verrucomicrobia of guinea pigs in model group (P＜0.01); At the genus level, Shenlingbaizhu Pills could increase the proportions of erysipelotrichaceae＿unclassified, ruminococcus＿1, and ileibacterium of guinea pigs in model group (P＜0. 01 or P＜0. 05 ), reduce the proportion of akkermansia and eubacterium＿coprostanoligenes＿group ( P＜0.01). Conclusion Shenlingbaizhu Pills had significantly therapeutic effect on hyperlipidemia, and its specific mechanism was related to the regulation of cholesterol transport and intestinal flora.

The present study developed an oral hepatocyte growth factor (HGF) gene therapy strategy for gastric ulcers treatment. An attenuated Salmonella typhimurium that stably expressed high HGF (named as TPH) was constructed, and the antiulcerogenic effect of TPH was evaluated in a rat model of gastric ulcers that created by acetic acid subserosal injection. From day 5 after injection, TPH (1 × 10⁹ cfu), vehicle (TP, 1 × 10⁹ cfu), or sodium bicarbonate (model control) was administered orally every alternate day for three times. Then ulcer size was measured at day 21 after ulcer induction. The ulcer area in TPH-treated group was 10.56 ± 3.30 mm², which was smaller when compared with those in the TP-treated and model control groups (43.47 ± 4.18 and 56.25 ± 6.38 mm², respectively). A higher level of reepithelialization was found in TPH-treated group and the crawling length of gastric epithelial cells was significantly longer than in the other two groups (P < 0.05). The microvessel density in the ulcer granulation tissues of the TPH-treated rats was 39.9 vessels/mm², which was greater than in the TP-treated and model control rats, with a significant statistical difference. These results suggest that TPH treatment significantly accelerates the healing of gastric ulcers via stimulating proliferation of gastric epithelial cells and enhancing angiogenesis on gastric ulcer site.
Acetic Acid ; Animals ; Epithelial Cells ; Genetic Therapy ; Granulation Tissue ; Hepatocyte Growth Factor* ; Hepatocytes* ; Microvessels ; Models, Animal ; Rats* ; Salmonella typhimurium ; Salmonella* ; Sodium Bicarbonate ; Stomach Ulcer* ; Ulcer

Objective To investigate dose escalation by metabolic sub-volume based on standard uptake values ( SUV) gradient of pre-treatment positron emission tomography/computed tomography ( PET/CT) for locally advanced non-small cell lung cancer ( NSCLC) radiotherapy. Methods The pre-treatment 18 F-FDG PET/CT images of 29 patients with locally advanced NSCLC were analyzed retrospectively. Gross tumor volume ( GTV) was delineated on the PET/CT fusion images. Tumor metabolic sub-volume was segmented according to the threshold of 50% and 75% maximum standard uptake values ( SUVmax ) . The region that under 50% SUVmax was defined as GTV1. From 50% to 75% SUVmax was defined as GTV2,and over 75% SUVmax was defined as GTV3. PTV (planning target volume), PTV1, PTV2 and PTV3 were extended from GTV, GTV1, GTV2 and GTV3, and different plans were designed subsequently. Plan 1 was designed for PTV with prescription dose 60 Gy, and Plan 2 was designed for PTV1, PTV2 and PTV3 with prescription dose 60-66 Gy, 66-72 Gy and≥72 Gy, respectively. The dosimetric parameters between tumor target and organs at risk (OARs) were compared. Results Compared to Plan 1, the absorbed dose in Plan 2 that covers 2% volume of the PTV ( D2 ) was increased from 66. 5 Gy to 78. 5 Gy and the dose was escalated by about 23. 2%. The average dose of PTV1, PTV2 and PTV3 increased by 2. 8% (62. 7-64. 4 Gy), 10. 3% (63. 5 -70. 0 Gy), 18. 7% (63. 8 -75. 8 Gy), and the average dose of PTV increased by 8. 9% (63. 2-68. 8 Gy). The sub-regional dose had been effectively improved. There was no significant difference in target coverage between Plan 1 and Plan 2 ( P >0. 05 ) . Homogeneity index (HI) was decreased with the escalation of maximum dose for Plan 2(t=23. 3, P<0. 05). There was no statistically significant difference in radiation dose of OARs between two plans ( P>0. 05 ) . Conclusions Dose escalation based on metabolic sub-volume from 18 F-FDG PET/CT was feasible, and radiation dose escalation of sub-volume with high metabolic activity can be achieved without increasing the OARs dose.

BACKGROUND:Al ogeneic hematopoietic stem cel transplantation (HSCT) is one of the effective methods in the treatment of leukemia. The haploidentical HSCT is an option for the patients who need a HSCT without a human leukocyte antigen (HLA)-matched donor. OBJECTIVE:To study the clinical efficacy of HLA-haploidentical HSCT on leukemia and its complications. METHODS:A total of 23 patients (4 cases of acute lymphoblastic leukemia, 12 of acute myelogenous leukemia, and 7 of chronic granulocytic leukemia) who had been treated with HLA-haploidentical HSCT from November 2007 to March 2015 were enrol ed. Conditioning regimen I was set as cyclohexyl nitrosourea+cytarabine+busulfan+cyclophosphamide; regimen II as cyclophosphamide+total body irradiation;regimen III as fludarabine+cytarabine+busulfan+cyclophosphamide; and regimen IV as busulfan+cyclophosphamide. Cyclosporin A, mycophenlate mofetil, antithymocyte globulin and methotrexate were used to prevent graft-versus-host disease (GVHD). Hematopoietic remodeling, complications and prognosis were observed in al patients undergoing HLA-haploidentical HSCT. RESULTS AND CONCLUSION:Of the 23 patients, 22 achieved reconstitution of the granulocyte series, and 19 achieved reconstruction of the megakaryocyte series. Additional y, there were 7 cases of acute GVHD and 4 of chronic GVHD. Transplant-related mortality was 22%(5/23) within 100 days post transplantation including graft failure, acute GVHD, intracranial hemorrhage and disseminated infections. There were 14 cases of disease-free survival from 100 days to 24 months post transplantation, 2 cases of death due to GVHD and fungal infection, or recurrence and chronic GVHD, and 2 cases of recurrence under treatment. These findings indicate that HLA-haploidentical HSCT is an effective approach for the treatment of patients with leukemia, which is worth further investigation in clinical practice.