Analysis of the immunological response to antiviral therapy in patients with different subtypes of HIV/AIDS: a retrospective cohort study.

OBJECTIVE: To evaluate the effectiveness of standardised antiretroviral therapy (ART) among different HIV subtypes in people living with HIV/AIDS (PLWHA), and to screen the best ART regimen for this patient population. DESIGN: A retrospective cohort study was performed, and PLWHA residing in Huzhou, China, between 2018 and 2020, were enrolled. SETTING AND PARTICIPANTS: Data from 625 patients, who were newly diagnosed with HIV/AIDS in the AIDS Prevention and Control Information System in Huzhou between 2018 and 2020, were reviewed. ANALYSIS AND OUTCOME MEASURES: Data regarding demographic characteristics and laboratory investigation results were collected. Immune system recovery was used to assess the effectiveness of ART, and an increased percentage of CD4+ T lymphocyte counts >30% after receiving ART for >1 year was determined as immunopositive. A multiple logistic regression model was used to comprehensively quantify the association between PLWHA immunological response status and virus subtype. In addition, the joint association between different subtypes and treatment regimens on immunological response status was investigated. RESULTS: Among 326 enrolled PLWHA with circulating recombinant forms (CRFs) CRF01_AE, CRF07_BC and other HIV/AIDS subtypes, the percentages of immunopositivity were 74.0%, 65.6% and 69.6%, respectively. According to multivariate logistic regression models, there was no difference in the immunological response between patients with CRF01_AE, CRF07_BC and other subtypes of HIV/AIDS who underwent ART (CRF07_BC: adjusted OR (aOR) (95% CI) = 0.8 (0.4 to 1.4); other subtypes: aOR (95% CI) = 1.2 (0.6 to 2.3)). There was no evidence of an obvious joint association between HIV subtypes and ART regimens on immunological response. CONCLUSIONS: Standardised ART was beneficial to all PLWHA, regardless of HIV subtypes, although it was more effective, to some extent, in PLWHA with CRF01_AE.

HIV subtypes and molecular transmission characteristics among elderly HIV-infected individuals aged 50 and above: a cross-sectional study in Huzhou City, Eastern China.

OBJECTIVE: To analyse the HIV-1 subtypes and molecular transmission characteristics of HIV-infected older individuals aged 50 and above in Huzhou City, and provide a scientific basis for prevention and treatment strategies for them. DESIGN: A cross-sectional study with clustered molecular transmission network cases was performed, and basic epidemiological information was retrieved from the Chinese Centres for Disease Prevention and Control (CDC) Information System. SETTING AND PARTICIPANTS: A molecular epidemiological study was conducted in 899 newly diagnosed HIV-infected individuals from January 2019 and March 2023 in Huzhou city, Zhejiang province, Eastern China. Out of these, HIV sequences were successfully obtained from 673 individuals, including 274 who were older individuals aged 50 and above. PRIMARY AND SECONDARY OUTCOMES: Reverse transcription-polymerase chain reaction (PCR) and nested PCR were used to amplify the polymerase gene of HIV-1, and gene sequencing was performed. We used univariate and multivariate logistic regression to describe the association of clustered molecular transmission network cases. RESULTS: In total, 274 valid HIV sequences of older individuals were obtained, which revealed 14 subtypes. Circulating recombinant forms (CRF) 07_BC accounted for 55.8% and CRF01_AE accounted for 20.1% of the subtypes. Data of 150 older individuals were included in the molecular transmission network, and the proportion of elderly individuals in clustered cases is 52.26% (150/287). The results of multivariable logistic regression analysis showed that the older age group (60-82 years) and CRF07_BC subtype were associated with case clustering (transmission risk). CONCLUSIONS: The key high-risk transmission network was mainly composed of the older age group (60-82 years) and CRF07_BC subtype. It is necessary to further strengthen AIDS health promotion and education for individuals aged 60 years and above, as well as for patients with the CRF07_BC subtype, to reduce HIV transmission and clustering risk.

Pre-coating cRGD-modified bovine serum albumin enhanced the anti-tumor angiogenesis of siVEGF-loaded chitosan-based nanoparticles by manipulating the protein corona composition.

Chitosan-based nanoparticles inevitably adsorb numerous proteins in the bloodstream, forming a protein corona that significantly influences their functionality. This study employed a pre-coated protein corona using cyclic Arg-Gly-Asp peptide (cRGD)-modified bovine serum albumin (BcR) to confer tumor-targeting capabilities on siVEGF-loaded chitosan-based nanoparticles (CsR/siVEGF NPs) and actively manipulated the serum protein corona composition to enhance their anti-tumor angiogenesis. Consequently, BcR effectively binds to the nanoparticles' surface, generating nanocarriers of appropriate size and stability that enhance the inhibition of endothelial cell proliferation, migration, invasion, and tube formation, as well as suppress tumor proliferation and angiogenesis in tumor-bearing nude mice. Proteomic analysis indicated a significant enrichment of serotransferrin, albumin, and proteasome subunit alpha type-1 in the protein corona of BcR-precoated NPs formed in the serum of tumor-bearing nude mice. Additionally, there was a decrease in proteins associated with complement activation, immunoglobulins, blood coagulation, and acute-phase responses. This modification resulted in an enhanced impact on anti-tumor angiogenesis, along with a reduction in opsonization and inflammatory responses. Therefore, pre-coating of nanoparticles with a functionalized albumin corona to manipulate the composition of serum protein corona emerges as an innovative approach to improve the delivery effectiveness of chitosan-based carriers for siVEGF, targeting the inhibition of tumor angiogenesis.

Anemia is independently associated with mortality in people living with human immunodeficiency virus/acquired immune deficiency syndrome: A propensity score matching-based retrospective cohort study in China.

Although previous studies have suggested that hemoglobin is related to the health status of people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) (PLWHA), the role of anemia in mortality remains unclear. This study aimed to comprehensively quantify the effect of anemia on the mortality risk of PLWHA. In this retrospective cohort study, we thoroughly estimated the effect of anemia on PLWHA mortality, using data collected from January 2005 to June 2022 in the Huzhou area, in 450 subjects extracted from the database of the China Disease Prevention and Control Information System and matched them using a propensity score matching approach to balance potential confounding bias. The potential exposure-response relationship between anemia, hemoglobin concentration, and the mortality of PLWHA was also carefully estimated. A series of subgroup analyses, including interaction analysis, was further conducted to validate the robustness of the effect of anemia on PLWHA death risk. Anemia was significantly associated with an elevated death risk in PLWHA, with an increase of 74% (adjusted hazard ratio [AHR]: 1.74; 95% confidence interval [CI]: 1.03-2.93; p = 0.038) in those with anemia after adjusting for potential confounders. PLWHA with moderate or severe anemia had a higher risk of death, with an 86% increase (AHR = 1.86; 95% CI: 1.01-3.42; p = 0.045). Meanwhile, the AHR tended to increase by 85% on average (AHR = 1.85, 95% CI: 1.37-2.50; p < 0.001) with a per standard deviation (SD) decrease in plasma hemoglobin. Consistent relationships between plasma hemoglobin and the risk of death were further observed in the results from multiple quantile regression models, restricted cubic spline regression models, and a series of subgroup analyses. Anemia is an independent risk factor for HIV/AIDS-related mortality. Our findings may provide new insights into the relevance of PLWHA administration to public health policy, which demonstrate that this low-cost and routinely measured marker (hemoglobin) can be a marker of poor prognosis even before the start of HAART.

Nomogram for predicting the probability of permanent stoma in patients with acute obstructive colorectal cancer.

BACKGROUND: Acute obstructive colorectal cancer is a high-risk emergency among colorectal cancer (CRC). Approximately 20% of CRC patients are associated with a permanent stoma, which greatly affects the lifestyle of patients. This study aimed to investigate risk factors for predicting permanent stoma (PS) in patients with acute obstructive colorectal cancer. METHODS: We retrospectively analyzed the clinical-pathological features of patients with acute obstructive colorectal cancer who underwent treatments from our hospital between January 2015 and December 2020. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for predicting PS chances of CRC patients using a nomogram method. Furthermore, the operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to assess the discrimination power of the nomogram. Calibration plot was used to evaluate nomogram's calibration. RESULTS: A total of 98 patients with acute obstructive colorectal cancer were enrolled in this study, including 24 PS patients with permanent stoma and 74 non-PS patients. Multivariate analysis showed that age [odds ratio (OR): 1.068, 95% confidence interval (CI): 1.006 ~ 1.135, P = 0.032], carcinoembryonic antigen (CEA) [OR: 1.015, 95% CI: 1.003 ~ 1.028, P = 0.013], and surgical method [emergency group vs. stent group, OR: 14.066, 95% CI: 3.625 ~ 54.572, p < 0.001] were independent risk factors for PS. These risk factors were incorporated into a nomogram and showed that the AUC of the nomogram was 0.867 (95% CI: 0.782-0.951). The calibration plot got consistent with prediction for PS in the nomogram. CONCLUSION: Age, CEA, and surgical method were independent risk factors for PS in patients with acute obstructive colorectal cancer. Our nomogram has favorable predictive power for PS in CRC patients.

Factors Influencing Survival Status of HIV/AIDS after HAART in Huzhou City, Eastern China.

Background: Highly active antiretroviral therapy (HAART) can effectively reduce the risk of death and opportunistic infections in patients with HIV/AIDS. The aim of this study was to analyse the survival status and its influencing factors in HIV/AIDS after HAART. Methods: The data on patients' sociodemographic characteristics, treatment information, and follow-up results from the Information Management System of the Chinese Center for Disease Control and Prevention were obtained. Bivariate and stepwise multivariate Cox proportional hazards regression model analyses were performed. Results: A total of 1812 participants were included in this study, of which 1716 were still alive (survival group) and 96 had died (death group). The results indicated that respondents who were elderly (HR = 1.053, 95% CI: 1.037-1.069, P < 0.01), who had heterosexual transmission (HR = 2.422, 95% CI: 1.314-4.465, P < 0.01) and whose current WHO clinical stage was stage III or IV (HR = 2.399, 95% CI: 1.215-4.735, P < 0.05) were more likely to have died; respondents whose baseline CD4+ T-lymphocyte count was equal to or more than 200 cells/µL (HR = 0.412, 95% CI: 0.275-0.616, P < 0.05) were unlikely to have died. Conclusions: It is recommended that HAART be provided to HIV/AIDS patients at an early clinical stage and that the health services for HIV/AIDS patients after taking medicines be strengthened, which will help promote adherence to therapeutic regimens and improve quality of life.

Mechanical Stirring Synthesis of 1D Electrode Materials and Designing of Pyramid/Inverted Pyramid Interlocking for Highly Flexible and Foldable Li-Ion Batteries with High Mass Loading.

Flexible and foldable Li-ion batteries (LIBs) are presently attracting immense research interest for their potential use in wearable electronics but are still limited to electrodes with very small mass loading, low bending/folding endurance, and poor electrochemical stability during repeated bending and folding movements. Moreover, one-dimensional (1D) structured electrode materials have shown excellent electrochemical performance but are still restricted by the high cost and complicated fabrication process. Here, we present a very simple yet novel approach for fabricating extra-long Li4Ti5O12 (LTO) and LiCoO2 (LCO) nanofiber precursors by directly stirring the reagents in an atmospheric vessel. In addition, we present multilayer pyramid/inverted pyramid interlocking inside the LTO and LCO nanofiber films as well as between films and current collectors, which can create strengthened interfacial bonding like a zipper and tangentially disperse the strains generated during folding through the pyramidal planes and edges, leading to the realization of thick-film electrodes with outstanding electrochemical stability during folding movements. The foldable LIBs that are assembled with LTO and LCO nanofiber electrodes at a practical level of mass loading (14.9-19.4 mg cm-2) can maintain 102% of the initial capacity after 15 000 times of fully folding (180°) motions.

Dioscin Inhibited Glycolysis and Induced Cell Apoptosis in Colorectal Cancer via Promoting c-myc Ubiquitination and Subsequent Hexokinase-2 Suppression.

PURPOSE: Dioscin is a natural product isolated from traditional Chinese medicines and is reported to have antitumor activities against several cancers. In the present study, we aimed to investigate its potency against colorectal cancers, especially the effects on tumor glycolysis, and to elaborate related molecular mechanisms. METHODS: The antitumor activities of dioscin were evaluated by cell proliferation assays and colony formation assays in vitro and the mouse xenograft models in vivo. The effects of dioscin on tumor glycolysis were determined by measuring glucose absorption and lactate generation. Cell apoptosis was detected by cleaved PARP and the activity of caspase-3. Protein overexpression or gene knockdown was conducted to illustrate molecular mechanisms. Immunoprecipitation experiments were applied to identify the interaction between different proteins. RESULTS: Dioscin substantially inhibited colorectal cancer cell proliferation in vitro and suppressed the xenograft growth in nude mice. After dioscin treatment, with the suppression of hexokinase-2, the tumor glycolysis was significantly decreased. Dioscin substantially impaired the interaction between hexokinase-2 and VDAC-1, and induced cell apoptosis. Exogenous overexpression of hexokinase-2 significantly antagonized the glycolysis suppression and apoptosis induction by dioscin. Through enhancing the binding of E3 ligase FBW7 to c-myc, dioscin promoted the ubiquitination of c-myc and gave rise to c-myc degradation, which contributed to the inhibition of hexokinase-2. CONCLUSION: Our studies revealed a novel mechanism by which dioscin exerted its antitumor activity in colorectal cancer, and verified that dioscin or its analog might have potentials for colorectal cancer therapy.

Construction of a circular RNA-microRNA-messengerRNA regulatory network in stomach adenocarcinoma.

OBJECTIVES: Circular RNAs (circRNAs) can interact with microRNAs (miRNAs) to regulate gene expression in cancer cells. However, the roles of competitive endogenous RNA (ceRNA) networks consisting of differentially expressed circRNAs (DECs), miRNAs, and messenger RNAs (mRNAs) in stomach adenocarcinoma (STAD) remain unclear. This study was performed to explore novel regulatory networks in STAD. METHODS: The circRNA expression profiles, as well as miRNA and mRNA sequence data of STAD, were retrieved from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), respectively. Candidates were identified to construct a network through a comprehensive bioinformatics strategy. The expression of hub-genes identified by protein-protein interactions (PPI) was validated by quantitative reverse transcription (RT) polymerase chain reaction. RESULTS: A total of 51 DECs were identified in the GSE83521 and GSE89143 datasets of GEO. A total of 11 448 differentially expressed mRNAs (DEMs) and 458 differentially expressed miRNAs (DEMIs) were obtained by RNA sequencing of TCGA-STAD. Prediction by using five online databases (Cancer-Specific CircRNA, CircInteractome, miRTarBase, miRDB, and TargetScan) resulted in the selection of 6 DECs, 6 DEMIs, and 36 DEMs to establish a circRNA-miRNA-mRNA regulatory network based on the interactions of circRNA-miRNA and miRNA-mRNA. Through PPI analysis, four hub-genes (COL10A1, COL5A2, COL4A1, and COL3A1) were discovered. Moreover, overexpressions of COL10A1, COL5A1, and COL4A1 were associated with a poor overall survival rate of patients with STAD. On the basis of TNM staging, we found that the expressions of COL10A1, COL5A2, and COL3A1 in T2, T3, and T4 was significantly higher than in T1. Hub-genes expressions were validated in STAD tissues and cell lines. CONCLUSIONS: Our study provides a novel perspective on the regulatory mechanism of STAD involving ceRNAs including DECs, DEMIs, and DEMs.

Solute carrier family 34 member 2 overexpression contributes to tumor growth and poor patient survival in colorectal cancer.

Solute carrier family 34 member 2 (SLC34A2) is a well-known sodium-dependent phosphate transporter that has recently been linked to cancer development. However, its specific oncogenic role remains controversial in numerous human malignancies, and is currently unknown in colorectal cancer (CRC). Therefore, in this study we firstly used Oncomine database to determine its expression in cancer tissues and found it is overexpressed in thyroid, ovarian and renal cancer, while it is opposite in lung, breast and pancreas cancer. Using qRT-PCR and western blot, we then demonstrated its overexpression in CRC tissues as compared with adjacent normal tissues (n = 20). In a retrospective cohort enrolling 190 CRC patients, we proved its expression was significantly correlated with N stage. Furthermore, high SLC34A2 expression is associated with higher postoperative metastasis rate and serves as an independent adverse factor affecting patient prognosis. In subgroup analysis, SLC34A2 expression could stratify the patient prognosis in stage II and III CRC, but failed in stage IV CRC. In cellular assays in vitro, knockdown of SLC34A2 dramatically inhibited the proliferation and colony formation, induced the apoptosis and arrests the cell cycle progression of HCT-116 CRC cells. In cellular assays in vivo, knockdown of SLC34A2 significantly inhibited the growth of xenografts, decreasing Ki-67 and proliferating cell nuclear antigen (PCNA) expression and increasing apoptosis rate. Taken together, our study indicates SLC34A2 plays a crucial promoting role in CRC development and therefore has great potential to be further developed as a reliable biomarker for CRC diagnosis and treatment.

Missing-in-metastasis B (MIM-B) combined with caveolin-1 promotes metastasis of hepatocellular carcinoma.

BACKGROUND: Increasing amounts of evidence indicate that Missing in metastasis B (MIM-B) promotes cancer metastasis. Here, we sought to better understand the mechanism through which MIM-B promotes tumor metastasis in hepatocellular carcinoma (HCC). METHODS: We performed confocal microscopy analysis to determine the distributions of MIM-B and caveolin-1 and conducted co-immunoprecipitation assays to detect the interactions between MIM-B and caveolin-1 in vitro. We performed transwell assays to analyze the invasive ability of HCC cells. Changes in the expression levels of key genes and some molecular makers were detected by immunohistochemistry and western blotting in HCC tissue samples. RESULTS: We found that MIM-B co-localizes with caveolin-1 and demonstrated that MIM-B and caveolin-1 interact in vitro. Repressing MIM-B and caveolin-1 expression inhibited the epidermal growth factor receptor signaling pathway. We overexpressed MIM-B and caveolin-1 in Hep3B cells, which enhanced Hep3B cell invasiveness. Furthermore, MHCC97H cell invasiveness was significantly decreased in cells in which MIM-B and caveolin-1 expression was inhibited. Additionally, we found that MIM-B and caveolin-1 were expressed at higher levels in HCC tissues than in paired normal tissues. Moreover, HCC patients with MIM-B and caveolin-1 up-regulation experienced significantly worse outcomes than controls (P < 0.001), and HCC patients with high MIM-B and caveolin-1 expression levels often developed pulmonary metastasis (P < 0.001). CONCLUSIONS: MIM-B combined with caveolin-1 promotes metastasis of HCC, and elevated MIM-B and caveolin-1 expression levels are associated with a poor prognosis in HCC patients; therefore, MIM-B and caveolin-1 may represent novel targets for the diagnosis and treatment of HCC.

The BET-Bromodomain Inhibitor JQ1 synergized ABT-263 against colorectal cancer cells through suppressing c-Myc-induced miR-1271-5p expression.

Colorectal cancer (CRC) cells undergo apoptosis in the presence of the small-molecule inhibitor ABT-263 by up-regulating antiapoptotic Bcl-2 family members. However, the resistance to ABT-263 gradually developed in most solid tumors due to its low affinity to Mcl-1. Here, we found the BET-Bromodomain inhibitor JQ1, when combined with ABT-263, synergistically reduced Mcl-1 protein level, induced apoptosis, and decreased cell viability in the CRC HCT-15, HT-29 and SW620 cells. The subsequent mechanism study revealed that a pathway of c-Myc/miR-1271-5p/Noxa/Mcl-1 underlies the synergistic effect of such combination treatment. We discovered that miR-1271-5p, the key mediator for the synergistic effect, is transcriptionally activated by c-Myc, and binds to the 3'-UTR of noxa to inhibit its protein production. The combination treatment of JQ1 and ABT-263 inhibited c-Myc protein level and also c-Myc-driven expression of miR-1271-5p, subsequently increased the protein level of Noxa, and finally promotes the degradation of Mcl-1. Our findings provide an alternative strategy to resolve the resistance during treatment of CRC by JQ1, and also discovered a novel miR-1271-5p-dependent regulatory mechanism for gene expression of noxa.

The chemokine CXCL9 expression is associated with better prognosis for colorectal carcinoma patients.

The chemokine CXCL9 has been demonstrated to play an important role in the development of human malignancies. However, its prognostic significance in cancer patients remains unclear and less is known about its role in colonrectal carcinoma (CRC) patients. In this study, we found that the relative mRNA expression level of CXCL9 in primary colorectal tumor tissues was significantly higher than that in corresponding normal colon tissues. CXCL9 protein expression was also detected in 102 of 130 primary CRC patients by immunochemistry. Thus, CXCL9 might play a vital role in the progression of colorectal cancer. By analyzing the correlation between clinicopathological factors of patients and expression of CXCL9 protein, we showed that the expression of CXCL9 was significantly associated with tumor differentiation, tumor invasion, lymph node metastasis, distant metastasis, and vascular invasion, but not with other factors of CRC patients including age, gender, tumor location and tumor size. Furthermore, by performing Kaplan-Meier method as well as Cox's univariate and multivariate hazard regression model, we found that the higher the CXCL9 expression, the higher overall survival rate was observed, and CXCL9 expression was a significant independent prognostic factor for CRC patients. Therefore, CXCL9 is a useful predictor of better clinical outcome in CRC patients.

MiR-145 regulates PAK4 via the MAPK pathway and exhibits an antitumor effect in human colon cells.

MicroRNAs (miRNAs) are regulators of numerous cellular events; accumulating evidence indicates that miRNAs play a key role in a wide range of biological functions, such as cellular proliferation, differentiation, and apoptosis in cancer. Down-regulated expression of miR-145 has been reported in colon cancer tissues and cell lines. The molecular mechanisms underlying miR-145 and the regulation of colon carcinogenesis remain unclear. In this study, we investigated the levels of miR-145 in human colon cancer cells using qRT-PCR and found markedly decreased levels compared to normal epithelial cells. We identified PAK4 as a novel target of miR-145 using informatics screening. Additionally, we demonstrated that miR-145 targets a putative binding site in the 3'UTR of PAK4 and that its abundance is inversely associated with miR-145 expression in colon cancer cells; we confirmed this relationship using the luciferase reporter assay. Furthermore, restoration of miR-145 by mimics in SW620 cells significantly attenuated cell growth in vitro, in accordance with the inhibitory effects induced by siRNA mediated knockdown of PAK4. Taken together, these findings demonstrate that miR-145 downregulates P-ERK expression by targeting PAK4 and leads to inhibition of tumor growth.

The prognostic significance of chemokine receptor CXCR3 expression in colorectal carcinoma.

The expression of chemokine receptor CXCR3 has been associated with tumor dissemination and poor prognosis in breast cancer patients. However, it is still unclear whether CXCR3 can be used as an independent molecular marker for predicting the prognosis of colonrectal carcinoma (CRC) patients. In this study, we found that the relative level of CXCR3 mRNA expression in primary colorectal cancer tissues was significantly higher than that in corresponding non-tumor colon tissues. CXCR3 protein expression was also detected in 98 of 112 primary CRC patients. Thus, CXCR3 might play a vital role in the progression of colorectal cancer. By analyzing the correlation between clinicopathological factors of patients and expression of CXCR3 protein, we showed that high level of CXCR3 protein expression was significantly associated with tumor differentiation, tumor size, lymph node metastasis, distant metastasis, and Dukes' classification, but not with other factors of CRC patients including gender, age, tumor location and tumor invasion. Furthermore, patients with high CXCR3 expression showed poorer overall survival than those with low CXCR3 expression. Univariate and multivariate analysis indicated that the status of CXCR3 protein expression might be an independent prognostic marker for CRC patients. Therefore, CXCR3 is an indicator of a poor prognosis and a promising target for cancer therapy in colorectal cancer.

Interleukin 1 receptor antagonist reduces lethality and intestinal toxicity of 5-Fluorouracil in a mouse mucositis model.

Chemotherapy induced intestinal mucositis is still an unmet medical problem. 5-fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra has less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy induced intestinal mucositis are warranted.

CXCL9 attenuated chemotherapy-induced intestinal mucositis by inhibiting proliferation and reducing apoptosis.

Mucositis arising from cancer chemotherapy is a common problem for which there is no definitive treatment. 5-fluorouracil (5-FU) is a common cytotoxic agent used to treat solid tumors. A global gene expression array was performed to identify genetic signals involved in the pathogenesis of mucositis. The chemokine (C-X-C motif) ligand 9 (CXCL9) was one of the candidates identified that presented a characteristic gene expression profile; its temporal expression pattern was correlated with the damage and regeneration phases of the small intestine upon 5-FU chemotherapy. We found that prophylactic CXCL9 administration was able to attenuate the severity of mucositis, weight loss and diarrhea caused by chemotherapy. CXCL9 also increased the tolerance of the mice to lethal-dose chemotherapy. Moreover, we demonstrated that CXCL9 was able to promote the proliferation and regeneration of intestinal cells by inhibiting the proliferation of normal intestinal mucosal cells prior to chemotherapy and by reducing the 5-FU-induced apoptosis in intestinal crypts. Thus, pretreatment with CXCL9 is a new and promising strategy for the alleviation of chemotherapy-induced intestinal mucositis in clinical settings.

Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice.

PURPOSE: The aim of this study was to investigate the relationship between changes in IL-1ß expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine. METHODS: Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200 mg/kg). IL-1Ra (1 mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1ß induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining. RESULTS: The variation of IL-1ß expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1ß and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice. CONCLUSIONS: Our studies elucidate that IL-1ß is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy. Administered with IL-1Ra protects mice against intestinal apoptosis induced by 5-FU, relieves mucosal impairment of the small intestine, and facilitates the recovery of the intestinal mucosa. IL-1Ra treatment offers a novel promising strategy for the prevention and cure of chemotherapy-induced intestinal mucositis in clinical practice.

Interleukin 1 receptor antagonist reduces lethality and intestinal toxicity of 5-fluorouracil in a mouse mucositis model.

Chemotherapy-induced intestinal mucositis is still an unmet medical problem. 5-Fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra had less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy-induced intestinal mucositis are warranted.