Kupffer cells (KCs), as residents and sentinels of the liver, are involved in the formation of hepatic fibrosis (HF). However, the biological functions of circular RNAs (circRNAs) in KCs to HF have not been determined. In this study, the expression levels of circRNAs, microRNAs, and messenger RNAs (mRNAs) in KCs from a mouse model of HF mice were investigated using microarray and circRNA-Seq analyses. circDcbld2 was identified as a candidate circRNA in HF, as evidenced by its up-regulation in KCs. Silver staining and mass spectrometry showed that Wtap and Igf2bp2 bind to cirDcbld2. The suppression of circDcbld2 expression decreased the KC inflammatory response and oxidative stress and inhibited hepatic stellate cell (HSCs) activation, attenuating mouse liver fibrogenesis. Mechanistically, Wtap mediated the N ⁶-methyladenosine (m6A) methylation of circDcbld2, and Igf2bp2 recognized m6A-modified circDcbld2 and increased its stability. circDcbld2 contributes to the occurrence of HF by binding miR-144-3p/Et-1 to regulate the inflammatory response and oxidative stress. These findings indicate that circDcbld2 functions via the m6A/circDcbld2/miR-144-3p/Et-1 axis and may act as a potential biomarker for HF treatment.

Tumors exhibit abnormal glucose metabolism, consuming excessive glucose and excreting lactate, which constructs a tumor microenvironment that facilitates cancer progression and disrupts immunotherapeutic efficacy. Currently, tumor glucose metabolic dysregulation to reshape the immunosuppressive microenvironment and enhance immunotherapy efficacy is emerging as an innovative therapeutic strategy. However, glucose metabolism modulators lack specificity and still face significant challenges in overcoming tumor delivery barriers, microenvironmental complexity, and metabolic heterogeneity, resulting in poor clinical benefit. Nanomedicines, with their ability to selectively target tumors or immune cells, respond to the tumor microenvironment, co-deliver multiple drugs, and facilitate combinatorial therapies, hold significant promise for enhancing immunotherapy through tumor glucose metabolic reprogramming. This review explores the complex interactions between tumor glucose metabolism-specifically metabolite transport, glycolysis processes, and lactate-and the immune microenvironment. We summarize how nanomedicine-mediated reprogramming of tumor glucose metabolism can enhance immunotherapy efficacy and outline the prospects and challenges in this field.

Tumor recurrence and metastasis is the leading cause of mortality for postoperative breast cancer patients. However, chemotherapy intervention after surgery is often unsatisfactory, because residual microtumors are difficult to target and require frequent administration. Here, an all-in-one and once-for-all drug depot based on in situ-formed hydrogel was applied to fit the irregular surgical trauma, and enable direct contact with residual tumors and sustained drug release. Our immunological analysis after resection of orthotopic breast tumor revealed that postsurgical activation of CXCR4-CXCL12 signal exacerbated the immunosuppression and correlated with adaptive upregulation of PD-L1 in recurrent tumors. Thus, a multifunctional hydrogel toolkit was developed integrating strategies of CXCR4 inhibition, immunogenicity activation and PD-L1 blockade. Our results showed that the hydrogel toolkit not only exerted local effect on inhibiting residual tumor cell "seeds" but also resulted in abscopal effect on disturbing pre-metastatic "soil". Furthermore, vaccine-like effect and durable antitumor memory were generated, which resisted a secondary tumor rechallenge in 100% cured mice. Strikingly, one single dose of such modality was able to eradicate recurrent tumors, completely prevent pulmonary metastasis and minimize off-target toxicity, thus providing an effective option for postoperative intervention.

Multidrug resistance (MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here, based on the previous research of -(2-hydroxypropyl)methacrylamide (HPMA) polymer-drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin (Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide (MPP) and then attached to (HPMA) copolymers (P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species (ROS) as well as reduction of adenosine triphosphate (ATP) production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.

Objective To observe the migration ofmesenchymal stem cells (MSCs) transfected with recombinant lentiviral vectors carried brain derived neurotrophic factor (BDNF) gene from lateral ventricle to intracerebral hemorrhage stove in rats and to discuss the protective effect of BDNF on MSCs.Methods Intracerebral hemorrhagic models were constructed in 60 SD rats and randomly divided into 4 groups:phosphate buffer solution (PBS) group,BMSCs group,BMSCs-enhanced green fluorescent protein (EGFP) group and BMSCs-EGFP-BDNF group (n=15); PBS,BMSCs,lentiviral vector (LV)carried EGFP and LV carried BDNF-EGFP were,respectively,injected into the lateral cerebral ventricle of each group; 7,14 and 21 d after the injection,BDNF protein expression in the BMSCs of each group was detected by Western blotting and immunofluorescence; the migration of BMSCs from lateral ventricle to intracerebral hemorrhage stove was observed by signal labeling immunofluorescent staining.Results Western blotting and immunofluorescence showed that the BDNF protein expression in the MSCs-EGFP-BDNF group was significantly higher than that in the MSCs group and MSCs-EGFP group (P＜0.05); signal labeling immunofluorescent staining of brain tissue section indicated that the MSCs-EGFP-BDNF group had significantly larger number of BMSCs-positive cells which migrated to the surrounding issues of intracerebral hemorrhage stove than MSCs group and MSCs-EGFP group (P＜0.05),while there were no significant differences between the latter two except on the 7th d of establishment of models.Conclusion BMSCs modified with recombinant LV carried BDNF gene have high expression level of BDNF,indicating that BDNF performs a protective effect on BMSCs.

Objective To observe the curative effect of transplantation of mesenchymal stem cells (MSCs) transfected with recombinant lentiviral vectors carrying brain-derived neurotrophic factor (BDNF) gene on intracerebral hemorrhage in rats.Methods MSCs were isolated from the rat bone marrow,cultured and transfected by recombinant lentiviral vectors carrying BDNF gene.Intracerebral hemorrhagic models were constructed and randomly divided into 4 groups:phosphate buffered saline transplanted (PBS) group,MSCs group,mesenchymal stem cells transfected with empty lentiviral vectors transplanted (MSCs-EGFP) group and mesenchymal stem cells transfected with recombinant lentiviral vectors carrying brain-derived neurotrophic factor gene transplanted (MSCs-EGFP-BDNF) group.PBS and MSCs were transplanted according to the groups 72 hours after the establishment of models.The improvements of the neurological function were recorded of each group 7 d,14 d,and 21 d after the transplantation.Double labeling immunofluorescent staining were used to detect the migration and the differentiation of transplanted MSCs.Results MSCs-EGFP-BDNF group had significant higher levels of BDNF gene and protein expression than MSCs group and MSCs-EGFP group.All MSCs transplanted groups (MSCs groups:7 d:1.6 ±0.2,14 d:1.2 ±0.3,21 d:0.8 ±0.2; MSCs-EGFP groups:7 d:1.6 ±0.3,14 d:1.1 ±0.2,21 d:0.8 ±0.3; MSCs-EGFP-BDNFgroup:7 d:1.2 ±0.3,14 d:0.6 ±0.1,21 d:0.2±0.2) had more improvements in the neural function (F=6.667,18.417,20.882,all P ＜0.05) than PBS group(7 d:2.0 ±0.4,14 d:1.7 ±0.2,21 d:1.3 ±0.2),and MSCs-EGFP-BDNF group had the most significant improvement.With double labeling immunofluorescent staining,the MSCs-EGFP-BDNF group had significantly higher positive rates of glial fibrilary acidicprotein,neuron specific nuclear protein,2',3 '-cyclic nucleotide 3'-phosphodiesterase than MSCs group and MSCs-EGFP group,while there was no significant differences between the latter two.Conclusions The expression levels of gene and protein are higher for the MSCs modified with recombinant lentiviral vectors carrying BDNF gene.The modified MSCs can migrate to the perihematomal brain issue of intracerebral hemorrhage,express the characteristic molecules of neurons and improve the neural function after intracerebral hemorrhage.

[Objective] To observe levels of plasma endothelin (ET) and calcitonin gene - related peptide (CGRP) in rats with myocardial hypertrophic heart failure affected by Yang Xin Kang (composed of Radix Ginseng, Radix Ophio-pogonis, Radix flicis Pubescetis, etc.) and its mechanism. [Methods] Rat models with myocardial hypertrophic heart failure was established by subcutaneous injection of isoprenaline for 13 days. Fifty rats were allocated to five groups: normal control (Group A), model (Group B), digoxin (Group C), high dosage of Yang Xin Kang (Group D) and low dosage of Yang Xin Kang (Group E). ET and CGRP levels were measured by radioimmunoassay method. [Results] ET level in Group B was higher and CGRP level lower than those in Group A (P

[Objective] To investigate the effect of Bao Xin Kang (BXK) on levels of cyclic adenosine monophosphate (cGMP) and cyclic guanosine monophosphate (cAMP) in vascular smooth muscle of rats with myocatdial hypertrophic heart failure and to explore its mechanism. [Methods] Fifty rats were randomly allocated to five groups: normal control group (Group A) , model group (Group B) , digoxin group (Group C), large - dose BXK group (Group D) and small - dose BXK group (Group E). Rat models with myocardial hypertrophic heart failure were established by subcutaneous injection of isoprenaline for 13 days. Radioimmunoassay was used to measure the levels of cAMP, cGMP and the ratio of cAMP/cGMP in vascular smooth muscle. The body weight and the weight of heart, liver and lung were measured and his-tomorphologic features of heart, liver and lung also examined. [Results] The levels of cAMP and cGMP and the heart index (heart weight /body weight) and the liver index (liver weight/body weight) in Group B were increased as compared with those in Group A (P