Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer.

Mitochondriopathy inspired adenosine triphosphate (ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration (IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites, leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages. Briefly, the reported transformable nucleopeptide (NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei, which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines (T24, EJ and RT-112) revealed that the half-maximal inhibitory concentration (IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.

In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy.

Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a prominent therapeutic strategy for tumor suppression. However, the wide application of GPX4 inhibitors in tumor therapy is hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-assembly, we develop a peptide-ferriporphyrin conjugate with tumor microenvironment specific activation to improve tumor penetration, endocytosis and GPX4 inhibition, ultimately enhancing its anticancer activity via ferroptosis. Briefly, a GPX4 inhibitory peptide is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferriporphyrin to produce the peptide-ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenvironment of the tumor, the Gi-F-CAA self-assembles into large nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of CAA, improving tumor endocytosis efficiency. Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (AEB) effect, augmenting the oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our findings suggest that this peptide-ferriporphyrin conjugate design with AEB effect can improve the therapeutic effect via induction of ferroptosis, providing an alternative strategy for overcoming chemoresistance.

An In Vivo Self-Assembled Bispecific Nanoblocker for Enhancing Tumor Immunotherapy.

Anti-PD-L1 monoclonal antibody has achieved substantial success in tumor immunotherapy by T-cells activation. However, the excessive accumulation of extracellular matrix components induced by unsatisfactory T-cells infiltration and poor tumor penetration of antibodies make it challenging to realize efficient tumor immunotherapy. Herein, a peptide-based bispecific nanoblocker (BNB) strategy is reported for in situ construction of CXCR4/PD-L1 targeted nanoclusters on the surface of tumor cells that are capable of boosting T-cells infiltration through CXCR4 blockage and enhancing T-cells activation by PD-L1 occupancy, ultimately realizing high-performance tumor immunotherapy. Briefly, the BNB strategy selectively recognizes and bonds CXCR4/PD-L1 with deep tumor penetration, which rapidly self-assembles into nanoclusters on the surface of tumor cells. Compared to the traditional bispecific antibody, BNB exhibits an intriguing metabolic behavior, that is, the elimination half-life (t1/2 ) of BNB in the tumor is 69.3 h which is ≈50 times longer than that in the plasma (1.4 h). The higher tumor accumulation and rapid systemic clearance overcome potential systemic side effects. Moreover, the solid tumor stress generated by excessive extracellular matrix components is substantially reduced to 44%, which promotes T-cells infiltration and activation for immunotherapy efficacy. Finally, these findings substantially strengthen and extend clinical applications of PD-1/PD-L1 immunotherapy.

Spatial genetic patterns and distribution dynamics of Begonia grandis (Begoniaceae), a widespread herbaceous species in China.

Introduction: Begonia L., one of the 10 largest plant genera, contains over 2,100 species, most of which have a very limited distribution range. Understanding the spatial genetic structure and distribution dynamics of a widespread species in this genus will contribute to clarifying the mechanism responsible for Begonia speciation. Methods: In this study, we used three chloroplast DNA markers (ndhF-rpl32, atpI-atpH, and ndhA intron), coupled with species distribution modeling (SDM), to investigate the population genetic structure and distribution dynamics of Begonia grandis Dryand., the species of Begonia with the widest distribution in China. Results: Thirty-five haplotypes from 44 populations clustered into two groups, and haplotype divergence began in the Pleistocene (1.75 Mya). High genetic diversity (H d = 0.894, H T = 0.910), strong genetic differentiation (F ST = 0.835), and significant phylogeographical structure (G ST/N ST = 0.848/0.917, P < 0.05) were observed. The distribution range of B. grandis migrated northwards after the last glacial maximum, but its core distribution area remained stable. Discussion: Combined, the observed spatial genetic patterns and SDM results identified the Yunnan-Guizhou Plateau, the Three Gorges region, and the Daba Mountains as potential refugia of B. grandis. BEAST-derived chronogram and haplotype network analysis do not support the Flora Reipublicae Popularis Sinicae and Flora of China for subspecies classification based on morphological characteristics. Our results support the hypothesis that population-level allopatric differentiation may be an important speciation process for the Begonia genus and a key contributor to its rich diversity.

Protective Effects of Allicin on ISO-Induced Rat Model of Myocardial Infarction via JNK Signaling Pathway.

OBJECTIVE: This research was aimed to explore protective effects of allicin on rat model of myocardial infarction via JNK signaling pathway. METHODS: Rat myocardial ischemia model was established with subcutaneous injection of isoproterenol (ISO). Seventy-five rats were randomly divided into 5 groups (n = 15): sham group, ISO group, low-dose group (1.2 mg/kg/days for 7 days), medium-dose group (1.8 mg/kg/days for 7 days), and high-dose group (3.6 mg/kg/days for 7 days). Routine HE staining and Masson staining were performed to observe myocardial histopathology. The expression of oxidative stress-related indicators, heart tissue apoptosis-related proteins, and JNK and p-JNK proteins were measured for different groups. RESULTS: Compared with the sham group, the T wave value of the ISO group was significantly increased (p < 0.01). When allicin was administered, the T wave values at different time points in all groups were all decreased. Compared with the sham group, the ratio of eNOS, Bcl-2/Bax was significantly decreased, and p-eNOS, iNOS, caspase-3, caspase-9, and Cyt-c were significantly elevated in the ISO group (p < 0.05). After allicin was administered, significant changes in these proteins were observed in the medium- and high-dose groups. There was no significant change in the expression of JNK protein in the ISO group compared with the sham group; however, the expression of eNOS and p-JNK protein were significantly upregulated (p < 0.01) and the expression of p-eNOS and iNOS were significantly downregulated (p < 0.01). When allicin was administered, expression of p-JNK protein was significantly downregulated. CONCLUSION: Allicin can reduce oxidative stress damage and cardiomyocyte apoptosis in rat model of myocardial infarction and can significantly regulate JNK signaling pathway.

Low-Dose Mitomycin C Decreases the Postoperative Recurrence Rate of Pterygium by Perturbing NLRP3 Inflammatory Signalling Pathway and Suppressing the Expression of Inflammatory Factors.

A pterygium is generally believed to be a chronic inflammatory lesion caused by external stimuli that develops from the conjunctiva and grows onto the cornea. Simple bare sclera excision is the most commonly used method to treat pterygium. However, the high postoperative recurrence rate of pterygium remains a persistent challenge. Mitomycin C (MMC) is an antineoplastic antibiotic that inhibits DNA, RNA, and protein synthesis. In recent years, although MMC has proven useful for the treatment of pterygium, its application has been controversial because of its clear toxicity and the possibility of ocular complications. In the current study, we prospectively recruited patients to receive or not receive a local injection of MMC (0.4 mg/ml). Follow-up was conducted with the patients to determine the postoperative recurrence rate of pterygium and/or to observe any ocular complications. The remarkable results demonstrated that MMC can decrease the postoperative recurrence rate of pterygium without leading to serious eye complications. Further results indicated that MMC can inhibit the activation of the NLRP3 inflammatory signalling pathway and thus downregulate the expression of downstream molecules, including IL-18 and IL-1ß. MMC also reduced the expression of inflammatory factors TGF-ß1, VEGF, and IL-6. In addition to influencing these factors, MMC suppressed neovascularization and the proliferation of corneal fibroblasts to effectively reduce the recurrence rate of pterygium. Taken together, our results provide a theoretical basis for the development of prevention and treatment strategies for pterygium and suggest that MMC is highly effective as an adjunctive treatment after excision of primary pterygia.

Baicalein Protects Rats with Diabetic Cardiomyopathy Against Oxidative Stress and Inflammation Injury via Phosphatidylinositol 3-Kinase (PI3K)/AKT Pathway.

BACKGROUND The aim of this study was to explore the effect of baicalein on diabetic cardiomyopathy (DCM) rats and the mechanisms involved, and to determine the theoretical basis for clinical anti-tumor therapy. MATERIAL AND METHODS DCM rat model was induced with a single injection of streptozotocin. Then, DCM rats were treated with baicalein alone or co-treated with baicalein and PI3K/Akt inhibitor. Myocardial pathological changes were detected by HE and Masson staining. The activities of SOD, GSH-Px, and MDA in myocardial tissue were measured by biochemical tests. The levels of TNF-α, IL-1ß, and cTn-I were examined by ELISA. NADP+/NADPH ratio was measured with the NADP+/NADPH assay kit. RT-PCR was used to detect the levels of PI3K and Akt. The levels of Bax, Bcl-2, Caspase-3, GSK-3ß, PI3K, and Akt were detected by Western blot. RESULTS Baicalein could improve pathological injury. SOD and GSH-Px activity decreased while the level of MDA increased in myocardial tissue. Baicalein treatment enhanced SOD activity in a dose-dependent manner but markedly reduced MDA. Similar changes were observed in both serum inflammatory factors and the NADP+/NADPH ratio. After adding PI3K-Akt inhibitor, the levels of PI3K and Akt mRNA expression were significantly decreased, but were not significantly different from the DCM group. Levels of Bcl-2, PI3K, p-GSK-3ß/GSK-3ß, and p-Akt were decreased in the DCM group, while the levels of Bax and Caspase-3 were obviously increased. CONCLUSIONS Baicalein can protect DCM rats against damage from oxidative stress and inflammation in myocardial tissue, and PI3K/Akt signaling pathway may be involved to mediating these effects.