APOBEC3A suppresses cervical cancer via apoptosis.

Background: Family members of Apolipoprotein B mRNA-editing enzyme catalytic 3 (APOBEC3) play critical roles in cancer evolution and development. However, the role of APOBEC3A in cervical cancer remains to be clarified. Methods: We used bioinformatics to investigate APOBEC3A expression and outcomes using The Cancer Genome Atlas (TCGA)-cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) dataset, GTEx, and GSE7803. Immunohistochemistry was then used to identify APOBEC3A's expression pattern. We performed Cell Counting Kit-8, wound-healing, Transwell, and flow cytometry assays to measure proliferation, migration, invasion, and apoptosis, respectively, using the SiHa and HeLa cell lines transfected with APOBEC3A. BALB/c nude mice were used to investigate the effects of APOBEC3A in vivo. The phosphorylated gamma-H2AX staining assay was applied to measure DNA damage. RNA sequencing (RNA-Seq) was applied to explore APOBEC3A-related signaling pathways. Results: APOBEC3A was more significantly expressed in cancer tissues than in adjacent normal tissues. Higher expression of APOBEC3A was associated with better outcomes in TCGA-CESC and GTEx. Immunohistochemistry showed that the expression of APOBEC3A was significantly higher in cancer tissues than in normal tissues. Transfection experiments showed that APOBEC3A inhibited proliferation, upregulated S-phase cells, inhibited migration and invasion, induced DNA damage, and promoted apoptosis. Overexpression of APOBEC3A inhibited tumor formation in the mouse model. RNA-seq analysis showed that ectopic expression of APOBEC3A inhibited several cancer-associated signaling pathways. Conclusions: APOBEC3A is significantly upregulated in cervical cancer, and higher expression of APOBEC3A is associated with better outcomes. APOBEC3A is a tumor suppressor whose overexpression induces apoptosis in cervical cancer.

The efficacy and safety of different systemic combination therapies on advanced hepatocellular carcinoma: a systematic review and meta-analysis.

Background and aims: Systemic combinations have recently brought significant therapeutic benefits for advanced hepatocellular carcinoma (aHCC). To design the most effective combination regimens, a systematic review (PROSPERO ID: CRD42022321949) was conducted to evaluate the efficacy and safety of systemic combinations on aHCC. Methods: We retrieved all the studies from PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Infrastructure (CNKI) using the Medical Subject Headings (MeSH) terms until December 21, 2022. The effect indicators (hazard ratio [HR], relative risk [RR], and median) were pooled by a fixed- or random-effects model. A subgroup analysis was conducted according to types and specific therapies. Results: In total, 88 eligible studies were selected from 7249 potential records. Each kind of combination treatment (chemotherapy plus chemotherapy, targeted plus immune checkpoint inhibitor (ICI) therapy, targeted plus chemotherapy, and targeted plus targeted therapy) had a better objective response rate (ORR) in patients with aHCC, compared to the monotherapy mostly with sorafenib (RR: 1.57 [1.44-1.71]; I 2 = 30%). Of those, targeted plus ICI therapy showed better therapeutic efficiency in overall survival (median: 15.02 [12.67-17.38]), progression-free survival (median: 7.08 [6.42-7.74]), and ORR (RR: 1.81 [1.55-2.13]), compared to the monotherapy. Specifically, Atezo plus Beva showed all those benefits. Our pooled result showed all the combinations had increased ≥3 Grade treatment-related adverse events (TrAEs), with an RR of 1.25 [95% CI: 1.15-1.36], compared to the monotherapy. Conclusion: The systemic combinations, especially targeted plus ICI therapy, including Atezo plus Beva, significantly improve clinical outcomes but increase side effects in patients with aHCC. Future trials should concentrate on improvement in therapeutic efficiency and reduction of toxicity of targeted plus ICI therapy. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022321949.

Monkfish (Lophius litulon) Peptides Ameliorate High-Fat-Diet-Induced Nephrotoxicity by Reducing Oxidative Stress and Inflammation via Regulation of Intestinal Flora.

BACKGROUND: Renal damage and intestinal flora imbalance due to lipotoxicity are particularly significant in terms of oxidative stress and inflammation, which can be alleviated with bioactive peptides. The monkfish (Lophius litulon) is rich in proteins, which can be used as a source of quality bioactive peptides. This study aimed to examine the protective effect of monkfish peptides on renal injury and their potential role in regulating gut microbiota. METHODS: Monkfish meat was hydrolyzed using neutral protease and filtered, and the component with the highest elimination rate of 2,2-diphenyl-1-picrylhydrazyl was named lophius litulon peptides (LPs). Lipid nephrotoxicity was induced via high-fat diet (HFD) feeding for 8 weeks and then treated with LPs. Oxidative stress, inflammatory factors, and intestinal flora were evaluated. RESULTS: LP (200 mg/kg) therapy reduced serum creatinine, uric acid, and blood urea nitrogen levels by 49.5%, 31.6%, and 31.6%, respectively. Renal vesicles and tubules were considerably improved with this treatment. Moreover, the activities of superoxide dismutase, glutathione peroxidase, and total antioxidant capacity increased significantly by 198.7%, 167.9%, 61.5%, and 89.4%, respectively. LPs attenuated the upregulation of HFD-induced Toll-like receptor 4 and phospho-nuclear factor-kappa B and increased the protein levels of heme oxygenase 1, nicotinamide quinone oxidoreductase 1, and nuclear factor erythroid 2-related factor 2. The dysbiosis of intestinal microbiota improved after LP treatment. CONCLUSIONS: LPs significantly improve antioxidant activity, reduce inflammatory cytokine levels, and regulate intestinal dysbiosis. Thus, LPs are potential compounds that can alleviate HFD-induced renal lipotoxicity.

A dicyanomethylene-4H-pyran-based fluorescence probe with high selectivity and sensitivity for detecting copper (II) and its bioimaging in living cells and tissue.

Copper (Cu) plays a significant role in the process of oxygenic photosynthesis in living systems. The detection of copper ion (Cu2+) is valuable and meaningful for further investigating the functions of Cu2+ under physiological and pathological conditions. In this paper, a novel fluorescence probe DCM-Cu based on the near-infrared (NIR) fluorophore dicyanomethylene-4H-pyran (DCM) was designed for Cu2+ detection. The probe DCM-Cu possessed characteristic of "turn-on" fluorescent signal in the presence of Cu2+ through the enhanced ICT process. It exhibited satisfactory sensitivity and selectivity toward Cu2+. A good linear correlation was observed between the concentrations of Cu2+ and the fluorescence intensities at 700 nm. The detection limit (LOD) of DCM-Cu toward Cu2+ was calculated to be 2.54 × 10-8 M. Importantly, DCM-Cu was successfully applied in the detection of Cu2+ in living MCF-7 cells and tumor tissue with low cytotoxicity. Therefore, this probe would have the potential to monitor cellular Cu2+ in the living system and be applied to the diagnosis of related diseases.

Computational characterization of double reduction in autotetraploid natural populations.

Population genetic theory has been well developed for diploid species, but its extension to study genetic diversity, variation and evolution in autopolyploids, a class of polyploids derived from the genome doubling of a single ancestral species, requires the incorporation of multisomic inheritance. Double reduction, which is characteristic of autopolyploidy, has long been believed to shape the evolutionary consequence of organisms in changing environments. Here, we develop a computational model for testing and estimating double reduction and its genomic distribution in autotetraploids. The model is implemented with the expectation-maximization (EM) algorithm to dissect unobservable allelic recombinations among multiple chromosomes, enabling the simultaneous estimation of allele frequencies and double reduction in natural populations. The framework fills an important gap in the population genetic theory of autopolyploids.

The improved targeting of an aspirin prodrug albumin-based nanosystem for visualizing and inhibiting lung metastasis of breast cancer.

Lung metastasis is the principal reason for the majority of deaths from breast cancer. The nonsteroidal anti-inflammatory drug aspirin can prevent lung metastasis in breast tumors via inhibiting heparanase. However, the lack of specific targets and limited accumulation at the site of the tumor have thus far hindered the use of aspirin in oncotherapy. In this study, we developed the nanoplatform FA-BSA@DA and loaded it with the versatile aspirin prodrug DA to visualize and inhibit breast cancer metastasis via targeting heparanase. This nanosystem can be effectively targeted to folic acid (FA)-positive tumor cells, and would then subsequently release a high dose of DA, whose ester bond is specifically ruptured by H2O2 in the tumor microenvironment to afford the therapeutic drug aspirin and near-infrared (NIR) fluorescent reporter DCM. The released aspirin can effectively prevent breast cancer lung metastasis through the inhibition of heparanase activity, and the NIR fluorescent signals emitted from DCM can be used to monitor and evaluate the metastasis levels of breast cancer. Our results showed that the expression of heparanase was significantly decreased, and lung metastasis from breast cancer was effectively monitored and inhibited after treatment with FA-BSA@DA. Furthermore, the collaborative therapy nanoplatform FA-BSA@DA/DOX exhibited strong therapeutic effects in the treatment of breast cancer in vitro and in vivo via the introduction of doxorubicin (DOX) to the system, which resulted in an even stronger result due to its synergistic effects with aspirin. This heparanase-reliant strategy has profound significance for the extended development of nanoplatforms based on versatile aspirin prodrugs, which may offer a solution to clinically prevent breast cancer recurrence and lung metastasis.

A FRET-based upconversion nanoprobe assembled with an electrochromic chromophore for sensitive detection of hydrogen sulfide in vitro and in vivo.

Hydrogen sulfide (H2S) as an important gaseous signaling molecule is closely related to numerous biological processes in living systems. To further study the physiological and pathological roles of H2S, convenient and efficient detection techniques for endogenous H2S in vivo are still in urgent demand. In this study, an electrochromic chromophore, dicationic 1,1,4,4-tetra-aryl butadiene (EM1), was innovatively introduced into upconversion nanoparticles (UCNPs) and a nanoprobe, PAAO-UCNPs-EM1, was constructed for the detection of H2S. This nanosystem was made of core-shell upconversion nanoparticles (NaYF4:Yb,Tm@NaYF4:Yb,Er), EM1, and polyacrylic acid (PAA)-octylamine. The EM1 with strong absorption ranging from 500 to 850 nm could serve as an energy acceptor to quench the upconversion luminescence of UCNPs through the Förster resonance energy transfer (FRET) process. In the presence of H2S, the EM1 in the nanoprobe was reduced to a colorless diene (EM2), resulting in the linear enhancement of luminescence emissions at 660 nm and 800 nm under the excitation of 980 nm light because the FRET was switched off. The nanoprobe PAAO-UCNPs-EM1PAAO-UCNPs-EM1 exhibited fast response and high sensitivity to H2S with a LoD of 1.21 × 10-7 M. Moreover, it was successfully employed in detecting the endogenous and exogenous H2S in living cells with high selectivity and low cytotoxicity. Also, this nanoprobe could distinguish normal and tumor cells by an upconversion luminescence imaging of endogenous H2S. Furthermore, the nanoprobe could significantly monitor H2S in a tumor-bearing nude mouse model. Therefore, we anticipate that this novel nanoprobe assembled with an electrochromic chromophore for responding to H2S and for bioimaging this molecule would have a promising prospect in biological and clinical investigations.

Spinal somatostatin-positive interneurons transmit chemical itch.

Recent studies have made significant progress in identifying distinct populations of peripheral neurons involved in itch transmission, whereas the cellular identity of spinal interneurons that contribute to itch processing is still a debate. Combining genetic and pharmacological ablation of spinal excitatory neuronal subtypes and behavioral assays, we demonstrate that spinal somatostatin-positive (SOM) excitatory interneurons transmit pruritic sensation. We found that the ablation of spinal SOM/Lbx1 (SOM) neurons caused significant attenuation of scratching responses evoked by various chemical pruritogens (chemical itch). In an attempt to identify substrates of spinal itch neural circuit, we observed that spinal SOM neurons partially overlapped with neurons expressing natriuretic peptide receptor A (Npra), the receptor of peripheral itch transmitter B-type natriuretic peptide. Spinal SOM neurons, however, did not show any overlap with itch transmission neurons expressing gastrin-releasing peptide receptor in the dorsal spinal cord, and the gastrin-releasing peptide-triggered scratching responses were intact after ablating spinal SOM neurons. Dual ablation of SOM and Npra neurons in the spinal cord reduced chemical itch responses to a greater extent than ablation of SOM or Npra neurons alone, suggesting the existence of parallel spinal pathways transmitting chemical itch. Furthermore, we showed that SOM peptide modulated itch processing through disinhibition of somatostatin receptor 2A-positive inhibitory interneuron. Together, our findings reveal a novel spinal mechanism for sensory encoding of itch perception.