N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo.

Gastric cancer is the most common malignant tumor of the digestive tract and is great challenge in clinical treatment. N6-(2-Hydroxyethyl)-adenosine (HEA), widely present in various fungi, is a natural adenosine derivative with many biological and pharmacological activities. Here, we assessed the antineoplastic effect of HEA on gastric carcinoma. HEA exerted cytotoxic effects against gastric carcinoma cells (SGC-7901 and AGS) in a dose and time-dependent manner. Additionally, we found that HEA induced reactive oxygen species production and mitochondrial membrane potential depolarization. Moreover, it could trigger caspase-dependent apoptosis, promoting intracellular Ca2+-related endoplasmic reticulum (ER) stress and autophagy. On the other hand, HEA could significantly inhibit the growth of transplanted tumors in nude mice and induce apoptosis of tumor tissues cells in vivo. In conclusion, HEA induced apoptosis of gastric carcinoma cells in vitro and in vivo, demonstrating that HEA is a potential chemotherapeutic agent for gastric carcinoma.

Nanoparticles Encapsulated in Red Blood Cell Membranes for Near-Infrared Second Window Imaging-Guided Photothermal-Enhanced Immunotherapy on Tumors.

Photothermal therapy (PTT), which uses the high thermal conversion ability of photothermal agents to ablate tumor cells at high temperatures, has gained significant attention because it has the advantages of high selectivity and specificity, precise targeting of tumor sites, and low invasiveness and trauma. However, PTT guided by the NIR-I has limitations in tissue penetration depth, resulting in limited imaging monitoring and therapeutic effects on deep-seated tumor tissues. Moreover, nanoparticles are easily cleared by the immune system and difficult to passively target tumor sites during the process of treatment. To address these issues, we prepared nanoparticles using NIR-II dyes IR1048 and DSPE-PEG-OH and further encapsulated them in red blood cell membranes derived from mice. These biomimetic nanoparticles, called RDIR1048, showed reduced clearance by the immune system and had long circulation characteristics. They effectively accumulated at tumor sites, and strong fluorescence could still be observed at the tumor site 96 h after administration. Furthermore, through mouse thermal imaging experiments, we found that RDIR1048 exhibited good PTT ability. When used in combination with an immune checkpoint inhibitor, anti-PD-L1 antibodies, it enhanced the immunogenic cell death of tumor cells caused by PTT and improved the therapeutic effect of immunotherapy, which demonstrated good therapeutic efficacy in the treatment of tumor-bearing mice. This study provides a feasible basis for the future development of NIR-II nanoparticles with long circulation properties.

Low­dose venetoclax combined with azacitidine in older and frail patients with newly diagnosed acute myeloid leukaemia.

In the present study, the aim was to evaluate the clinical efficacy and safety of low-dose venetoclax combined with azacitidine for the treatment of older and frail patients with newly diagnosed acute myeloid leukaemia (AML). Data of 26 older patients with newly diagnosed AML admitted to Yuyao People's Hospital (Yuyao, China) between January 2021 and May 2023 were retrospectively analysed. The treatment regimens were as follows: Subcutaneous injection of 100 mg azacitidine on days 1-5 and 100 mg oral venetoclax on days 3-16 or 200 mg oral venetoclax on days 3-30. The median age of the 26 patients was 73 years. After the first course of treatment, the complete remission (CR) and CR with incomplete haematological recovery rate was 84.6%, and the objective response rate was 96.2%. The most common adverse events noted during treatment were haematological adverse events including grade 3/4 granulocytosis (57.7%), febrile neutropenia (30.8%), pulmonary infection (32.0%), thrombocytopenia (42.3%) and anaemia (42.3%). A total of 13 (50.0%) patients did not require platelet (PLT) infusion during treatment. The main non-haematological adverse reactions included gastrointestinal reactions such as nausea, vomiting and diarrhoea. Patients were followed up until December 2023, with a median follow-up time of 9.5 months (range, 1.9-26.0 months). Of the 26 patients, nine (34.6%) patients experienced relapse, with a mean recurrence time of 5.9 months. In conclusion, preliminary results indicated that low-dose venetoclax combined with azacitidine is effective and safe for the treatment of older and frail patients with newly diagnosed AML, providing a new treatment option for these patients.

CLLU1 as an emerging biomarker in chronic lymphoid leukemia.

CLLU1, a disease-specific gene associated with chronic lymphoid leukemia (CLL), is located on chromosome 12q22. Previous studies considered CLLU1 to be a non-coding RNA; however, recent research has discovered that its coding sequence region possesses the potential to encode a short peptide similar to interleukin-4. Remarkably, abnormally elevated expression of CLLU1 has only been detected in chronic lymphoid leukemia among all hematological cancers. High CLLU1 expression often indicates more malignant pathological features and an unfavorable prognosis for patients. Importantly, the expression level of CLLU1 remains unaffected by the passage of time or therapeutic interventions, thus rendering it a novel prognostic marker. This article provides a comprehensive summary of relevant research findings on CLLU1 in the context of CLL prognosis and clinical applications, aiming to guide subsequent theoretical and clinical investigations in this field.

PM2.5 induced neurotoxicity through unbalancing vitamin B12 metabolism by gut microbiota disturbance.

Fine particulate matter (PM2.5) in the atmosphere is easily accompanied by toxic and harmful substances, causing serious harm to human health, including cognitive impairment. Vitamin B12 (VitB12) is an essential micronutrient that is synthesized by bacteria and contributes to neurotransmitter synthesis as a nutrition and signaling molecule. However, the relationship between VitB12 attenuation of cognitive impairment and intestinal microbiota regulation in PM2.5 exposure has not been elucidated. In this study, we demonstrated that PM2.5 caused behavioral defects and neuronal damage in Caenorhabditis elegans (C. elegans), along with significant gene expression changes in neurotransmitter receptors and a decrease in VitB12 content, causing behavioral defects and neuronal damage in C. elegans. Methylcobalamin (MeCbl), a VitB12 analog, alleviated PM2.5-induced neurotoxicity in C. elegans. Moreover, using in vivo and in vitro models, we discovered that long-term exposure to PM2.5 led to changes in the structure of the gut microbiota, resulting in an imbalance of the VitB12-associated metabolic pathway followed by cognitive impairment. MeCbl supplementation could increase the diversity of the bacteria, reduce harmful substance contents, and restore the concentration of short-chain fatty acids (SCFAs) and neurotransmitters to the level of the control group to some degree. Here, a new target to mitigate the harm caused by PM2.5 was discovered, supplying MeCbl for relieving intestinal and intracellular neurotransmitter disorders. Our results also provide a reference for the use of VitB12 to target the adjustment of the human intestinal microbiota to improve metabolic disorders in people exposed to PM2.5.

Self-Assembled Aza-BODIPY and Iron(III) Nanoparticles for Photothermal-Enhanced Chemodynamic Therapy in the NIR-II Window.

Despite its promising potential in cancer treatment, synergistic photothermal/chemodynamic therapy remains underdeveloped with regard to the utilization of metal-organic materials under second near-infrared (NIR-II) laser excitation. Herein, we report a three-dimensional network constructed via the metal coordination between catechol-functionalized aza-boron dipyrromethenes and iron ions (ABFe), which was further encapsulated by F127 to obtain ABFe nanoparticles (NPs) for combined photothermal/chemodynamic therapy. ABFe NPs exhibited intense absorption in the NIR-II range and negligible fluorescence. Upon 1064 nm laser irradiation, ABFe NPs showed high photothermal conversion efficiency (PCE = 55.0%) and excellent photothermal stability. The results of electron spin resonance spectra and o-phenylenediamine chromaticity spectrophotometry proved that ABFe NPs were capable of generating harmful reactive oxygen species from hydrogen peroxide for chemodynamic therapy, which was promoted by photothermal performance. Notably, in vitro and in vivo experiments demonstrated the great potential of ABFe NPs in photoacoustic imaging and photothermal-enhanced chemodynamic therapy under NIR-II laser irradiation. Therefore, the current work presents a prospective NIR-II excitation therapeutic nanomedicine for combination therapy, offering a novel strategy for simultaneously achieving extended NIR absorption of aza-BODIPY and enhanced chemodynamic therapy with metal-organic materials.

Breeding and preliminarily phenotyping of a congenic mouse model with alopecia areata.

In the current study, the alopecia areata gene was introduced into the C57BL/6 (B6) mouse through repeated backcrossing/intercrossing, and the allelic homozygosity of congenic AA(tj)mice (named B6.KM-AA) was verified using microsatellites. The gross appearance, growth characteristics, pathological changes in skin, and major organs of B6.KM-AA mice were observed. Counts and proportions of CD4⁺ and CD8⁺ T lymphocytes in peripheral blood were determined by flow cytometry. Results show that congenic B6.KM-AA mice were obtained after 10 generations of backcrossing/intercrossing. B6.KM-AA mice grew slower than B6 control mice and AA skin lesions were developed by four weeks of age. The number of hair follicles was reduced, but hair structures were normal. Loss of hair during disease progression was associated with CD4⁺ and CD8⁺ T lymphocytes infiltration peri-and intra-hair follicles. No pathological changes were found in other organs except for the skin. In the peripheral blood of B6.KM-AA mice, the percentage of CD4⁺ T cells was lower and percentage of CD8⁺ T cells higher than in control mice. These findings indicate that B6.KM-AA mice are characterized by a dysfunctional immune system, retarded development and T-cell infiltration mediated hair loss, making them a promising new animal model for human alopecia areata.

[Phenotype analysis and mutant gene location of ventral yellow mouse (VY(Slac))].

The ventri-yellow pigmentation mouse (temporarily named VY(Slac)) arose spontaneously in the C57BL/6J inbred mouse strain, found and bred by Shanghai SLAC Laboratory Animal Co., Ltd. VY(Slac) presented a special phenotype marked by yellow coat on the ventral surface of neck and trunk that was without melanin deposition but maintained a normal structure. The number of melanocytes in epidermis and melanin in hair follicle of the abdominal skin of the mutant mouse were less than that of their background strain, while there was no significant difference between the dorsal skins of the two strains. This mutant phenotype was inherited as single-gene dominant inheritance, confirmed by genetic experiment, and there was no significant difference between VY(Slac) and B(6) for other biological parameters such as weight, anatomic and histological structures of major organs and blood physiology. When the linkage relationship between the genomic DNA samples of F(2) 48 mice (VY(Slac)D(2)F(1)×D(2)) and mutant phenotype were evaluated, the mutant gene was confirmed on chromosome 2 near D2Mit229. New microsatellite and SNP markers were selected to amplify genomic DNA samples of 196 F(2) mice and the mutant gene was narrowed down to 5.3 Mb region between rs13476833 and rs27310903 on chromosome 2. The preliminary results of our phenotype analysis and gene location provides a solid basis for further identification of this mutant gene.