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Diabetes increases the risk of cardiovascular diseases. Berberine (BBR), an isoquinoline alkaloid used in Chinese medicine, exerts anti-diabetic effect by lowering blood glucose and regulating lipid metabolism. It has been reported that BBR decreases mortality in patients with chronic congestive heart failure. However, the molecular mechanisms of these beneficial effects are incompletely understood. In the present study, we sought to determine whether BBR exerts cardioprotective effect against ischemia/reperfusion (I/R) injury in diabetic rats and the underlying mechanisms. Male Sprague-Dawley rats were injected with low dose streptozotocin and fed with a high-fat diet for 12 weeks to induce diabetes. The diabetic rats were intragastrically administered with saline or BBR (100, 200 and 400 mg/kg/d) starting from week 9 to 12. At the end of week 12, all rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. BBR significantly improved the recovery of cardiac systolic/diastolic function and reduced myocardial apoptosis in diabetic rats subjected to myocardial I/R. Furthermore, in cultured neonatal rat cardiomyocytes, BBR (50 μmol/L) reduced hypoxia/reoxygenation-induced myocardial apoptosis, increased Bcl-2/Bax ratio and decreased caspase-3 expression, together with enhanced activation of PI3K–Akt and increased adenosine monophosphate-activated protein kinase (AMPK) and eNOS phosphorylation. Pretreatment with either PI3K/Akt inhibitor wortmannin or AMPK inhibitor Compound C blunted the anti-apoptotic effect of BBR. Our findings demonstrate that BBR exerts anti-apoptotic effect and improves cardiac functional recovery following myocardial I/R via activating AMPK and PI3K–Akt–eNOS signaling in diabetic rats.

Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice ( Gch1 fl/fl ; Sftpa1-Cre +/− mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice ( Gch1 lsl/lsl ; Sftpa1-Cre +/− mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury. Radiation-induced Lung Injury Mitigated by GCH1-Mediated ROS Regulation Radiation therapy for cancer can harm healthy tissues, causing swelling and oxidative stress (an imbalance between free radicals and antioxidants in your body). This research examined the part of a molecule named tetrahydrobiopterin (BH4) in this. The scientists discovered that radiation therapy decreases the amount of BH4 in the body, which then leads to a rise in harmful reactive oxygen species (ROS - molecules that can damage cells). However, when BH4 amounts were artificially boosted, this lowered ROS levels and shielded against radiation-caused harm. This implies that BH4 might be used as a treatment to guard against the damaging side effects of radiation therapy. More research is required to further investigate this potential in clinic. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

The extensive application of nuclear technology has increased the potential of uncontrolled radiation exposure to the public. Since skin is the largest organ, radiation‐induced skin injury remains a serious medical concern. Organisms evolutionally develop distinct strategies to protect against environment insults and the related research may bring novel insights into therapeutics development. Here, 26 increased peptides are identified in skin tissues of frogs (Pelophylax nigromaculatus) exposed to electron beams, among which four promoted the wound healing of irradiated skin in rats. Specifically, radiation‐induced frog skin peptide‐2 (RIFSP‐2), from histone proteolysis exerted membrane permeability property, maintained cellular homeostasis, and reduced pyroptosis of irradiated cells with decreased TBK1 phosphorylation. Subsequently, stearyl‐CoA desaturase 1 (SCD1) is identified, a critical enzyme in biogenesis of monounsaturated fatty acids (MUFAs) as a direct target of RIFSP‐2 based on streptavidin‐biotin system. The lipidomic analysis further assured the restrain of MUFAs biogenesis by RIFSP‐2 following radiation. Moreover, the decreased MUFA limited radiation‐induced and STING‐mediated inflammation response. In addition, genetic depletion or pharmacological inhibition of STING counteracted the decreased pyroptosis by RIFSP‐2 and retarded tissue repair process. Altogether, RIFSP‐2 restrains radiation‐induced activation of SCD1‐MUFA‐STING axis. Thus, the stress‐induced amphibian peptides can be a bountiful source of novel radiation mitigators. Radiation‐induced skin injury remains a serious medical concern. The radiation induced frog skin peptide‐2 (RIFSP‐2), identified in this study exerts membrane permeability property and accelerates tissue repair process of irradiated skin tissues. Mechanically, RIFSP‐2 directly interacts with SCD1 and restrains biogenesis of MUFAs, which further limits the STING‐mediated phosphorylation of TBK1 and subsequently the inflammatory cell injury of irradiated cells.

Overexposure to ultraviolet light (UV) has become a major dermatological problem since the intensity of ultraviolet radiation is increasing. As an adaption to outside environments, amphibians gained an excellent peptide‐based defense system in their naked skin from secular evolution. Here, we first determined the adaptation and resistance of the dark‐spotted frogs (Pelophylax nigromaculatus) to constant ultraviolet B (UVB) exposure. Subsequently, peptidomics of frog skin identified a series of novel peptides in response to UVB. These UV‐induced frog skin peptides (UIFSPs) conferred significant protection against UVB‐induced death and senescence in skin cells. Moreover, the protective effects of UIFSPs were boosted by coupling with the transcription trans‐activating (TAT) protein transduction domain. In vivo, TAT‐conjugated UIFSPs mitigated skin photodamage and accelerated wound healing. Transcriptomic profiling revealed that multiple pathways were modulated by TAT‐conjugated UIFSPs, including small GTPase/Ras signaling and MAPK signaling. Importantly, pharmacological activation of MAPK kinases counteracted UIFSP‐induced decrease in cell death after UVB exposure. Taken together, our findings provide evidence for the potential preventive and therapeutic significance of UIFSPs in UV‐induced skin damage by antagonizing MAPK signaling pathways. In addition, these results suggest a practicable alternative in which potential therapeutic agents can be mined from organisms with a fascinating ability to adapt. We found a series of UV‐induced frog skin peptides (UIFSPs) from P. nigromaculatus. These peptides conferred significant protection against UVB‐induced skin damage, and the photo‐protective efficacy of UIFSPs was enhanced by UIFSPs modification with TAT protein transduction domain. Mechanistically, TAT‐conjugated UIFSPs internalized into skin cells and suppressed UVB‐induced activation of Ras/PI3K/AKT and Ras/MAPKs pathways, thereby preventing skin photodamage.

Radiation‐induced intestinal injury is a serious concern during abdominal and pelvic cancers radiotherapy. Ubiquitin (Ub) is a highly conserved protein found in all eukaryotic cells. This study aims to explore the role and mechanism of free Ub against radiogenic intestinal injury. We found that free Ub levels of irradiated animals and human patients receiving radiotherapy were upregulated. Radiation‐induced Ub expression was associated with the activation of interferon regulatory factor 1 (IRF1). Intraperitoneal injection of free Ub significantly reduced the mortality of mice following 5–9 Gy total body irradiation (TBI) through the Akt pathway. Free Ub facilitates small intestinal regeneration induced by TBI or abdominal irradiation. At the cellular level, free Ub or its mutants significantly alleviated cell death and enhanced the survival of irradiated intestinal epithelial cells. The radioprotective role of free Ub depends on its receptor CXCR4. Mechanistically, free Ub increased fibroblast growth factor‐2 (FGF2) secretion and consequently activated FGFR1 signaling following radiation in vivo and in vivo. Thus, free Ub confers protection against radiation‐induced intestinal injury through CXCR4/Akt/FGF2 axis, which provides a novel therapeutic option. IRF1 is activated by ionizing radiation and promotes ubiquitin (Ub) expression. Free Ub activates the cellular membrane receptor CXCR4, which increases Akt phosphorylation and FGF2 secretion. FGF2 protects irradiated intestinal cells through its receptor FGFR1. Thus, free Ub confers protection against radiation‐induced intestinal injury through the CXCR4/FGF2 axis.

The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.

Prophylactic cerebral irradiation (PCI) reduces the rate of brain metastasis and improves the prognosis of patients with small cell lung cancer (SCLC), but little is known about the effect of PCI on second-line chemotherapy in patients with relapsed sensitive SCLC. This retrospective cohort study included a total of 164 patients with relapsed sensitive SCLC, 20 of whom were administered temozolomide (TMZ). Categorical clinical variables were compared between subgroups with the chi-square test or Fisher's exact test, continuous clinical variables were compared with the t-test or one-way ANOVA, and the impact on overall survival (OS) was assessed using Kaplan-Meier analysis with the log-rank test. In general, TMZ prolonged the OS of patients with SCLC with brain metastasis from 12.0 to 19.0 months [P=0.0109, hazard ratio (HR): 0.4789, 95% CI: 0.2470-0.9287]. Furthermore, the administration of PCI improved the effects of TMZ on patients with SCLC with brain metastasis, with an increase in OS from 16.0 to 36.5 months (P=0.0017, HR: 3.634, 95% CI: 1.083-12.20); additionally, no difference was observed on the basis of the history of chemotherapy or state of brain metastasis. For the local response evaluation, the overall response rate reached 75.0% for both brain metastasis and extracranial lesions in the two-cycle evaluation, remained at 30.0 and 25.0% in the four-cycle and more-cycle evaluations, respectively, and was minimally influenced by the history of chemotherapy or PCI. In conclusion, the results of this study suggest that PCI may be valuable for patients with relapsed sensitive SCLC with brain metastasis who are receiving TMZ treatment, and it may also serve as an effective regimen to prevent local progression of extracranial lesions; however, more evidence is needed.

Radiation-induced skin injury (RISI) is a common complication of radiotherapy, affecting up to 95% of cancer patients. It manifests as acute erythema and ulceration or chronic fibrosis and telangiectasia, severely compromising patients' quality of life. The pathogenesis of RISI involves oxidative stress, inflammation, DNA damage, and cellular senescence. However, current treatments are largely supportive and fail to address underlying mechanisms. Berberine (BBR), a natural isoquinoline alkaloid, exhibits anti-inflammatory, antioxidant, and wound-healing properties, making it a promising candidate for managing RISI. Single-cell RNA sequencing and proteomic analyses were employed to characterize the molecular and cellular changes in patient, rats and cells exposed to ionizing radiation. Differentially expressed genes (DEGs) and proteins were identified, and functional enrichment analyses were performed. Key senescence markers were validated using molecular docking and in vitro assays. The therapeutic effect of BBR was validated in skin cells and in mouse models of radiation-induced skin injury, focusing on wound healing and systemic health. Transcriptomic analysis identified 217 DEGs in RISI, highlighting pathways such as TNF, p53, and NF-kappa B signaling. Key senescence markers, including CDKN1A, IGFBP7, and CTSL, were overexpressed, correlating with impaired wound healing. Proteomic analysis revealed that BBR modulated 684 proteins, enhancing keratinocyte migration and reducing oxidative damage. BBR treatment promoted the proliferation and migration of skin cells, alleviated radiation-induced cellular senescence, and downregulated inflammatory pathways including p53, ROS, and JAK-STAT. BBR-treated mice exhibited significantly reduced skin injury scores, improved body weight retention, and enhanced wound healing. Radiation injury leads to persistent senescence, inflammation, and impaired wound healing in skin tissues. CDKN1A, IGFBP7, and CTSL are core senescence markers in RISI. By downregulating the expression of senescence markers and suppressing inflammatory pathways (including p53, ROS, and JAK-STAT), BBR accelerates radiation-induced wound healing, offering a novel therapeutic strategy for managing RISI.

The cancer survivor population is growing due to advances in detection and treatment. For improved long-term patient management, it is critical to examine the clinical characteristics and outcomes of second primary malignancies (SPMs). An SPM is defined as a second distinct pathological diagnosis, with the same or different origin as the first primary malignancy (FPM). In the present retrospective study, categorical clinical variables were compared between subgroups and the impact on overall survival was evaluated. A total of 1,188 patients with an FPM were included, of which 102 experienced an SPM (8.59%). When compared with the patients who did not develop an SPM, patients with an SPM were significantly older at first diagnosis, had a higher pathological stage and higher rates of biliary tract disease and thyroid disease. In addition, patients with an SPM were more likely to have received postoperative chemotherapy (28.43 vs. 12.16%, P<0.0001) and to be long-term consumers of cigarettes and alcohol (25.00 vs. 8.95%, P<0.05). In addition, an increase in the number of regimens received but not in the number of courses of chemotherapy was associated with a reduction in the time interval to SPM development. Non-small cell lung cancer (NSCLC) was the most common type of FPM (18.27%). In patients with NSCLC the occurrence of SPMs was relatively low (5.07%) and the SPM-associated mortality rate was 2.30%. Breast cancer was the second common type of FPM (12.09%). Patients with breast cancer had a relatively high likelihood of developing an SPM (9.30%), for which family history of malignancy and postoperative chemotherapy were identified as potential risk factors. Patients with stomach cancer were the most vulnerable to SPM (17.95%) and patients with digestive tract cancer had the longest time interval between the FPM and SPM development. In addition, thyroid adenoma was identified as a potential risk factor for SCLC. The findings of the present study may provide valuable guidance for the short- and long-term monitoring of FPM survivors.