AdipoRon promotes amyloid-ß clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer's disease.

BACKGROUND AND PURPOSE: Amyloid-ß (Aß) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aß. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aß and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aß clearance remain unclear. EXPERIMENTAL APPROACH: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process. KEY RESULTS: AdipoRon promotes Aß clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aß deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD. CONCLUSION AND IMPLICATIONS: AdipoRon promotes the clearance of Aß by enhancing autophagy through the AdipoR1/AMPK-dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.

Enhanced Efficacy of Chemotherapy by Addition of Immune Checkpoint Inhibitors in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung: A Real-World Analysis.

Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a high-grade malignancy with limited treatment options. Despite promising results of immunotherapy in non-small cell and small cell lung cancers, its benefit in LCNEC remains elusive. Methods: We included 24 patients diagnosed with stage IV LCNEC from the Moffitt Cancer Center database who received systemic therapy between January 2016 and May 2021. Group A comprised patients who received first-line CT and ICI (anti-PD-1 or anti-PD-L1 therapy for ICI, n = 11), and Group B received first-line CT only (n = 13). The collected data encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicities since treatment initiation. Results: Kaplan-Meier survival analysis revealed median OS was 56 weeks (95%CI = 22.2-89.8) and 28 weeks (95% CI=16.3-39.7) in groups A and B, respectively. Log-rank test showed the difference was statistically significant (p=0.029). Median PFS was 32 weeks (95%CI=14.7-49.3) in group A and 20 weeks (95% CI=13.8-26.2) in groups B, but the difference was not statistically significant (p= 0.136). Univariate Cox analysis confirmed that the addition of ICI to CT significantly improved OS in patients with stage IV LCNEC (HR=0.35, 95% CI=0.13-0.95, p = 0.039). The ORR (63.6% vs 45.4%, p= 0.670) and DCR (81.8% vs 63.6%, p= 0.635) tended to be higher in group A than in group B but the difference was not statistically significant. Importantly, the combined treatment demonstrated a satisfactory safety profile, with only two patients reporting grade 2 or higher adverse events. Conclusions: Our results suggest that the combination of immunotherapy with chemotherapy holds potential for improving outcomes in stage IV LCNEC. Despite the retrospective nature and limited sample size of our study, these preliminary findings provide a valuable insight into the potential of immunotherapy in LCNEC treatment and encourage further research through larger, prospective trials.

Emerging Immunotherapy Approaches for Treating Prostate Cancer.

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) T cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes from completed clinical trials and strategies to improve clinical efficacy that are being tested in ongoing clinical trials. Imperative endeavors include biomarker discovery for patient selection, deciphering resistance mechanisms, refining cellular therapies such as CAR T cells, and early-stage intervention were reviewed. These ongoing efforts instill optimism that immunotherapy may eventually deliver significant clinical benefits and expand treatment options for patients with advanced prostate cancer.

Comparison of Homo-Polyimide Films Derived from Two Isomeric Bis-Benzimidazole Diamines.

Heteroaromatic polyimides (PIs) containing benzimidazole have attracted tremendous attention due to their positive impact on the properties of PIs. Some research on PIs containing 4,4'-[5,5'-bi-1H-benzimidazole]-2,2'-diylbis-benzenamine (4-AB) has been reported. However, reports are lacking on homo-polyimides (homo-PIs) containing 3,3'-[5,5'-bi-1H-benzimidazole]-2,2'-diylbis-benzenamine (3-AB), which is one of the isomers of 4-AB. In this paper, the influence of amino groups' positions on the performance of homo-PIs was investigated. It was found that the net charge of the amine N group in 4-AB was lower than that of 3-AB, resulting in higher reactivity of 4-AB. Consequently, PIs containing 4-AB displayed better mechanical performance. Molecular simulation confirmed that 3-AB and its corresponding PI chain exhibited distorted conformation, leading to the PI films containing 3-AB having a lighter color. In addition, the 3-AB structure was calculated to have higher rotational energy compared to 4-AB, resulting in a higher glass transition temperature (Tg) in PIs prepared from 3-AB. On the other hand, PIs containing 4-AB exhibited a higher level of molecular linearity, leading to a lower coefficient of thermal expansion (CTE) compared to PIs prepared from 3-AB. Furthermore, all PIs showed higher thermal stability with a 5% weight loss temperature above 530 °C and Tg higher than 400 °C.

Overcoming acquired resistance to cancer immune checkpoint therapy: potential strategies based on molecular mechanisms.

Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1/PD-L1 to boost tumor-specific T lymphocyte immunity have opened up new avenues for the treatment of various histological types of malignancies, with the possibility of durable responses and improved survival. However, the development of acquired resistance to ICI therapy over time after an initial response remains a major obstacle in cancer therapeutics. The potential mechanisms of acquired resistance to ICI therapy are still ambiguous. In this review, we focused on the current understanding of the mechanisms of acquired resistance to ICIs, including the lack of neoantigens and effective antigen presentation, mutations of IFN-γ/JAK signaling, and activation of alternate inhibitory immune checkpoints, immunosuppressive tumor microenvironment, epigenetic modification, and dysbiosis of the gut microbiome. Further, based on these mechanisms, potential therapeutic strategies to reverse the resistance to ICIs, which could provide clinical benefits to cancer patients, are also briefly discussed.

Association of Age With Treatment-Related Adverse Events and Survival in Patients With Metastatic Colorectal Cancer.

Importance: While the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited. Objective: To evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors. Design, Setting, and Participants: This cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022. Exposures: Metastatic colorectal cancer. Main Outcomes and Measures: Survival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years. Results: In the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P < .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P < .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [>65 years]; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P < .001), and severe rash (2.8% vs 1.2% vs 0.4% P = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002). Conclusions and Relevance: In this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.

The Pivotal Role of Benzimidazole in Improving the Thermal and Dielectric Performance of Upilex-Type Polyimide.

Polyimide (PI) with ultra-high thermal resistance and stability is essential for application as a flexible substrate in electronic devices. Here, the Upilex-type polyimides, which contained flexibly "twisted" 4,4'-oxydianiline (ODA), have achieved various performance improvements via copolymerization with a diamine containing benzimidazole structure. With the rigid benzimidazole-based diamine bearing conjugated heterocyclic moieties and hydrogen bond donors fused into the PI backbone, the benzimidazole-containing PI showed outstanding thermal, mechanical, and dielectric performance. Specifically, the PI containing 50% bis-benzimidazole diamine achieved a 5% decomposition temperature at 554 °C, an excellent high glass transition temperature of 448 °C, and a coefficient of thermal expansion lowered to 16.1 ppm/K. Meanwhile, the tensile strength and modulus of the PI films containing 50% mono-benzimidazole diamine increased to 148.6 MPa and 4.1 GPa, respectively. Due to the synergistic effect of rigid benzimidazole and hinged, flexible ODA, all PI films exhibited an elongation at break above 4.3%. The electrical insulation of the PI films was also improved with a dielectric constant lowered to 1.29. In summary, with appropriate mixing of rigid and flexible moieties in the PI backbone, all the PI films showed superior thermal stability, excellent flexibility, and acceptable electrical insulation.

Emerging Immunotherapy Approaches for Advanced Clear Cell Renal Cell Carcinoma.

The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). While localized ccRCC can be cured with surgery, metastatic disease has a poor prognosis. Recently, immunotherapy has emerged as a promising approach for advanced ccRCC. This review provides a comprehensive overview of the evolving immunotherapeutic landscape for metastatic ccRCC. Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 inhibitors have demonstrated clinical efficacy as monotherapies and in combination regimens. Combination immunotherapies pairing ICIs with antiangiogenic agents, other immunomodulators, or novel therapeutic platforms such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy are areas of active research. Beyond the checkpoint blockade, additional modalities including therapeutic vaccines, cytokines, and oncolytic viruses are also being explored for ccRCC. This review discusses the mechanisms, major clinical trials, challenges, and future directions for these emerging immunotherapies. While current strategies have shown promise in improving patient outcomes, continued research is critical for expanding and optimizing immunotherapy approaches for advanced ccRCC. Realizing the full potential of immunotherapy will require elucidating mechanisms of response and resistance, developing predictive biomarkers, and rationally designing combination therapeutic regimens tailored to individual patients. Advances in immunotherapy carry immense promise for transforming the management of metastatic ccRCC.

Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer.

Immunotherapy has been used in the clinical treatment of colorectal cancer (CRC); however, most patients fail to achieve satisfactory survival benefits. Biomarkers with high specificity and sensitivity are being increasingly developed to predict the efficacy of CRC immunotherapy. In addition to DNA alteration markers, such as microsatellite instability/mismatch repair and tumor mutational burden, immune cell infiltration and immune checkpoints (ICs), epigenetic changes and no-coding RNA, and gut microbiomes all show potential predictive ability. Recently, the hypoxic tumor microenvironment (TME) has been identified as a key factor mediating CRC immune evasion and resistance to treatment. Hypoxia-inducible factor-1α is the central transcription factor in the hypoxia response that drives the expression of a vast number of survival genes by binding to the hypoxia response element in cancer and immune cells in the TME. Hypoxia regulates angiogenesis, immune cell infiltration and activation, expression of ICs, and secretion of various immune molecules in the TME and is closely associated with the immunotherapeutic efficacy of CRC. Currently, various agents targeting hypoxia have been found to improve the TME and enhance the efficacy of immunotherapy. We reviewed current markers commonly used in CRC to predict therapeutic efficacy and the mechanisms underlying hypoxia-induced angiogenesis and tumor immune evasion. Exploring the mechanisms by which hypoxia affects the TME will assist the discovery of new immunotherapeutic predictive biomarkers and development of more effective combinations of agents targeting hypoxia and immunotherapy.

Efficacy and safety of apatinib in patients with recurrent or metastatic head and neck squamous cell carcinoma: a retrospective multi-center study.

Apatinib is a novel antiangiogenic agent that targets vascular endothelial growth factor 2. The aim of our study was to explore the efficacy and safety of apatinib in the treatment of patients with recurrence or metastasis (R/M) inoperable head and neck squamous cell carcinoma (HNSCC). This multi-center retrospective study analyzed 53 cases of recurrent or metastatic inoperable HNSCC who had progressed or recurred after undergoing standard radiotherapy, chemotherapy, and immunotherapy treated with apatinib from March 2017 to August 2021. Patients continued apatinib until the time of disease progression or onset of intolerable adverse events. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), and disease control rate (DCR) and incidence of adverse events. Univariable and multivariable analyses were performed to determine prognostic factors. The main adverse events were counted, and the severity of the adverse reactions was evaluated. Fifty-three patients with recurrent or metastatic inoperable R/M HNSCC who had progressed or recurred after standard radiotherapy, chemotherapy, and immunotherapy were included. The ORR was 15.1%, and the DCR was 86.8%. The median PFS was 4.4 months (95% confidence interval [CI] 3.7-5.0 months) and the median OS was 6.6 months (95% CI 5.3-7.9 months). The number of apatinib lines was an influencing factor for both PFS and OS, and the Eastern Cooperative Oncology Group (ECOG) score, tumor differentiation, and apatinib duration were only the influencing factors for OS. Of these, only the ECOG score was an independent predictor of OS. The most common adverse reactions were hypertension (39.6%), hand-foot syndrome (32.1%), fatigue (32.1%), oral ulcers (28.3%), and nausea and vomiting (20.8%). Most adverse reactions were grade 1 or 2. Apatinib mesylate has good efficacy for recurrent/metastatic inoperable HNSCC as second-line and above-line treatment. ECOG score was an independent prognostic factors of OS in patients who were treated with apatinib. In addition, the adverse effects of apatinib mesylate were relatively mild.

Cooperation effects of radiation and ferroptosis on tumor suppression and radiation injury.

Ferroptosis is a kind of oxidative stress-dependent cell death characterized by iron accumulation and lipid peroxidation. It can work in conjunction with radiation to increase reactive oxygen species (ROS) generation and disrupt the antioxidant system, suppressing tumor progression. Radiation can induce ferroptosis by creating ROS, depleting glutathione, activating genes linked to DNA damage and increasing the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) in tumor cells. Furthermore, ferroptosis can enhance radiosensitivity by causing an iron overload, destruction of the antioxidant system, and lipid peroxidation. Radiation can also cause ferroptosis in normal cells, resulting in radiation injury. The role of ferroptosis in radiation-induced lung, intestinal, skin, and hematological injuries have been studied. In this review, we summarize the potential mechanisms linking ferroptosis, oxidative stress and radiation; analyze the function of ferroptosis in tumor suppression and radiation injury; and discuss the potential of ferroptosis regulation to improve radiotherapy efficacy and reduce adverse effects.

Potential targets and treatments affect oxidative stress in gliomas: An overview of molecular mechanisms.

Oxidative stress refers to the imbalance between oxidation and antioxidant activity in the body. Oxygen is reduced by electrons as part of normal metabolism leading to the formation of various reactive oxygen species (ROS). ROS are the main cause of oxidative stress and can be assessed through direct detection. Oxidative stress is a double-edged phenomenon in that it has protective mechanisms that help to destroy bacteria and pathogens, however, increased ROS accumulation can lead to host cell apoptosis and damage. Glioma is one of the most common malignant tumors of the central nervous system and is characterized by changes in the redox state. Therapeutic regimens still encounter multiple obstacles and challenges. Glioma occurrence is related to increased free radical levels and decreased antioxidant defense responses. Oxidative stress is particularly important in the pathogenesis of gliomas, indicating that antioxidant therapy may be a means of treating tumors. This review evaluates oxidative stress and its effects on gliomas, describes the potential targets and therapeutic drugs in detail, and clarifies the effects of radiotherapy and chemotherapy on oxidative stress. These data may provide a reference for the development of precise therapeutic regimes of gliomas based on oxidative stress.

Sulforaphane inhibits angiotensin II-induced cardiomyocyte apoptosis by acetylation modification of Nrf2.

Oxidative stress is the central cause of angiotensin II (Ang II)-induced myocardial injury, and nuclear factor erythroid 2-related factor (Nrf2) is the core molecule of the anti-oxidant defense system. We have previously demonstrated that sulforaphane (SFN) can prevent Ang II-induced myocardial injury by activating Nrf2; however, the underlying molecular mechanism is still unclear. This study aimed to evaluate whether SFN prevents Ang II-induced cardiomyocyte apoptosis through acetylation modification of Nrf2. Wild-type and Nrf2 knockdown embryonic rat cardiomyocytes (H9C2) were exposed to Ang II to induce apoptosis, oxidative stress, and inflammatory responses. SFN treatment significantly reduced Ang II-induced cardiomyocyte apoptosis, inflammation and oxidative stress. Activation of Nrf2 played a critical role in preventing cardiomyocyte apoptosis. After Nrf2 was knockdown, the anti-inflammatory, antioxidant stress of SFN were eliminated. Furthermore, Nrf2 activation by SFN was closely related to the decreased activity of histone deacetylases (HDACs) and increased histone-3 (H3) acetylation levels in Nrf2 promoter region. These findings confirm that Nrf2 plays a key role in SFN preventing Ang II-induced cardiomyocyte apoptosis. SFN activates Nrf2 by inhibiting HDACs expression and activation.

Essential role of Nrf2 in sulforaphane-induced protection against angiotensin II-induced aortic injury.

AIMS: Cardiovascular disease (CVD) is the leading cause of death worldwide. Inflammation and oxidative stress are the primary factors underlying angiotensin II (Ang II)-induced aortic damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important antioxidative stress factor. Sulforaphane (SFN), which is naturally found in cruciferous vegetables, is an Nrf2 agonist that is safe for oral administration. Here, we aimed to explore the potential of SFN in protecting against Ang II-induced aortic damage by upregulating Nrf2 expression via the extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3 beta (GSK-3ß)/Fyn pathway. MAIN METHODS AND KEY FINDINGS: Wild-type (WT) C57BL/6J and Nrf2-knockout (Nrf2-KO) mice were injected with Ang II to induce aortic inflammation, oxidative stress, and cardiac remodeling (increased fibrosis and wall thickness). SFN treatment prevented aortic damage via Nrf2 activation in the WT mice. However, the protective effect of SFN on Ang II-induced aortic damage and upregulation of genes downstream of Nrf2 were not observed in Nrf2-KO mice. SFN induced the upregulation of aortic Nrf2 and inhibited the accumulation of ERK, GSK-3ß, and Fyn in the nuclei. SIGNIFICANCE: These results revealed that Nrf2 plays a central role in protecting against Ang II-induced aortic injury. Furthermore, SFN prevented Ang II-induced aortic damage by activating Nrf2 through the ERK/GSK-3ß/Fyn pathway.

Efficacy and Safety of Apatinib in Advanced Hepatocellular Carcinoma: A Multicenter Real World Retrospective Study.

Background and Purpose: Apatinib is a novel antiangiogenic agent that can target vascular endothelial cell growth factor 2. The aim of our study was to evaluate the efficacy and safety of apatinib mesylate in the treatment of advanced hepatocellular carcinoma (HCC) in the real world. Methods: We retrospectively analyzed 178 patients with advanced HCC who had been treated with apatinib mesylate from January 2017 to March 2020. The primary outcome indexes were progression-free survival (PFS) and overall survival (OS), and the secondary outcome indexes were overall response rate (ORR), disease control rate (DCR), and incidence of treatment-related adverse reactions. Results: Univariate analysis showed that patients with third-line treatment (p <0.001), alpha fetoprotein (AFP) ≥400 ng/ml (p <0.05), distant metastasis (p <0.05), portal vein tumor thrombus (PVTT) (p <0.05), and apatinib monotherapy (p <0.001) had shorter survival. Multivariate analysis confirmed that third-line drugs, PVTT, and combination therapy were independent prognostic factors for PFS in all patients. Univariate analysis showed that Eastern Cooperative Oncology Group (ECOG) scores (p <0.05), line of apatinib (p <0.001), AFP (p <0.001), tumor progression (p <0.05), PVTT (p <0.05), and combination therapy (p <0.001) may impact the OS. Multivariate analysis proved that AFP, PVTT, and combination therapy were independent prognostic factors for OS. The most common adverse reactions were secondary hypertension (29.21%), symptoms of fatigue (16.85%), hand and foot syndrome (16.29%), vomiting (14.04%), liver dysfunction (6.18%), and proteinuria (6.74%). Most of the adverse reactions were Grade 1 or 2. Conclusion: Apatinib mesylate is an effective treatment for advanced HCC, and its adverse reactions are relatively mild. Line of apatinib, PVTT, AFP level, and combination therapy were independent prognostic factors for patients with advanced HCC who were treated with apatinib.

ARTS, an unusual septin, regulates tumorigenesis by promoting apoptosis.

Apoptosis plays particularly important roles in tumorigenesis through various mechanisms. Apoptosis can be initiated by both extrinsic and intrinsic signals centered in and coming from the mitochondria. Antiapoptotic proteins promote tumor progression, and the occurrence and progression of tumors are closely related to antiapoptotic protein expression. As the only member of the septin gene family with proapoptotic function, apoptosis-related proteins in the TGF-ß signaling pathway (ARTS) has received extensive attention for its unique structure. In contrast, unlike other known inhibitors of apoptosis protein (IAP) antagonists, ARTS exhibits a stronger tumor suppressor potential. Recent research has shown that ARTS can bind and inhibit XIAP and Bcl-2 directly or assist p53 in the degradation of Bcl-XL. Here, we review recent advances in the molecular mechanisms by which the proapoptotic protein ARTS, with its unique structure, inhibits tumorigenesis. We also discuss the possibility of mimicking ARTS to develop small-molecule drugs.

Prospective Application of Ferroptosis in Hypoxic Cells for Tumor Radiotherapy.

Radiation therapy plays an increasingly important role in cancer treatment. It can inhibit the progression of various cancers through radiation-induced DNA breakage and reactive oxygen species (ROS) overload. Unfortunately, solid tumors, such as breast and lung cancer, often develop a hypoxic microenvironment due to insufficient blood supply and rapid tumor proliferation, thereby affecting the effectiveness of radiation therapy. Restraining hypoxia and improving the curative effect of radiotherapy have become difficult problems. Ferroptosis is a new type of cell death caused by lipid peroxidation due to iron metabolism disorders and ROS accumulation. It plays an important role in both hypoxia and radiotherapy and can enhance the radiosensitivity of hypoxic tumor cells by amplifying oxidative stress or inhibiting antioxidant regulation. In this review, we summarize the internal relationship and related mechanisms between ferroptosis and hypoxia, thus exploring the possibility of inducing ferroptosis to improve the prognosis of hypoxic tumors.

Research progress on mechanism and imaging of temporal lobe injury induced by radiotherapy for head and neck cancer.

Radiotherapy (RT) is an effective treatment for head and neck cancer (HNC). Radiation-induced temporal lobe injury (TLI) is a serious complication of RT. Late symptoms of radiation-induced TLI are irreversible and manifest as memory loss, cognitive impairment, and even temporal lobe necrosis (TLN). It is currently believed that the mechanism of radiation-induced TLI involves microvascular injury, neuron and neural stem cell injury, glial cell damage, inflammation, and the production of free radicals. Significant RT-related structural changes and dose-dependent changes in gray matter (GM) and white matter (WM) volume and morphology were observed through computed tomography (CT) and magnetic resonance imaging (MRI) which were common imaging assessment tools. Diffusion tensor imaging (DTI), dispersion kurtosis imaging (DKI), susceptibility-weighted imaging (SWI), resting-state functional magnetic resonance (rs-fMRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) can be used for early diagnosis and prognosis evaluation according to functional, molecular, and cellular processes of TLI. Early diagnosis of TLI is helpful to reduce the incidence of TLN and its related complications. This review summarizes the clinical features, mechanisms, and imaging of radiation-induced TLI in HNC patients. KEY POINTS: • Radiation-induced temporal lobe injury (TLI) is a clinical complication and its symptoms mainly include memory impairment, headache, and cognitive impairment. • The mechanisms of TLI include microvascular injury, cell injury, and inflammatory and free radical injury. Significant RT-related structural changes and dose-dependent changes in TL volume and morphology were observed through CT and MRI. • SWI, MRS, DTI, and DKI and other imaging examinations can detect anatomical and functional, molecular, and cellular changes of TLI.

Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress.

Radiation therapy is a common treatment for head and neck cancers. However, because of the presence of nerve structures (brain stem, spinal cord, and brachial plexus), salivary glands (SGs), mucous membranes, and swallowing muscles in the head and neck regions, radiotherapy inevitably causes damage to these normal tissues. Among them, SG injury is a serious adverse event, and its clinical manifestations include changes in taste, difficulty chewing and swallowing, oral infections, and dental caries. These clinical symptoms seriously reduce a patient's quality of life. Therefore, it is important to clarify the mechanism of SG injury caused by radiotherapy. Although the mechanism of radiation-induced SG injury has not yet been determined, recent studies have shown that the mechanisms of calcium signaling, microvascular injury, cellular senescence, and apoptosis are closely related to oxidative stress. In this article, we review the mechanism by which radiotherapy causes oxidative stress and damages the SGs. In addition, we discuss effective methods to prevent and treat radiation-induced SG damage.

Sulforaphane-Mediated Nrf2 Activation Prevents Radiation-Induced Skin Injury through Inhibiting the Oxidative-Stress-Activated DNA Damage and NLRP3 Inflammasome.

This article mainly observed the protective effect of sulforaphane (SFN) on radiation-induced skin injury (RISI). In addition, we will discuss the mechanism of SFN's protection on RISI. The RISI model was established by the irradiation of the left thigh under intravenous anesthesia. Thirty-two C57/BL6 mice were randomly divided into control group (CON), SFN group, irradiation (IR) group, and IR plus SFN (IR/SFN) group. At eight weeks after irradiation, the morphological changes of mouse skin tissues were detected by H&E staining. Then, the oxidative stress and inflammatory response indexes in mouse skin tissues, as well as the expression of Nrf2 and its downstream antioxidant genes, were evaluated by ELISA, real-time PCR, and Western blotting. The H&E staining showed the hyperplasia of fibrous tissue in the mouse dermis and hypodermis of the IR group. Western blotting and ELISA results showed that the inflammasome of NLRP3, caspase-1, and IL-1ß, as well as oxidative stress damage indicators ROS, 4-HNE, and 3-NT, in the skin tissues of mice in the IR group were significantly higher than those in the control group (p < 0.05). However, the above pathological changes declined sharply after SFN treatment (p < 0.05). In addition, the expressions of Nrf2 and its regulated antioxidant enzymes, including CAT and HO-1, were higher in the skin tissues of SFN and IR/SFN groups, but lower in the control and IR groups (p < 0.05). SFN may be able to suppress the oxidative stress by upregulating the expression and function of Nrf2, and subsequently inhibiting the activation of NLRP3 inflammasome and DNA damage, so as to prevent and alleviate the RISI.