Manipulating calcium homeostasis with nanoplatforms for enhanced cancer therapy.

Calcium ions (Ca2+) are indispensable and versatile metal ions that play a pivotal role in regulating cell metabolism, encompassing cell survival, proliferation, migration, and gene expression. Aberrant Ca2+ levels are frequently linked to cell dysfunction and a variety of pathological conditions. Therefore, it is essential to maintain Ca2+ homeostasis to coordinate body function. Disrupting the balance of Ca2+ levels has emerged as a potential therapeutic strategy for various diseases, and there has been extensive research on integrating this approach into nanoplatforms. In this review, the current nanoplatforms that regulate Ca2+ homeostasis for cancer therapy are first discussed, including both direct and indirect approaches to manage Ca2+ overload or inhibit Ca2+ signalling. Then, the applications of these nanoplatforms in targeting different cells to regulate their Ca2+ homeostasis for achieving therapeutic effects in cancer treatment are systematically introduced, including tumour cells and immune cells. Finally, perspectives on the further development of nanoplatforms for regulating Ca2+ homeostasis, identifying scientific limitations and future directions for exploitation are offered.

Dynamically changed HSP70 after reperfusion following cerebral infarction in human and rats: correlation with p38 MAPK.

We aimed to clarify the correlation between dynamic change of blood HSP70 and the prognosis of thrombolysis in human and rats, so as to explain the neuroprotection and early warning role of HSP70 in cerebral ischemia-reperfusion. Forty-two patients with acute ischemic stroke were divided into two groups according to the time from onset to thrombolytic therapy: 0 h-3 h (27 patients) and 3-4.5 h group (15 patients). The level of HSP70 in serum before and after thrombolysis was detected by ELISA. Furthermore, a rat model was also used to mimic the ischemic stroke and reperfusion. Peripheral blood of rat samples was collected to detect the level of HSP70 using Elisa. Several signal proteins from MAPK signaling pathway including JNK, p38, ERK (p42/44) were detected at different time points by Western blot of brain tissue. Patients who underwent thrombolytic therapy within 0-3 h had the highest HSP70 level at 1 h after thrombolysis. The higher HSP70 after thrombolysis, the better the patient prognosis. NIHSS scores showed HSP70 was positively correlated with cerebral ischemia. The levels of ERK family (p42/44 MAPK) and p-JNK were decreased gradually along with the time suffering cerebral ischemia. P-ERK, JNK, p-p38 had dynamic changes with increased ischemic time in the middle cerebral artery occlusion model. Dynamic change of HSP70 level in blood may be a biological index that reflects the functional condition of cell survival for cerebral ischemia and estimating the prognostic conditions. Importantly, HSP70 levels in blood were positively correlated with the p38 MAPK pathway in brain tissue.

Melatonin ameliorates retinal ganglion cell senescence and apoptosis in a SIRT1-dependent manner in an optic nerve injury model.

Melatonin is involved in exerting protective effects in aged-related and neurodegenerative diseases through a silent information regulator type 1 (SIRT1)-dependent pathway. However, little was known about the impact of melatonin on retinal ganglion cell (RGC) senescence and apoptosis following optic nerve crush (ONC). Thus, this study aimed to examine the effects of melatonin on RGC senescence and apoptosis after ONC and investigate the involvement of SIRT1 in this process. To study this, an ONC model was established. EX-527, an inhibitor of SIRT1, was injected intraperitoneally into mice. And melatonin was administrated abdominally into mice after ONC every day. Hematoxylin & eosin staining, retina flat-mounts and optical coherence tomography were used to evaluate the loss of retina cells/neurons. Pattern electroretinogram (p-ERG) was performed to evaluate the function of RGCs. Immunofluorescence and western blot were used to evaluate protein expression. SA-ß-gal staining was employed to detect senescent cells. The results demonstrated that melatonin partially rescued the expression of SIRT1 in RGC 3 days after ONC. Additionally, melatonin administration partly rescued the decreased RGC number and ganglion cell complex thickness observed 14 days after ONC. Melatonin also suppressed ONC-induced senescence and apoptosis index. Furthermore, p-ERG showed that melatonin improved the amplitude of P50, N95 and N95/P50 following ONC. Importantly, the protective effects of melatonin were reversed when EX-527 was administered. In summary, this study revealed that melatonin attenuated RGC senescence and apoptosis through a SIRT1-dependent pathway after ONC. These findings provide valuable insights for the treatment of RGC senescence and apoptosis.

Metformin Inhibits NLRP3 Inflammasome Expression and Regulates Inflammatory Microenvironment to Delay the Progression of Colorectal Cancer.

BACKGROUND: Colorectal cancer is a common malignant tumor, with about one million people diagnosed with it worldwide each year. Recent studies have found that metformin can inhibit the production of inflammatory factors and regulate the polarization of immune cells. However, whether metformin can regulate the inflammatory microenvironment and delay the progression of colorectal cancer by inhibiting the inflammatory response has not been deeply studied yet. OBJECTIVE: This study aimed to explore the molecular mechanism by which metformin inhibits the expression of NLRP3 inflammasome, regulates the inflammatory microenvironment, and delays the progression of colorectal cancer through in vitro cell experiments. METHODS: In this research, NLRP3 was knocked down in human colorectal cancer cells, and metformin was added to them. Cell proliferation ability was detected by CCK8, and cell migration and invasion abilities were assessed by Transwell assay. The apoptosis rate was determined by flow cytometry. In addition, the expression of NLRP3 inflammatory vesicles and inflammatory factors in each group of cells was studied by qRT-PCR and Western blotting. Finally, clinical colorectal cancer samples were analyzed by immunohistochemistry. RESULTS: The results of the study showed that NLRP3 expression was significantly increased in colorectal cancer cell lines and human colorectal cancer tissues. Knockdown of NLRP3 significantly inhibited tumor cell proliferation, migration, and invasion. In addition, the proliferation, migration and invasion of tumor cells were also significantly reduced by the addition of metformin intervention. Furthermore, qRT-PCR and WB results demonstrated that the expression of IL-1ß, IL-6, TNF- α, TGF-ß, and IL-10 was down-regulated in LS1034 tumor cells after NLRP3 knockdown. In addition, metformin intervention also resulted in different degrees of downregulation of NLRP3 and inflammatory factor expression (p <0.05). Notably, the reduction in inflammatory factors was more pronounced after the combination of NLRP3 knockdown and metformin intervention. CONCLUSION: Metformin can inhibit the expression of NLRP3 inflammasome, thereby suppressing the expression of inflammation-related factors, reducing the damage of the inflammatory microenvironment to normal cells, and delaying the progression of colorectal cancer.

Melatonin prevents EAAC1 deletion-induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence.

Normal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1-/- ) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion-induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis- and senescence-related redox-sensitive factors in EAAC1 deletion-induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1-/- mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox-sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.

Oxygen-Independent Synchronized ROS Generation and Hypoxia Prodrug Activation with Z-Scheme Heterostructure Sonosensitizer.

Combination therapy has emerged as a promising approach for effective tumor treatment. However, the combination of sonodynamic therapy (SDT) and hypoxia-activated prodrugs (HAPs) has not been explored due to the contradictory requirement of oxygen (O2 ) for reactive oxygen species (ROS) generation and the necessity to avoid O2 for the activation of HAPs. In this study, this challenge is addressed by developing BiOCl-Au-Ag2 S Z-scheme heterostructure nanoparticles loaded with tirapazamine (TPZ) to achieve O2 -independent therapy. These nanoparticles demonstrate efficient electron-hole separation under ultrasound irradiation while maintaining a high redox potential. The generated holes react with water to efficiently produce hydroxyl radicals, while the electrons autonomously activate TPZ, negating the need for O2 . In vitro and in vivo assessments validate the effective tumor elimination by these Z-scheme nanoparticles without disrupting the hypoxic environment. This innovative design overcomes the limitations associated with O2 requirement in SDT and introduces a novel strategy for HAP activation and synergistic therapy between ROS and HAPs-based therapy.

Synaptotagmin 1 Suppresses Colorectal Cancer Metastasis by Inhibiting ERK/MAPK Signaling-Mediated Tumor Cell Pseudopodial Formation and Migration.

Although synaptotagmin 1 (SYT1) has been identified participating in a variety of cancers, its role in colorectal cancer (CRC) remains an enigma. This study aimed to demonstrate the effect of SYT1 on CRC metastasis and the underlying mechanism. We first found that SYT1 expressions in CRC tissues were lower than in normal colorectal tissues from the CRC database and collected CRC patients. In addition to this, SYT1 expression was also lower in CRC cell lines than in the normal colorectal cell line. SYT1 expression was downregulated by TGF-ß (an EMT mediator) in CRC cell lines. In vitro, SYT1 overexpression repressed pseudopodial formation and reduced cell migration and invasion of CRC cells. SYT1 overexpression also suppressed CRC metastasis in tumor-bearing nude mice in vivo. Moreover, SYT1 overexpression promoted the dephosphorylation of ERK1/2 and downregulated the expressions of Slug and Vimentin, two proteins tightly associated with EMT in tumor metastasis. In conclusion, SYT1 expression is downregulated in CRC. Overexpression of SYT1 suppresses CRC cell migration, invasion, and metastasis by inhibiting ERK/MAPK signaling-mediated CRC cell pseudopodial formation. The study suggests that SYT1 is a suppressor of CRC and may have the potential to be a therapeutic target for CRC.

GSK840 Alleviates Retinal Neuronal Injury by Inhibiting RIPK3/MLKL-Mediated RGC Necroptosis After Ischemia/Reperfusion.

Purpose: This study aimed to explore the impact of GSK840 on retinal neuronal injury after retinal ischemia/reperfusion (IR) and its associated mechanism. Methods: We established an in vivo mouse model of IR and an in vitro model of oxygen and glucose deprivation/reoxygenation (OGDR) in primary mouse retinal ganglion cells (RGCs). GSK840, a small-molecule compound, was used to specifically inhibit RIPK3/MLKL-dependent necroptosis. Retinal structure and function evaluation was performed by using hematoxylin and eosin staining, optical coherence tomography, and electroretinography. Propidium Iodide (PI) staining was used for detection of necroptotic cell death, whereas Western blot analysis and immunofluorescence were used to assess necroptosis-related proteins and inner retinal neurons. Results: RIPK3/MLKL-dependent necroptosis was rapidly activated in RGCs following retinal IR or OGDR. GSK840 helped maintain relatively normal inner retinal structure and thickness by preserving inner retinal neurons, particularly RGCs. Meanwhile, GSK840 ameliorated IR-induced visual dysfunction, as evidenced by the improved amplitudes of photopic negative response, a-wave, b-wave, and oscillatory potentials. And GSK840 treatment significantly reduced the population of PI+ RGCs after injury. Mechanistically, GSK840 ameliorated RGC necroptosis by inhibiting the RIPK3/MLKL pathway. Conclusions: GSK840 exerts protective effects against retinal neuronal injury after IR by inhibiting RIPK3/MLKL-mediated RGC necroptosis. GSK840 may represent a protective strategy for RGC degeneration in ischemic retinopathy.

Procedural Promotion of Wound Healing by Graphene-Barium Titanate Nanosystem with White Light Irradiation.

Background: Wound healing is a continuous and complex process that comprises multiple phases including hemostasis, inflammation, multiplication (proliferation) and remodeling. Although a variety of nanomaterials have been developed to control infection and accelerate wound healing, most of them can only promote one phase but not multiple phases, resulting in lower efficient healing. Although various formulations such as nitric oxide releasing wound dressings were developed for dual action, the nanostructure synthesis and the encapsulation process were complex. Materials and Methods: Here, we report on the design of graphene-barium titanate nanosystem to procedural promote the wound healing process. The antibacterial effect was assessed in Gram-negative Escherichia coli bacteria (E. coli) and Gram-positive Staphylococcus aureus bacteria (S. aureus), the cell proliferation and migration experiment was investigated in mouse embryonic fibroblast (NIH-3T3) cells, and the wound healing effect was analyzed in female BALB/c mice with infected skin wound on the back. Results: Results showed that graphene-barium titanate nanosystem could generate abundant ROS to kill both E. coli and S. aureus. The growth curves, bacterial viability, colony number formation and scanning electron microscopy (SEM) images of E. coli and S. aureus all confirmed the antibacterial effect. Cell Counting Kit-8 (CCK-8) assay displayed that GBT possesses great biocompatibility. EdU assay showed that GBT plus white light irradiation significantly promoted the proliferation and migration of NIH-3T3 cells. Scratch assay found that GBT could achieve a fast scratch closure compared to the control. In vivo wound healing effect indicates that GBT can accelerate wound repair procedure. Conclusion: GBT nanocomposite is capable of programmatically accelerating wound healing through multiple stages, including production of a large amount of ROS after white light exposure to effectively kill E. coli and S. aureus to prevent wound infection and as a scaffold to accelerate fibroblast proliferation and migration to the wound to accelerate wound healing.

Neuroprotection of SRT2104 in Murine Ischemia/Reperfusion Injury Through the Enhancement of Sirt1-Mediated Deacetylation.

Purpose: Strategies for neuroprotection are the main targets of glaucoma research. The neuroprotective properties of SRT2104 administration have been proven in central nervous system degeneration diseases through the activation of nicotinamide adenine dinucleotide-dependent deacetylase-silence information regulator 1 (Sirt1). Here, we investigated whether SRT2104 could protect the retina from ischemia/reperfusion (I/R) injury and the underlying mechanisms. Methods: SRT2104 was intravitreally injected immediately after I/R induction. RNA and protein expression were detected by quantitative real-time PCR and Western blot. Protein expression and distribution were examined by immunofluorescence staining. Retinal structure and function were analyzed by hematoxylin and eosin staining, optical coherence tomography, and electroretinogram. Optic nerve axons were quantified using toluidine blue staining. Cellular apoptosis and senescence were evaluated by TUNEL assay and SA-ß-gal staining. Results: The protein expression of Sirt1 decreased dramatically after I/R injury and SRT2104 administration effectively enhanced the stability of Sirt1 protein without significantly influencing Sirt1 mRNA synthesis. SRT2104 administration alone exerted no influence on the structure and function of normal retinas. However, SRT2104 intervention significantly protected the inner retinal structure and neurons; partially restored retinal function after I/R injury. I/R-induced cellular apoptosis and senescence were effectively alleviated by SRT2104 administration. Additionally, SRT2104 intervention markedly reduced neuroinflammation, including reactive gliosis, retinal vascular inflammation, and the overexpression of pro-inflammatory cytokines after I/R injury. Mechanistically, I/R-induced acetylation of p53, NF-κB p65, and STAT3 was significantly reversed by SRT2104 intervention. Conclusions: We demonstrated that SRT2104 exerted potent protective effects against I/R injury by enhancing Sirt1-mediated deacetylation and suppressing apoptosis, senescence, and neuroinflammation-related pathways.

Cerium End-Deposited Gold Nanorods-Based Photoimmunotherapy for Boosting Tumor Immunogenicity.

BACKGROUND: Triple-negative breast cancer (TNBC) was closely related to high metastatic risk and mortality and has not yet found a targeted receptor for targeted therapy. Cancer immunotherapy, especially photoimmunotherapy, shows promising potential in TNBC treatment because of great spatiotemporal controllability and non-trauma. However, the therapeutic effectiveness was limited by insufficient tumor antigen generation and the immunosuppressive microenvironment. METHODS: We report on the design of cerium oxide (CeO2) end-deposited gold nanorods (CEG) to achieve excellent near-infrared photoimmunotherapy. CEG was synthesized through hydrolyzing of ceria precursor (cerium acetate, Ce(AC)3) on the surface of Au nanorods (NRs) for cancer therapy. The therapeutic response was first verified in murine mammary carcinoma (4T1) cells and then monitored by analysis of the anti-tumor effect in xenograft mouse models. RESULTS: Under near-infrared (NIR) light irradiation, CEG can efficiently generate hot electrons and avoid hot-electron recombination to release heat and form reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and activating part of the immune response. Simultaneously, combining with PD-1 antibody could further enhance cytotoxic T lymphocyte infiltration. CONCLUSIONS: Compared with CBG NRs, CEG NRs showed strong photothermal and photodynamic effects to destroy tumors and activate a part of the immune response. Combining with PD-1 antibody could reverse the immunosuppressive microenvironment and thoroughly activate the immune response. This platform demonstrates the superiority of combination therapy of photoimmunotherapy and PD-1 blockade in TNBC therapy.

Chromatin accessibility dynamics insight into crosstalk between regulatory landscapes in poplar responses to multiple treatments.

Perennial trees develop and coordinate endogenous response signaling pathways, including their crosstalk and convergence, to cope with various environmental stresses which occur simultaneously in most cases. These processes are involved in gene transcriptional regulations that depend on dynamic interactions between regulatory proteins and corresponding chromatin regions, but the mechanisms remain poorly understood in trees. In this study, we detected chromatin regulatory landscapes of poplar under abscisic acid, methyl jasmonate, salicylic acid and sodium chloride (NaCl) treatment, through integrating ATAC-seq and RNA-seq data. Our results showed that the degree of chromatin accessibility for a given gene is closely related to its expression level. However, unlike the gene expression that shows treatment-specific response patterns, changes in chromatin accessibility exhibit high similarities under these treatments. We further proposed and experimentally validated that a homologous gene copy of RESPONSIVE TO DESICCATION 26 mediates the crosstalk between jasmonic acid and NaCl signaling pathways by directly regulating the stress-responsive genes and that circadian clock-related transcription factors like REVEILLE8 play a central role in response of poplar to these treatments. Overall, our study provides a chromatin insight into the molecular mechanism of transcription regulatory networks in response to different environmental stresses and raises the key roles of the circadian clock of poplar to adapt to adverse environments.

Mace-Like Plasmonic Au-Pd Heterostructures Boost Near-Infrared Photoimmunotherapy.

Photoimmunotherapy, with spatiotemporal precision and noninvasive property, has provided a novel targeted therapeutic strategy for highly malignant triple-negative breast cancer (TNBC). However, their therapeutic effect is severely restricted by the insufficient generation of tumor antigens and the weak activation of immune response, which is caused by the limited tissue penetration of light and complex immunosuppressive microenvironment. To improve the outcomes, herein, mace-like plasmonic AuPd heterostructures (Au Pd HSs) have been fabricated to boost near-infrared (NIR) photoimmunotherapy. The plasmonic Au Pd HSs exhibit strong photothermal and photodynamic effects under NIR light irradiation, effectively triggering immunogenic cell death (ICD) to activate the immune response. Meanwhile, the spiky surface of Au Pd HSs can also stimulate the maturation of DCs to present these antigens, amplifying the immune response. Ultimately, combining with anti-programmed death-ligand 1 (α-PD-L1) will further reverse the immunosuppressive microenvironment and enhance the infiltration of cytotoxic T lymphocytes (CTLs), not only eradicating primary TNBC but also completely inhibiting mimetic metastatic TNBC. Overall, the current study opens a new path for the treatment of TNBC through immunotherapy by integrating nanotopology and plasmonic performance.

Vessels that encapsulate tumor clusters (VETC) pattern predicts the efficacy of adjuvant TACE in hepatocellular carcinoma.

PURPOSE: Postoperative adjuvant trans-catheter arterial chemoembolization (TACE) is regarded as a common strategy for hepatocellular carcinoma (HCC) patients at a high risk of recurrence. However, there are currently no clinically available biomarkers to predict adjuvant TACE response. Vessels that encapsulate tumor clusters (VETC) can be used as an independent predictor of HCC prognosis. In this study, we aimed to explore whether the VETC pattern could predict adjuvant TACE benefit. METHODS: Vascular pattern and HIF-1α expression were detected in immunohistochemistry. The survival benefit of adjuvant TACE therapy for patients with or without VETC pattern (VETC+ /VETC-) was evaluated. RESULTS: The adjuvant TACE therapy obviously improved the TTR and OS in VETC+ patients, while adjuvant TACE therapy could not benefit from VETC- patients. Univariate and multivariate analysis revealed that adjuvant TACE therapy significantly improved the TTR and OS in VETC+ patients, but not in VETC- patients. In addition, the VETC+ , but not VETC- , patients could benefit from adjuvant TACE therapy in patients with high-risk factors of vascular invasion, larger tumor or multiple tumor. The mechanistic investigations revealed that the favorable efficacy of adjuvant TACE on VETC+ patients, but not VETC- ones, may be not due to the activation of HIF-1α pathway. CONCLUSION: The VETC pattern may represent a novel and reliable factor for selecting HCC patients who may benefit from adjuvant TACE therapy, and the combination of VETC pattern and tumor characteristics may help stratify patients' outcomes and responses to adjuvant TACE therapy.

Respiratory Exposure to Copper Oxide Particles Causes Multiple Organ Injuries via Oxidative Stress in a Rat Model.

Introduction: The wide application of copper oxide nanoparticles (CuO NPs) in industry, agriculture, environmental remediation, and biomedicine has increased the risk of human exposure to CuO NPs. Recent studies suggested that CuO NPs have genotoxic and cytotoxic effects on various cells. However, little is known about the toxicity of CuO NPs on major peripheral organs after respiratory exposure. Materials and Methods: We investigated the toxicities of CuO NPs on human bronchial epithelial (BEAS-2B) and human cardiomyocytes (AC16) cells in vitro, and on the lungs, liver, kidneys, and heart of spontaneously hypertensive rats (SHRs) at 24 and 72 h after intrabronchial instillation in vivo. Results: CuO NPs induced concentration-dependent toxicities in both BEAS-2B and AC16 cells mainly through hierarchical oxidative stress mechanisms, involving generation of reactive oxygen species (ROS), upregulation of heme oxygenase-1 (HO-1), mitochondrial dysfunction, and secretion of proinflammatory and profibrogenic cytokines. Respiratory exposure to CuO NPs induced acute multiple organ injuries in SHRs manifesting through inflammation and fibrosis. However, cardiac injury was relatively less severe than injuries in the lungs, liver, and kidneys. Upregulation of serum C-reaction protein (CRP), tumor necrosis factor α (TNF-α), intercellular adhesion molecule 1 (ICAM-1), endothelin-1 (ET-1), angiotensin converting enzyme (ACE), and von Willebrand factor (vWF) after exposure to CuO NPs indicated systematic inflammation, endothelial injury, and potential prothrombosis. Conclusion: Respiratory exposure to CuO NPs induced acute injuries in main peripheral organs, including the lungs, liver, kidneys, and heart. Individuals with existing cardiovascular diseases were susceptible to exposure to CuO NPs. This study provides a warning about the extensive toxic effects of CuO NPs, especially in the susceptible population.

Values of OAS gene family in the expression signature, immune cell infiltration and prognosis of human bladder cancer.

BACKGROUND: Bladder cancer (BLCA) is one of the most common genitourinary malignancies in the world, but its pathogenic genes have not been fully identified and the treatment outcomes are still unsatisfactory. Although the members of 2', 5'-oligoadenylate synthetase (OAS) gene family are known involved in some tumorous biological processes, the roles of the OAS gene family in BLCA are still undetermined. METHODS: By combining vast bioinformatic datasets analyses of BLCA and the experimental verification on clinical BLCA specimen, we identified the expressions and biological functions of OAS gene family members in BLCA with comparison to normal bladder tissues. RESULTS: The expression levels of OAS gene family members were higher in BLCA than in normal bladder tissues. The expression levels of most OAS genes had correlations with genomic mutation and methylation, and with the infiltration levels of CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells in the microenvironment of BLCA. In addition, high expressions of OAS1, OAS2, OAS3, and OASL predicted better overall survival in BLCA patients. CONCLUSIONS: The highly expressed OAS genes in BLCA can reflect immune cells infiltration in the tumor microenvironment and predict the better overall survival of BLCA, and thus may be considered as a signature of BLCA. The study provides new insights into the diagnosis, treatment, and prognosis of BLCA.

Repeated turnovers keep sex chromosomes young in willows.

BACKGROUND: Salicaceae species have diverse sex determination systems and frequent sex chromosome turnovers. However, compared with poplars, the diversity of sex determination in willows is poorly understood, and little is known about the evolutionary forces driving their turnover. Here, we characterized the sex determination in two Salix species, S. chaenomeloides and S. arbutifolia, which have an XY system on chromosome 7 and 15, respectively. RESULTS: Based on the assemblies of their sex determination regions, we found that the sex determination mechanism of willows may have underlying similarities with poplars, both involving intact and/or partial homologs of a type A cytokinin response regulator (RR) gene. Comparative analyses suggested that at least two sex turnover events have occurred in Salix, one preserving the ancestral pattern of male heterogamety, and the other changing heterogametic sex from XY to ZW, which could be partly explained by the "deleterious mutation load" and "sexually antagonistic selection" theoretical models. We hypothesize that these repeated turnovers keep sex chromosomes of willow species in a perpetually young state, leading to limited degeneration. CONCLUSIONS: Our findings further improve the evolutionary trajectory of sex chromosomes in Salicaceae species, explore the evolutionary forces driving the repeated turnovers of their sex chromosomes, and provide a valuable reference for the study of sex chromosomes in other species.

Anti-PANoptosis is involved in neuroprotective effects of melatonin in acute ocular hypertension model.

Acute ocular hypertension (AOH) is the most important characteristic of acute glaucoma, which can lead to retinal ganglion cell (RGC) death and permanent vision loss. So far, approved effective therapy is still lacking in acute glaucoma. PANoptosis (pyroptosis, apoptosis, and necroptosis), which consists of three key modes of programmed cell death-apoptosis, necroptosis, and pyroptosis-may contribute to AOH-induced RGC death. Previous studies have demonstrated that melatonin (N-acetyl-5-methoxytryptamine) exerts a neuroprotective effect in many retinal degenerative diseases. However, whether melatonin is anti-PANoptotic and neuroprotective in the progression of acute glaucoma remains unclear. Thus, this study aimed to explore the role of melatonin in AOH retinas and its underlying mechanisms. The results showed that melatonin treatment attenuated the loss of ganglion cell complex thickness, retinal nerve fiber layer thickness, and RGC after AOH injury, and improved the amplitudes of a-wave, b-wave, and oscillatory potentials in the electroretinogram. Additionally, the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells was decreased, and the upregulation of cleaved caspase-8, cleaved caspase-3, Bax, and Bad and downregulation of Bcl-2 and p-Bad were inhibited after melatonin administration. Meanwhile, both the expression and activation of MLKL, RIP1, and RIP3, along with the number of PI-positive cells, were reduced in melatonin-treated mice, and p-RIP3 was in both RGC and microglia/macrophage after AOH injury. Furthermore, melatonin reduced the expression of NLRP3, ASC, cleaved caspase-1, gasdermin D (GSDMD), and cleaved GSDMD, and decreased the number of Iba1/interleukin-1ß-positive cells. In conclusion, melatonin ameliorated retinal structure, prevented retinal dysfunction after AOH, and exerted a neuroprotective effect via inhibition of PANoptosis in AOH retinas.

Compositions and Biological Activities of Pomegranate Peel Polyphenols Extracted by Different Solvents.

Pomegranate peel extract (PPE), which is abundant in polyphenols, holds immerse prospects for the treatment of airway infection. In this study, water and ethanol of 30%, 50%, and 80% were used to prepare PPE. A total of 18 phenols belonging to 8 categories of polyphenols were identified in PPE by HPLC-MS/MS. The PPE from the four extraction solvents possessed different antioxidant, antibacterial, and anti-inflammatory activities. Principal component analysis revealed that though total flavonoids (TFs), total polyphenols (TPs), and total tannins (TTs) were responsible for the reducing power of PPE, only TFs contributed to the effect of PPE in inhibiting lipid membrane peroxidation. TPs, TTs, and punicalagin were positively correlated with the antibacterial strength against S. aureus while TTs alone contributed to the inhibition of methicillin-resistant S. aureus, implying the crucial role of TT in suppressing bacteria. Meanwhile, TTs was associated with the prevention of IL-6 release. The PPE with higher contents of TPs, TTs, and punicalagin had a weaker capacity to decrease nitric oxide secretion. PPE of 30% ethanol gained the highest integrated score due to its stronger antioxidant, antibacterial, and anti-inflammatory activities. It is a suitable candidate for the therapy of respiratory tract infection.

Nitric Oxide-Releasing Platforms for Treating Cardiovascular Disease.

Cardiovascular disease (CVD) is the first leading cause of death globally. Nitric oxide (NO) is an important signaling molecule that mediates diverse processes in the cardiovascular system, thereby providing a fundamental basis for NO-based therapy of CVD. At present, numerous prodrugs have been developed to release NO in vivo. However, the clinical application of these prodrugs still faces many problems, including the low payloads, burst release, and non-controlled delivery. To address these, various biomaterial-based platforms have been developed as the carriers to deliver NO to the targeted tissues in a controlled and sustained manner. This review aims to summarize recent developments of various therapeutic platforms, engineered to release NO for the treatment of CVD. In addition, two potential strategies to improve the effectiveness of existing NO therapy are also discussed, including the combination of NO-releasing platforms and either hydrogen sulfide-based therapy or stem cell therapy. Hopefully, some NO-releasing platforms may provide important therapeutic benefits for CVD.