TRß activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA.

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRß fuels cell maturation in lung regeneration. Using a specific TRß agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRß in mice. Cellularly, TRß activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRß activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRß-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

The efficacy of socially assistive robots in improving children's pain and negative affectivity during needle-based invasive treatment: A systematic review and meta-analysis.

BACKGROUND: The ability of socially assistive robots (SARs) to treat dementia and Alzheimer's disease has been verified. Currently, to increase the range of their application, there is an increasing amount of interest in using SARs to relieve pain and negative emotions among children in routine medical settings. However, there is little consensus regarding the use of these robots. OBJECTIVE: This study aimed to evaluate the effect of SARs on pain and negative affectivity among children undergoing invasive needle-based procedures. DESIGN: This study was a systematic review and meta-analysis of randomized controlled trials that was conducted in accordance with the Cochrane Handbook guidelines. METHODS: The PubMed, CINAHL, Web of Science, Cochrane Library, Embase, CNKI, and WanFang databases were searched from inception to January 2024 to identify relevant randomized controlled trials (RCTs). We used the Cochrane Risk of Bias tool 2.0 (RoB2.0) to assess the risk of bias among the included studies, and we used RevMan 5.4 software to conduct the meta-analysis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess the quality of the evidence. RESULTS: Ten RCTs involving 815 pediatric subjects were selected for this review and reported outcomes related to pain and emotions during IV placement, port needle insertion, flu vaccination, blood sampling, and dental treatment. Children undergoing needle-related procedures with SARs reported less anxiety (SMD= -0.36; 95% CI= -0.64, -0.09) and fewer distressed avoidance behaviors (SMD= -0.67; 95% CI= -1.04, -0.30) than did those receiving typical care. There were nonsignificant differences between these groups in terms of in pain (SMD = -0.02; 95% CI = - 0.81, 0.78) and fear (SMD = 0.38; 95% CI= -0.06, 0.82). The results of exploratory subgroup analyses revealed no statistically significant differences based on the intervention type of robots or anesthetic use. CONCLUSIONS: The use of SARs is a promising intervention method for alleviating anxiety and distress among children undergoing needle-related procedures. However, additional high-quality randomized controlled trials are needed to further validate these conclusions. TRIAL REGISTRATION: The protocol of this study has been registered in the database PROSPERO (registration ID: CRD42023413279).

Incidence and predictors of in-stent restenosis following intervention for pulmonary vein stenosis due to fibrosing mediastinitis.

BACKGROUND: Fibrosing mediastinitis (FM) is a rare yet fatal condition, caused by different triggers and frequently culminating in the obstruction of the pulmonary vasculature and airways, often leading to pulmonary hypertension and right heart failure. Percutaneous transluminal pulmonary venoplasty (PTPV) is an emerging treatment for pulmonary vein stenosis (PVS) caused by FM. Our previous study showed as high as 24% of in-stent restenosis (ISR) in FM. However, the predictors of ISR are elusive. OBJECTIVES: We sought to identify the predictors of ISR in patients with PVS caused by extraluminal compression due to FM. METHODS: We retrospectively enrolled patients with PVS-FM who underwent PTPV between July 1, 2018, and December 31, 2022. According to ISR status, patients were divided into two groups: the ISR group and the non-ISR group. Baseline characteristics (demographics and lesions) and procedure-related information were abstracted from patient records and analyzed. Univariate and multivariate analyses were performed to determine the predictors of ISR. RESULTS: A total of 142 stents were implanted in 134 PVs of 65 patients with PVS-FM. Over a median follow-up of 6.6 (3.4-15.7) months, 61 of 134 PVs suffered from ISR. Multivariate analysis demonstrated a significantly lower risk of ISR in PVs with a larger reference vessel diameter (RVD) (odds ratio (OR): 0.79; 95% confidence interval [CI]: 0.64 to 0.98; P = 0.032), and stenosis of the corresponding pulmonary artery (Cor-PA) independently increased the risk of restenosis (OR: 3.41; 95% CI: 1.31 to 8.86; P = 0.012). The cumulative ISR was 6.3%, 21.4%, and 39.2% at the 3-, 6-, and 12-month follow-up, respectively. CONCLUSION: ISR is very high in PVS-FM, which is independently associated with RVD and Cor-PA stenosis. TRAIL REGISTRATION: Chinese Clinical Trials Register; No.: ChiCTR2000033153. URL: http://www.chictr.org.cn .

Nanoarchitectonics of Injectable Biomimetic Conjugates for Cartilage Protection and Therapy Based on Degenerative Osteoarthritis Progression.

Osteoarthritis (OA) is a common age-related degenerative disease characterized by changes in the local tissue environment as inflammation progresses. Inspired by the wind-dispersal mechanism of dandelion seeds, this study develops responsive biomimetic microsphere-drug conjugate for OA therapy and protection. The conjugate integrates dibenzaldehyde polyethylene glycol (DFPEG) with chitosan and polyethylene glycol diacrylate (PEGDA) through dynamic covalent bonds to form a dual-network hydrogel microsphere. Based on the progression of OA, the conjugate with the surface-anchored cyclic peptide cortistatin-14 (CST-14) achieves targeted drug therapy and a self-regulating hydrogel network. In cases of progressing inflammation (pH < 5), CST-14 dissociates from the microsphere surface (viz. the drug release rate increased) and inhibits TNF-α signaling to suppress OA. Concurrently, the monomer DFPEG responsively detaches from the hydrogel network and scavenges reactive oxygen species (ROS) to protect the cartilage tissue. The ROS scavenging of DFPEG is comparable to that of coenzyme Q10 and vitamin C. The degraded PEGDA microspheres provide tissue lubrication through reused conjugates. The rat OA model successfully achieved a synergistic therapeutic effect greater than the additive effect (1 + 1 > 2). This strategy offers an approach for anchoring amine-containing drugs and has marked potential for OA treatment and protection.

Vancomycin-encapsulated hydrogel loaded microarc-oxidized 3D-printed porous Ti6Al4V implant for infected bone defects: Reconstruction, anti-infection, and osseointegration.

Infected bone defect is a formidable clinical challenge. Conventional approaches to prevention and treatment for infected bone defects are unsatisfactory. The key elements of the treatment are bone defect reconstruction, anti-infection, and osteogenesis. Conventional treatment methods remain unsatisfactory owing to the absence of composite integrating materials with anti-infective, and osteogenic activities as well as proper mechanical strength at the same time. In this study, we fabricated a vancomycin-encapsulated hydrogel with bacteria-responsive release properties combined with a shaved porous (submicron-micron) three-dimensional-printed Ti6Al4V implant. The implant surface, modified with submicron-sized pores through microarc oxidation (MAO), showed enhanced osteogenic activity and integrated well with the hydrogel drug release system, enabling sustained vancomycin release. In vitro experiments underscored the commendable antibacterial ability, biosafety, and osteoinductive potential. Effective antibacterial and osteogenic abilities of the implant were further demonstrated in vivo in infected rabbit bone defects. These results showed that the vancomycin-encapsulated hydrogel-loaded microarc-oxidized 3D-printed porous Ti6Al4V can repair the infected bone defects with satisfactory anti-infection and osseointegration effects.

Impact of examined lymph node count on survival outcomes in patients with stage T1-2N0M0 small cell lung cancer undergoing surgery: A retrospective cohort study.

To explore the relationship between the count of examined lymph nodes (ELNs) and survival outcomes in patients with stage T1-2N0M0 small cell lung cancer (SCLC) after surgical treatment. We analyzed data from patients with SCLC in the Surveillance, Epidemiology, and End Results database. The study focused on examining the correlation between the ELN count and both cancer-specific survival (CSS) and overall survival (OS). This relationship was investigated using restricted cubic spline curves within the framework of multivariable Cox regression models. The cutoff value for both CSS and OS was 7 ELN counts. Patients with ELN < 7 had a median CSS of 64 months, significantly lower than 123 months of patients with ELN ≥ 7 (P = .012). Multivariable Cox regression analysis indicated that ELN ≥ 7 was an independent prognostic factor for CSS (hazard ratio = 0.50, 95% confidence interval: 0.30-0.83; P = .007). Similarly, Patients with ELN < 7 had a median OS of 41 months for patients with ELN < 7, compared to 103 months for those with ELN ≥ 7 (P = .004). Multivariable Cox regression analysis confirmed that ELN ≥ 7 was an independent prognostic factor for OS (hazard ratio = 0.54, 95% confidence interval: 0.36-0.81; P = .003). ELN ≥ 7 is recommended as the threshold for evaluating the quality of postoperative lymph node examination and for prognostic stratification in patients with stage T1-2N0M0 SCLC undergoing surgery.

Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

Activation of ß3-AR by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue.

AIMS: ß3-AR (ß3-adrenergic receptor) is essential for cardiovascular homeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate ß3-AR activation-mediated PVAT function in AD/AA. METHODS AND RESULTS: Aortas from patients with thoracic aortic dissection (TAD) were collected to detect ß3-AR expression in PVAT. ApoE-/- and ß-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA, and subsequently received either placebo or mirabegron, a ß3-AR agonist. The results demonstrated an up-regulation of ß3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of ß3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor VEGF-C in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes (LNs) of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. CONCLUSIONS: Our findings illustrated the therapeutic potential of ß3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.

An Experimental Study on the Thermomechanical Coupling Effects of Carbon-Fiber-Reinforced Polyetheretherketone under Dynamic Impact.

Carbon-fiber-reinforced polyetheretherketone (CF/PEEK) composites are widely utilized in aerospace, medical devices, and automotive industries, renowned for their superior mechanical properties and high-temperature resistance. Despite these advantages, the thermomechanical coupling behavior of CF/PEEK under dynamic loading conditions is not well understood. This study aims to explore the thermomechanical coupling effects of CF/PEEK at elevated strain rates, employing Hopkinson bar impact tests and scanning electron microscopy (SEM) for detailed characterization. Our findings indicate that an increase in temperature led to significant reductions in the yield strength, peak stress, and specific energy absorption of CF/PEEK, while fracture strain had no significant effect. For instance, at 200 °C, the yield strength, peak stress, and specific energy absorption decreased by 39%, 37%, and 38%, respectively, compared to their values at 20 °C. Furthermore, as the strain rate increased, the yield strength, peak stress, specific energy absorption, and fracture strain all exhibited strain-hardening effects. However, as the strain rate further increased, above 4000 s-1, the enhancing effect of the strain rate on the yield strength and peak stress gradually diminished. The interaction of the temperature and strain rate significantly affected the mechanical performance of CF/PEEK under high-speed impact conditions. While the strain rate generally enhanced these properties, the strain-hardening effect on the yield strength weakened as the temperature increased, and both the temperature and strain rate contributed to the increase in specific energy absorption. Microdamage mechanism analysis revealed that interface debonding and sliding between the fibers and the matrix were more pronounced under static compression than under dynamic compression, thereby diminishing the efficiency of stress transfer. Additionally, higher temperatures caused the PEEK matrix to soften and exhibit increased viscoelastic behavior, which in turn affected the material's toughness and the mechanisms of stress transfer. These insights hold substantial engineering significance, particularly for the optimization of CF/PEEK composite design and applications in extreme environments.

Biological Fate Tracking of Nitric Oxide-Propelled Microneedle Delivery System Using an Aggregation-Caused Quenching Probe.

Nanoparticle-loaded dissolving microneedles (DMNs) have attracted increasing attention due to their ability to provide high drug loading, adjustable drug release behavior, and enhanced therapeutic efficiency. However, such delivery systems still face unsatisfied drug delivery efficiency due to insufficient driving force to promote nanoparticle penetration and the lack of in vivo fate studies to guide formulation design. Herein, an aggregation-caused quenching (ACQ) probe (P4) was encapsulated in l-arginine (l-Arg)-based nanomicelles, which was further formulated into nitric oxide (NO)-propelled nanomicelle-integrated DMNs (P4/l-Arg NMs@DMNs) to investigate their biological fate. The P4 probe could emit intense fluorescence signals in intact nanomicelles, while quenching with the dissociation of nanomicelles, providing a "distinguishable" method for tracking the fate of nanomicelles at a different status. l-Arg was demonstrated to self-generate NO under the tumor microenvironment with excessive reactive oxygen species (ROS), providing a pneumatic force to promote the penetration of nanomicelles in both three-dimensional (3D)-cultured tumor cells and melanoma-bearing mice. Compared with passive microneedles (P4 NMs@DMNs) without a NO propellant, the P4/l-Arg NMs@DMNs possessed a good NO production performance and higher nanoparticle penetration capacity. In conclusion, this study offered an ACQ probe-based biological fate tracking approach to demonstrate the potential of NO-propelled nanoparticle-loaded DMNs in penetration enhancement for topical tumor therapy.

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer.

How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.

Fibroin nanodisruptor with Ferroptosis-Autophagy synergism is potent for lung cancer treatment.

Chemotherapy agents for lung cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung cancer as it induces non-apoptotic cell death, namely ferroptosis. However, a bottleneck exists in FIN56-induced ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the ferroptosis treatment effect by increasing oxidative stress and connecting with the autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung cancer tumors. Notably, ferroptosis and autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of ferroptosis treatment for lung cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.

Characterization of a novel mitophagy-related 5-genes signature for diagnosis of acute myocardial infarction.

Myocardial infarction (MI) and the ensuing heart failure (HF) remain the main cause of morbidity and mortality worldwide. One of the strategies to combat MI and HF lies in the ability to accurately predict the onset of these disorders. Alterations in mitochondrial homeostasis have been reported to be involved in the pathogenesis of various cardiovascular diseases (CVDs). In this regard, perturbations to mitochondrial dynamics leading to impaired clearance of dysfunctional mitochondria have been previously established to be a crucial trigger for MI/HF. In this study, we found that MI patients could be classified into three clusters based on the expression levels of mitophagy-related genes and consensus clustering. We identified a mitophagy-related diagnostic 5-genes signature for MI using support vector machines-Recursive Feature Elimination (SVM-RFE) and random forest, with the area under the ROC curve (AUC) value of the predictive model at 0.813. Additionally, the single-cell transcriptome and pseudo-time analyses showed that the mitoscore was significantly upregulated in macrophages, endothelial cells, pericytes, fibroblasts and monocytes in patients with ischemic cardiomyopathy, while sequestosome 1 (SQSTM1) exhibited remarkable increase in the infarcted (ICM) and non-infarcted (ICMN) myocardium samples dissected from the left ventricle compared with control samples. Lastly, through analysis of peripheral blood from MI patients, we found that the expression of SQSTM1 is positively correlated with troponin-T (P < 0.0001, R = 0.4195, R2 = 0.1759). Therefore, this study provides the rationale for a cell-specific mitophagy-related gene signature as an additional supporting diagnostic for CVDs.

Calpeptin improves the cognitive function in Alzheimer's disease-like complications of diabetes mellitus rats by regulating TXNIP/NLRP3 inflammasome.

AIMS: Diabetes mellitus (DM) is closely associated with Alzheimer's disease (AD), and is considered an accelerator of AD. Our previous study has confirmed that the Calpain inhibitor Calpeptin may alleviate AD-like complications of diabetes mellitus. This work further investigated its underlying mechanism. MATERIALS AND METHODS: Diabetes mellitus rat model was constructed by a high-fat and high-sugar diet combined with streptozotocin, followed by the administration of Calpeptin. Moreover, rats were micro-injected with LV-TXNIP-OE/vector into the CA1 region of the hippocampus one day before streptozotocin injection. The Morris water maze test assessed the spatial learning and memory ability of rats. Immunohistochemistry and western blotting detected the expression of the pericyte marker PDGFRß, tight junction proteins occludin and ZO-1, calpain-1, calpain-2, APP, Aß, Aß-related, and TXNIP/NLRP3 inflammasome-related proteins. Immunofluorescence staining examined the blood vessel density and neurons in the hippocampus. Evans blue extravasation and fluorescence detected the permeability of the blood-brain barrier (BBB) in rats. Additionally, the oxidative stress markers and inflammatory-related factors were assessed by enzyme-linked immunosorbent assay. RESULTS: Calpeptin effectively reduced the expression of Calpain-2 and TXNIP/NLRP3 inflammasome-related proteins, improved the decreased pericyte marker (PDGFR-ß) and cognitive impairment in hippocampus of DM rats. The neuronal loss, microvessel density, permeability of BBB, Aß accumulation, inflammation, and oxidative stress injury in the hippocampus of DM rats were also partly rescued by calpeptin treatment. The influence conferred by calpeptin treatment was reversed by TXNIP overexpression. CONCLUSIONS: These data demonstrated that calpeptin treatment alleviated AD-like symptoms in DM rats through regulating TXNIP/NLRP3 inflammasome. Thus, calpeptin may be a potential drug to treat AD-like complications of diabetes mellitus.

Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation.

Aim: Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown. Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke. Methods and Results: Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke. In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes. The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection. Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining. Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains. Additionally, Ldha specific knockout in astrocytes (Aldh1l1 CreERT2; Ldha fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease in the volume of cerebral infarction in cKO mice compared to the control groups. Furthermore, blocking the protein Kla formation by inhibiting the writer p300 with its antagonist A-485 significantly alleviates neuronal death and glial activation of cerebral ischemia with a reduction in the protein Kla level, resulting in extending reperfusion window and improving functional recovery for ischemic stroke. Conclusion: Collectively, increased brain lactate derived from astrocytes aggravates ischemic brain injury by promoting the protein Kla formation, suggesting that inhibiting lactate production or the formation of protein Kla at the ischemia stage presents new therapeutic targets for the treatment of ischemic stroke.

Mechanisms and therapeutic targets of ferroptosis: Implications for nanomedicine design.

Ferroptosis is a nonapoptotic form of cell death and differs considerably from the well-known forms of cell death in terms of cell morphology, genetics, and biochemistry. The three primary pathways for cell ferroptosis are system Xc-/glutathione peroxidase 4 (GPX4), lipid metabolism, and ferric metabolism. Since the discovery of ferroptosis, mounting evidence has revealed its critical regulatory role in several diseases, especially as a novel potential target for cancer therapy, thereby attracting increasing attention in the fields of tumor biology and anti-tumor therapy. Accordingly, broad prospects exist for identifying ferroptosis as a potential therapeutic target. In this review, we aimed to systematically summarize the activation and defense mechanisms of ferroptosis, highlight the therapeutic targets, and discuss the design of nanomedicines for ferroptosis regulation. In addition, we opted to present the advantages and disadvantages of current ferroptosis research and provide an optimistic vision of future directions in related fields. Overall, we aim to provide new ideas for further ferroptosis research and inspire new strategies for disease diagnosis and treatment.

Nicotinamide Suppresses Hyperactivation of Dendritic Cells to Control Autoimmune Disease through PARP Dependent Signaling.

Dendritic cells (DCs) are crucial in initiating and shaping both innate and adaptive immune responses. Clinical studies and experimental models have highlighted their significant involvement in various autoimmune diseases, positioning them as promising therapeutic targets. Nicotinamide (NAM), a form of vitamin B3, with its anti-inflammatory properties, has been suggested, while the involvement of NAM in DCs regulation remains elusive. Here, through analyzing publicly available databases, we observe substantial alterations in NAM levels and NAM metabolic pathways during DCs activation. Furthermore, we discover that NAM, but not Nicotinamide Mononucleotide (NMN), significantly inhibits DCs over-activation in vitro and in vivo. The suppression of DCs hyperactivation effectively alleviates symptoms of psoriasis. Mechanistically, NAM impairs DCs activation through a Poly (ADP-ribose) polymerases (PARPs)-NF-κB dependent manner. Notably, phosphoribosyl transferase (NAMPT) and PARPs are significantly upregulated in lipopolysaccharide (LPS)-stimulated DCs and psoriasis patients; elevated NAMPT and PARPs expression in psoriasis patients correlates with higher psoriasis area and severity index (PASI) scores. In summary, our findings underscore the pivotal role of NAM in modulating DCs functions and autoimmune disorders. Targeting the NAMPT-PARP axis emerges as a promising therapeutic approach for DC-related diseases.

Correlations between Immunoinflammatory Factor Levels and Cognitive Functions and Brain Structural Magnetic Resonance Imaging Features among Patients with Primary Schizophrenia.

BACKGROUND: Schizophrenia is associated with significant cognitive impairment. However, the pathophysiological mechanisms underlying cognitive dysfunction in schizophrenia remain unclear. Based on the latest concept of cognition, immunoinflammatory factors and structural magnetic resonance imaging (sMRI) features of the brain are considered markers of schizophrenia. This study explored the correlations between cognitive function and immunoinflammatory factors and sMRI in primary schizophrenia patients. METHODS: Non-interventional cross-sectional study was conducted, including 21 patients with primary schizophrenia, who were identified based on the Diagnostic and Statistical Manual, Fifth Edition (DSM-V) and grouped under the observation group. Thirty healthy volunteers with age, gender, hand dominance, and education duration matched with those of the primary schizophrenia patients were recruited to the control group. All subjects underwent sMRI examination. MATRICS consensus cognitive battery (MCCB) was employed to assess the cognitive functions among patients with primary schizophrenia. The levels of serum amyloid A (SAA), monocyte chemoattractant protein 1 (MCP-1), and chitinase-3-like protein 1 (YKL-40) were measured by means of enzyme-linked immunosorbent assay (ELISA). Pearson's correlation analysis was carried out to analyze the correlation between immunoinflammatory factor levels and cognitive functions as well as brain sMRI features. RESULTS: The scores for all MCCB items and the total score for the observation group were apparently lower than those for the control group (p < 0.001), while the YKL-40 and SAA levels were notably higher in the observation group (t = 3.406, p < 0.05; t = 5.656, p < 0.001). Compared to the control group, the observation group exhibited reduced volumes of left and right insular lobes, left and right anterior cingulate cortexes, left and right hippocampi, right parahippocampal gyrus, right amygdala, left inferior occipital lobe, left superior temporal lobe, left temporal pole, and left middle and inferior temporal lobes (p < 0.001). The levels of YKL-40 and SAA were both negatively correlated with MCCB score (r = -0.3668, p = 0.004; r = -0.8495, p < 0.001). The volumes of right insular lobe, left and right anterior cingulate cortexes, right parahippocampal gyrus, right amygdala, and gray matter in left middle temporal lobe were all negatively correlated with the levels of YKL-40 and SAA (p < 0.05). CONCLUSION: Cognitive impairment in patients with primary schizophrenia is associated with increased serum SAA and YKL-40 levels and decreased gray matter volume.

Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.

Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an attractive drug target for reproductive diseases. Here, we demonstrated that KISS1R can couple to the Gi/o pathway besides the well-known Gq/11 pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-Gq and KISS1R-Gi complexes bound to the synthetic agonist TAK448 and structure of KISS1R-Gq complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling.