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Pyroptosis is an inflammasome‐dependent form of programmed cell death that is mediated by caspases‐1, ‐4, ‐5, and ‐11, and the gasdermin protein family. It is characterized by the rupture of cell membrane and the subsequent release of cell contents and interleukins, leading to inflammatory reaction and activation of the immune system. Recent studies have suggested that pyroptosis plays a role in the development of gastrointestinal tumors, impeding tumor generation and progression as well as providing a favorable microenvironment for tumor growth. In this review we outlined the current knowledge regarding the implications of pyroptosis in gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Background: Ptosis causes an extra folding of tissues lateral to the eyebrows. Different techniques aimed to correct this with varying outcomes and limitations. We analyzed the long-term results of an office-based technique for deep-plane subgaleal lift under local anesthesia and assessed patient satisfaction. Methods: We retrospectively analyzed the long-term outcome of a modified temporal brow lift technique in patients with lateral eyebrow ptosis. The incision lines were marked 3–5 mm behind the temporal lines, and then at the deep temporal fascia layer was dissected. The three key steps in the procedure included (1) detecting the sentinel vein by transillumination; (2) cutting the lateral orbital ligament; and (3) releasing the superior temporal septum by blunt and sharp dissections. Finally, the tissues were fixed to the deep temporal fascia. After 1 and 12–15 months, the distance between the lateral brow and lateral canthus was measured. Results: We operated on 44 Iranian women (ranging from 28 to 51 years) between 2019 and 2021. The mean post-surgical brow elevation was 11.5 mm (95% CI 10.8–12.2; 133.4% improvement) after 1 month and 7.2 mm (6.4–8.1; 88.2% improvement) after 12–15 months. Minor complication (i.e., the stitch abscess) was observed in 6.8% of patients (three patients). Major complications included a complete relapse (two patients; 4.5%) and alopecia (one patient; 2.3%). Overall, 88.6% of patients (39 patients) were satisfied with the outcome. Conclusions: Lateral brow ptosis could be corrected with a modified temporal lift technique using transillumination for the detection of the sentinel vein and preservation of the temporal branch of the facial nerve. The durability of this procedure could be enhanced with a complete release of septal adhesions and proper fixations. Level of evidence: level IV, therapeutic study. [ABSTRACT FROM AUTHOR]

Background Acute invasive fungal rhinosinusitis (AIFR) is a rare, rapidly progressive, and life-threatening infection involving the nasal cavity and paranasal sinuses. Purpose of this study is to describe imaging features of coronavirus disease-2019 (COVID-19)-associated AIFR. Methods This was a retrospective observational study. Inclusion criteria: (1) post-COVID-19 patients with fungal rhinosinusitis detected on potassium hydroxide smear or histopathology; (2) onset of symptoms (facial pain, dental pain, facial swelling or discoloration, nasal bleed, periorbital swelling, ptosis, redness of eyes, vision loss) less than 4 weeks; and (3) magnetic resonance imaging/computed tomography (MRI/CT) done within 5 days before surgery. Exclusion criteria: (1) cases of sinusitis without a history of previous COVID-19 infection; and (2) cases in whom fungal hyphae were not demonstrated on pathological examination. Noncontrast CT and dedicated MRI sequences were done initially. Site of involvement, unilateral/bilateral involvement, pattern of mucosal thickening, enhancement pattern, periantral invasion, orbital invasion, intracranial involvement, perineural spread, vascular involvement, and bony involvement were recorded. CT and MRI imaging features were compared. Results Analysis of 90 studies (CT and MRI) in 60 patients was done. Most common site of involvement was ethmoid followed by maxillary sinus. Bilateral disease was more common. Mucosal thickening with T2 hypointense septations was seen in 88.4% MRI studies. Periantral and orbital involvement was seen, respectively, in 84.6% and 55.7% cases of MRI. Intracranial involvement was noted in form of meningitis, cerebritis, abscess, infarct, hemorrhage, cavernous sinus, or perineural invasion. Vascular involvement was noted in form of vascular occlusion (n = 3), vascular narrowing (n = 3), and pseudoaneurysm (n = 2). MRI was more sensitive in detecting periantral invasion, deep infratemporal fossa, cavernous sinus involvement, perineural invasion, optic nerve involvement, and vascular occlusion and narrowing, while CT was superior in identification of bony erosions. Conclusion Early recognition of AIFR in post-COVID-19 patients is important to prevent disease-related morbidity/mortality. Several rarely described findings are noted in our series of AIFR, like optic nerve involvement, pituitary fungal abscess, perineural spread, fungal aneurysms, and arteritis-related posterior circulation infarcts. MRI is superior for early detection of disease and in estimation of extent of disease, compared with CT. Imaging can help in early detection of AIFR, which has a significant impact on patient outcome. [ABSTRACT FROM AUTHOR]

Cuproptosis is a newly discovered cell death form with a unique mechanism. Seven genes have been identified to facilitate the process. To explore the roles of cuproptosis in different cancers, we first used Gene Expression Profiling, Interactive Analysis, version 2, and cBioPortal to analyze expression, prognosis and mutation conditions in different cancers from The Cancer Genome Atlas (TCGA). Then, we conducted single sample gene set enrichment analysis to combine the signature of the cuproptosis-promoting genes for all TCGA cancers. Moreover, we performed a survival analysis to explore if cuproptosis-score could independently influence clinical outcomes. Next, we compared pathway enrichment, immune infiltration, gene set activity and gene mutation between different cuproptosis-score groups. Finally, based on the intersected genes from difference analysis and weighted gene co-expression network analysis, consensus clustering and Least Absolute Shrinkage and Selection Operator Cox regression were performed and nomograms were constructed. Cuproptosis-score was associated with a favorable prognosis in eight TCGA cancers. Cancer-associated fibroblasts, B cells, neutrophils and mast cells were generally less abundant, and ferroptosis activity was higher in high cuproptosis-score groups. The novel classifications could differentiate patients' overall survival, and the risk models could effectively predict patients' outcomes in kidney, renal clear cell carcinoma, liver hepatocellular carcinoma, mesothelioma and stomach adenocarcinoma. Cuproptosis activity was closely related to the prognosis of several cancers. Its effects on the immune microenvironment and its relationship with other cell death modes, especially ferroptosis, may become the focus of further research. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of levator resection and frontal sling surgery in patients with ptosis due to third cranial nerve (3rd CN) paralysis. Methods: A total of 16 patients who underwent frontal sling surgery (n=9, group 1) and levator resection (n=7, group 2) during follow-up due to ptosis due to 3rd CN paralysis in the oculoplastic surgery unit of our clinic were included in the study. The surgical procedure, preoperative levator muscle function test, marginal reflex distance 1 (MRD1) and palpebral fissure height (PFH) were recorded during follow-up. The MRD1 and PFH values of the patients in both groups were recorded in the postoperative 1st month and 12th month examinations, and during the last examination. All data were statistically compared between the two groups. Results: Seven (43.8%) patients were female and 9 (56.3%) were male. Preoperative mean MRD1 values in group 1 and group 2 were -1.78±1.56 mm (-4-0) and -1.29±0.76 mm (-2-0), respectively. In groups 1 and 2, both MRD1 and PFH showed a statistically significant increase compared with preoperative measurements (p=0.277). While postoperative success was 88.8% in the 1st month in group 1, it was 55.5% in the 12th month. In group 2, postoperative success rates were 85.7% in the 1st month and 71.4% in the 12th month examinations. In the comparison between the groups, MRD1 and PFH did not differ statistically (p=0.216). Conclusion: Although patients with ptosis due to 3rd CN paralysis are difficult to treat, they can be effectively and safely treated with frontal sling surgery or levator resection. [ABSTRACT FROM AUTHOR]

Nuclear factor e2–related factor 2 (Nrf2) plays a key role in cellular resistance to oxidative stress injury. Oxidative stress injury, caused by Nrf2 imbalance, results in increased pyroptosis, DNA damage, and inflammatory activation, which may lead to the arrest of alveolar development and bronchopulmonary dysplasia (BPD) in premature infants under hyperoxic conditions. We established a BPD mouse model to investigate the effects of tert-butylhydroquinone (TBHQ), an Nrf2 activator, on oxidative stress injury, pyroptosis, NLRP3 inflammasome activation, and alveolar development. TBHQ reduced abnormal cell death in the lung tissue of BPD mice and restored the number and normal structure of the alveoli. TBHQ administration activated the Nrf2/heme oxygenase-1 (HO-1) signaling pathway, resulting in the decrease in the following: reactive oxygen species (ROS), activation of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, and IL-18 and IL-1β expression and activation, as well as inhibition of pyroptosis. In contrast, after Nrf2 gene knockout in BPD mice, there was more severe oxidative stress injury and cell death in the lungs, there were TUNEL + and NLRP3 + co-positive cells in the alveoli, the pyroptosis was significantly increased, and the development of alveoli was significantly blocked. We demonstrated that TBHQ may promote alveolar development by enhancing Nrf2-induced antioxidation in the lung tissue of BPD mice and that the decrease in the NLRP3 inflammasome and pyroptosis caused by Nrf2 activation may be the underlying mechanism. These results suggest that TBHQ is a promising treatment for lung injury in premature infants with hyperoxia. [ABSTRACT FROM AUTHOR]

Background: It is now understood that ferroptosis plays a significant role in the progression of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke extract (CSE). However, the mechanisms underlying this relationship remain largely unclear. Methods: In this study, we established a COPD mouse model through exposure to cigarette smoke particulates, followed by H&E staining, analysis of bronchoalveolar lavage fluid, and immunohistochemistry assay. A549 cells were exposed to increasing concentrations of CSE, with the addition of the ferroptosis activator erastin or the inhibitor Fer-1. Cell viability, LDH (lactate dehydrogenase) release, inflammatory cytokines, total ROS (reactive oxygen species), and lipid ROS were measured using the corresponding assay kits. The acetylation level of GNPAT was determined through immunoprecipitation. We assessed the expression levels of molecules involved in plasmalogen biosynthesis (FAR1, AGPS, and GNPAT), GPX4, and SIRT4 using quantitative real-time PCR, western blot analysis, and immunofluorescence staining. Results: CSE-induced lung tissue damage was initially observed, accompanied by oxidative stress, ferroptosis, and increased plasmalogen biosynthesis molecules (FAR1, AGPS, and GNPAT). CSE also induced ferroptosis in A549 cells, resulting in reduced cell viability, GSH, and GPX4 levels, along with increased LDH, ROS, MDA (malondialdehyde) levels, oxidized lipids, and elevated FAR1, AGPS, and GNPAT expression. Knockdown of GNPAT mitigated CSE-induced ferroptosis. Furthermore, we found that CSE regulated the acetylation and protein levels of GNPAT by modulating SIRT4 expression. Importantly, the overexpression of GNPAT countered the inhibitory effects of SIRT4 on ferroptosis. Conclusions: Our study revealed GNPAT could be deacetylated by SIRT4, providing novel insights into the mechanisms underlying the relationship between CSE-induced ferroptosis and COPD. [ABSTRACT FROM AUTHOR]

Purpose: Lipoyltransferase 1 (LIPT1) has been recently identified as a cuproptosis‑related gene. As a key enzyme of lipoic acid metabolism, LIPT1 has been revealed to play important roles in hereditary diseases involved with lipoic acid biosynthesis defects, while its roles in hepatocellular carcinoma (HCC) remain to be elucidated. Hence, we aimed to explore the roles and mechanisms of LIPT1 in HCC progression. Methods: The expression of LIPT1 in HCC tissues and its clinical significance for HCC were evaluated by bioinformatic analysis and in our patient cohort. The influences of LIPT1 on the growth, migration, and lipid metabolism of HCC cells were assessed in vitro. The underlying mechanisms were explored using gene set enrichment analysis (GSEA) and molecular experiments. Results: LIPT1 expression was significantly elevated in HCC tissues compared to the normal tissues, and such upregulation was associated with more malignant pathological features and poor prognosis of patients with HCC. LIPT1 silencing significantly inhibited cell proliferation, migration, and lipid content. GSEA revealed that LIPT1 upregulation was significantly associated with various cancer-associated signaling pathways, including the PI3K-AKT signaling pathway and the Wnt/β-catenin pathway. Further molecular experiments indicated that LIPT1 silencing repressed the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and inactivated the AKT/GSK-3β/β-catenin signaling axis. Conclusions: Upregulation of LIPT1 is involved in metabolic dysregulation of fatty acid and poor prognosis of HCC patients, which suggests that LIPT1 plays an important role in reprogramming lipid metabolism and could act as a potential prognostic marker and therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Background: To correct mild and moderate congenital ptosis, traditional surgical techniques usually include dissection of the Müller’s muscle. Meanwhile, both the levator palpebrae superioris and the Müller’s muscle play a synergistic role to elevate the upper eyelid. Thus, to protect the Müller muscle and minimize injury, we developed and applied a levator imbrication technique in patients with mild and moderate congenital ptosis and followed it up to evaluate its clinical efficacy. Methods: This retrospective case series included 53 patients with mild and moderate congenital ptosis, all of whom had undergone ptosis correction using the levator imbrication technique at the Plastic and Aesthetic Department of the Second Affiliated Hospital of Zhengzhou University between June 2018 and June 2020. The outcomes of correction, upper eyelid appearance, and operative complications were observed and analyzed. The postoperative follow-up was 3–12 months. Results: Fifty cases of ptosis were fully corrected, and the bilateral double eyelids were smooth and natural. The eyelids of 20 patients were incompletely closed immediately after the operation but were able to close spontaneously within 2 weeks. No serious complications such as exposure keratitis were reported. Three patients with undercorrection underwent reoperation 3 months after the first operation, and ptosis was corrected. Conclusion: The levator imbrication technique for mild and moderate congenital ptosis is simple to perform and shortens the operation time with less damage, stable postoperative outcomes, and no long-term complications. [ABSTRACT FROM AUTHOR]

Background: Ferroptosis is a new therapeutic modality that holds promise for pancreatic cancer treatment. Dihydroartemisinin is the first generation of artemisinin derivatives with antimalarial activity, and it exerts anticancer activity through iron-dependent reactive oxygen species generation. This study assessed the potential value of dihydroartemisinin to induce ferroptosis in pancreatic cancer. Methods: The mRNA expression profiles, along with the corresponding clinical information of individuals diagnosed with pancreatic cancer, were acquired from publicly accessible repositories. We analyzed the association of ferroptosis-related gene expression with pancreatic cancer overall survival via The Cancer Genome Atlas. Utilizing molecular docking techniques, we evaluated the potential binding configurations of dihydroartemisinin with genes associated with ferroptosis. Moreover, in-vitro experiments were performed to verify these predicted outcomes. Results: In the The Cancer Genome Atlas cohort, there were significant differences in the expression levels of ten genes associated with ferroptosis when comparing pancreatic cancer tissues with normal tissues. Among them, a strong association between NQO1 expression and unfavorable prognosis was observed. Dihydroartemisinin can regulate target gene expression by interacting with the corresponding binding site, and a ferroptosis inhibitor could reverse the above events. Conclusion: The NQO1 gene, which is associated with ferroptosis, emerges as a robust and autonomous prognostic indicator for individuals with pancreatic cancer. Dihydroartemisinin may contribute to pancreatic cancer progression via the regulation of ferroptosis. [ABSTRACT FROM AUTHOR]

Purpose: To introduce a new supporting marker for discriminating different grades of ptosis called Sector Area Index (SAI) and a semi-automated technique to calculate it. Methods: In this cross-sectional comparative case series, a circle enclosing the intercanthal distance was automatically drawn after choosing two points as the medial and lateral canthus and manually selecting the palpebral fissure region. Finally, 15-degree apart sectors are applied to the enclosed circle. SAI was measured automatically by dividing the area of each 15-degree sector marked with the upper eyelid contour by the total area of the sector marked with the edge of the surrounding circle. SAI values and inter-eye SAI differences were compared between patients with different grades of ptosis as well as normal patients. Results: In the current study, 106 eyes were recruited (30, 25, 27, and 24 in the control, mild, moderate, and severe ptosis groups, respectively). Mean values of SAI in all sectors showed a decreasing trend from normal individuals toward patients with severe ptosis. The mean difference values of SAI between study eyes and fellow eyes in all four groups of patients showed a statistically significant difference (p < 0.05). In a pairwise comparison between groups, mean values of SAI in all nasal sectors from 15° to 60° showed a statistically significant difference between all groups (p < 0.05). Conclusion: The mean difference of SAI between study eyes and fellow eyes, including eyelid curvature, especially in 15°–60° and 120°–165° sectors, can demonstrate differentiating performance for detecting and discriminating varying grades of ptosis. [ABSTRACT FROM AUTHOR]

The central nervous system regulates all aspects of physiology to some extent. Neurodegenerative diseases (NDDs) lead to the progressive loss and dysfunction of neurons, which are particularly evident in Alzheimer's disease, Parkinson's disease, and many other conditions. NDDs are multifactorial diseases with complex pathogeneses, and there has been a rapid increase in the prevalence of NDDs. However, none of these diseases can be cured, making the development of novel treatment strategies an urgent necessity. Numerous studies have indicated how pyroptosis induces inflammation and affects many aspects of NDD. Therefore, components related to pyroptosis are potential therapeutic candidates and are attracting increasing attention. Here, we review the role of pyroptosis in the pathogenesis of NDDs and potential treatment options. Additionally, several of the current drugs and relevant inhibitors are discussed. Through this article, we provide theoretical support for exploring new therapeutic targets and updating clinical treatment strategies for NDDs. Notably, pyroptosis, a recently widely studied mode of cell death, is still under-researched compared to other traditional forms of cell death. Moreover, the focus of research has been on the onset and progression of NDDs, and the lack of organ-specific target discovery and drug development is a common problem for many basic studies. This urgent problem requires scientists and companies worldwide to collaborate in order to develop more effective drugs against NDDs. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 Envelope protein (E) is one of the crucial components in virus assembly and pathogenesis. The current study investigated its role in the SARS-CoV-2-mediated cell death and inflammation in lung and gastrointestinal epithelium and its effect on the gastrointestinal-lung axis. We observed that transfection of E protein increases the lysosomal pH and induces inflammation in the cell. The study utilizing Ethidium bromide/Acridine orange and Hoechst/Propidium iodide staining demonstrated necrotic cell death in E protein transfected cells. Our study revealed the role of the necroptotic marker RIPK1 in cell death. Additionally, inhibition of RIPK1 by its specific inhibitor Nec-1s exhibits recovery from cell death and inflammation manifested by reduced phosphorylation of NFκB. The E-transfected cells' conditioned media induced inflammation with differential expression of inflammatory markers compared to direct transfection in the gastrointestinal-lung axis. In conclusion, SARS-CoV-2 E mediates inflammation and necroptosis through RIPK1, and the E-expressing cells' secretion can modulate the gastrointestinal-lung axis. Based on the data of the present study, we believe that during severe COVID-19, necroptosis is an alternate mechanism of cell death besides ferroptosis, especially when the disease is not associated with drastic increase in serum ferritin. [ABSTRACT FROM AUTHOR]

Ptosis is a droop of the upper lid. It is an important observation for facial practitioners to recognise, as it can have implications in the decisions made regarding treatment. There are several causes of ptosis and not all of them stem from eyelid pathology. In this article, the author discusses the different types of ptosis; how to identify ptosis; how to examine; and when to refer or refuse aesthetic treatment. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To identify prevalence of blepharoptosis and lower lid laxity in dermatochalasis patients for paying more attention to it. Patients and Methods: A cross sectional study in which 83 patients visiting Ophthalmology Department - Almouassat University Hospital between 2020 and 2021. We take patients who have dermatochalasis despite their complaints. All patients underwent slit-lamp examination, measurement of marginal reflex distance MRD1 , lid distraction and snap back test. Based on these tests we determine the presence of blepharoptosis and lower lid laxity and their degrees. Results: A total of 83 patients were enrolled in the study. Mean age of patients was 64.4, 53.01% of participants were female. 27.7 % of patients had blepharoptosis. 65.2 % of patients had mild ptosis, 34.8 % had moderate ptosis and there was no severe ptosis in study group. 30.1% had lower lid laxity 19 of them were male, 72% were degree 1 and 28% were degree 2. Conclusion: The incidence of blepharoptosis and lower lid laxity increases with age especially those with periocular changes.

Objective To compare the efficacy of three surgical methods in clinical treatment of blepharoptosis: conjoint fascial sheath suspension, frontalis muscle suspension, and shortening of musculus levator palpebrae superioris. Methods Articles related to the three surgical methods were retrieved from Chinese and English databases such as CNKI, Wanfang, VIP, PubMed, Embase, and The Cochrane Library. Data were extracted for network Meta-analysis. Results This study included 28 studies and 1 816 patients. Meta-analysis showed that conjoint fascial sheath suspension outperformed frontalis muscle suspension and shortening of musculus levator palpebrae superioris. Moreover, there was no significant difference between frontalis muscle suspension and shortening of musculus levator palpebrae superioris. The SUCRA curve predicted that the efficacy of three surgical methods in clinical treatment of blepharoptosis was in the following order: conjoint fascial sheath suspension > frontalis muscle flap suspension > shortening of musculus levator palpebrae superioris. Conclusion In the surgical treatment of blepharoptosis, conjoint fascial sheath suspension shows the best outcome. However, plastic surgeons should make comprehensive choices based on the actual clinical situation.

Background The position of the eyebrows is critical when planning blepharoptosis surgery. However, insufficient scholarly attention has been paid to the details of postoperative eyebrow height changes at each anatomical landmark. This study investigated the effect of blepharoptosis surgery on brow height and evaluated the change in brow position. Methods After a retrospective review of 247 patients, this study analyzed 53 patients (106 eyelids) who underwent levator and Müller’s complex advancement between March 2010 and January 2022. Brow heights were measured from the distance between the upper brow margin of each landmark and horizontal line of pupillary center on a digital photograph. Results The mean change of eyebrow lowering was 1.54 mm (P

Background Elderly patients often have complications of blepharoptosis surgery that can result in the appearance or exacerbation of superficial punctate keratopathy (SPK). However, postoperative changes to SPK status have not been previously reported. We used subjective assessment of symptoms and measurement of SPK scale classification to investigate the safety and efficacy of blepharoptosis surgery in elderly patients.

Primary amyloidosis of the conjunctiva and eyelid is a rare and often misdiagnosed condition. It is characterized by the deposition of insoluble amyloid fibrils, which are misfolded proteins, in the body. Amyloidosis can be systemic or localized with different types of amyloid fibril proteins identified using mass spectrometry. Ocular involvement in amyloidosis can lead to corneal dystrophies, glaucoma, vitreous opacities, and other symptoms. Diagnosis involves clinical examination and histopathological assessment. Treatment options depend on the extent of involvement and may include surgical excision, glaucoma management, vitrectomy, or liver transplantation in rare cases. We present a rare case of localized conjunctival amyloidosis initially misdiagnosed as pyogenic granuloma, with clinical symptoms of ptosis, periorbital swelling, and conjunctival lesions. The patient underwent excision of the lesions, and subsequent evaluation did not reveal systemic amyloidosis. Ocular amyloidosis requires careful diagnosis and consideration of systemic involvement for appropriate management. [ABSTRACT FROM AUTHOR]

Tanu Rajput,1 Jyoti Mahawar,2 Mahendra Singh3 1Department of Paramedical, Starex University, Gurugram, Haryana, India; 2Department of Paramedical, NIMS University, Jaipur, India; 3Department of Optometry and Vision Science, CL Gupta Eye Institute, Moradabad, UP 244001, IndiaCorrespondence: Mahendra Singh, Email optommahendrasing@gmail.com

Purpose: Laryngeal squamous cell carcinomas (LSCCs) are aggressive tumors with the second-highest morbidity rate in patients with head and neck squamous cell carcinoma. Cuproptosis is a type of programmed cell death that impacts tumor malignancy and progression. The purpose of this study was to investigate the relationship between cuproptosis-related long non-coding RNAs (crlncRNAs) and the tumor immune microenvironment and chemotherapeutic drug sensitivity in LSCC, and crlncRNA impact on LSCC malignancy. Materials and methods: Clinical and RNA-sequencing data from patients with LSCC were retrieved from the Cancer Genome Atlas. Differentially expressed prognosis-related crlncRNAs were identified based on univariate Cox regression analysis, a crlncRNA signature for LSCC was developed and validated using LASSO Cox regression. Finally, the effect of LINC02454, the core signature crlncRNA, on LSCC malignancy progression was evaluated in vitro and in vivo. Results: We identified a four-crlncRNA signature (LINC02454, AC026310.1, AC090517.2, and AC000123.1), according to which we divided the patients into high- and low-risk groups. The crlncRNA signature risk score was an independent prognostic indicator for overall and progression-free survival, and displayed high predictive accuracy. Patients with a higher abundance of infiltrating dendritic cells, M0 macrophages, and neutrophils had worse prognoses and those in the high-risk group were highly sensitive to multiple chemotherapeutic drugs. Knockdown of LINC02454 caused tumor suppression, via cuproptosis induction. Conclusions: A novel signature of four crlncRNAs was found to be highly accurate as a risk prediction model for patients with LSCC and to have potential for improving the diagnosis, prognosis, and treatment of LSCC. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 is associated with tumours and inflammatory diseases. However, the role of TRIM45 in SAE and the relationship between TRIM45 and microglial pyroptosis are unknown. In this study, we found that TRIM45 played an important role in regulating microglial pyroptosis and the molecular mechanism. Methods: SAE was induced by intraperitoneal injection of LPS in WT and AAV-shTRIM45 mice. BV2 cells were treated with LPS/ATP in vitro. Cognitive function was assessed by the Morris water maze. Nissl staining was used to evaluate histological and structural lesions. ELISA was used to dectect neuroinflammation. qPCR was used to detect the mRNA levels of inflammatory cytokines, NLRP3, and autophagy genes. Western blotting and immunofluorescence analysis were used to analyse the expression of the proteins. Changes in reactive oxygen species (ROS) in cells were observed by flow cytometry. Changes in mitochondrial membrane potential in BV2 cells were detected by JC-1 staining. Peripheral blood mononuclear cells were extracted from blood by density gradient centrifugation and then used for qPCR, western blotting and flow detection. To further explore the mechanism, we used the overexpression plasmids TRIM45 and Atg5 as well as siRNA-TRIM45 and siRNA-Atg5 to analyse the downstream pathway of NLRP3. The protein and mRNA levels of TRIM45 in peripheral blood mononuclear cells from sepsis patients were examined. Results: Knocking down TRIM45 protected against neuronal damage and cognitive impairment in septic mice. TRIM45 knockdown inhibited microglial pyroptosis and the secretion of inflammatory cytokines in vivo and in vitro, which was mediated by NLRP3/Gsdmd-N activation. Overexpression of TRIM45 could activate NLRP3 and downstream proteins. Further examination showed that TRIM45 regulated the activation of NLRP3 by altering Atg5 and regulating autophagic flux. It was also found that overexpression and knockdown of TRIM45 affected the changes in ROS and mitochondrial membrane potential. Thus, knocking down TRIM45 could reduce microglial pyroptosis, the secretion of proinflammatory cytokines, and neuronal damage and improve cognitive function. In addition, the level of TRIM45 protein in septic patients was increased. There was a positive linear correlation between APACHE II score and TRIM45, between SOFA score and TRIM45. Compared to group GCS > 9, level of TRIM45 were increased in group GCS ≤ 8. Conclusion: TRIM45 plays a key role in neuroinflammation caused by LPS, and the mechanism may involve TRIM45-mediated exacerbation of microglial pyroptosis via the Atg5/NLRP3 axis. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion injury (MIRI) is one of the main reasons for poor prognosis in patients with ischemic cardiomyopathy (ICM). To date, the mechanism remains unknown. As members of the silent information regulator 2 (SIR2) family, both SIRT1 and SIRT3 have been shown to play critical roles in protecting cardiomyocytes against MIRI, but their specific protective mechanism, their interact between the two and their relationship with ferroptosis are still unclear. Hence, in this study, we investigated the interact and specific mechanism of SIRT1 and SIRT3 in protecting cardiomyocytes against MIRI, as well as their association with ferroptosis. Methods: Bioinformatics analysis methods were used to explore the expression of SIRT1 and SIRT3 during MIRI, and then a cell hypoxia/reoxygenation injury model was constructed to verify the results. Then, Pearson correlation analysis was further used to explore the relationship between SIRT1 and SIRT3, whose roles in the regulation of ferroptosis were also analysed by gene knock down, Western Blotting and flow cytometry. Several biomarkers, such as Fe2+ concentration, lipid peroxidation marker MDA and mitochondrial membrane potential (MMP), were used to evaluate changes in ferroptosis. Results: The expression of SIRT1 and SIRT3 was abnormal during MIRI, and SIRT1 was significantly negatively correlated with SIRT3 in the SIRT1-SIRT3 axis. Further analysis revealed that the SIRT1-SIRT3 axis was closely correlated with ferroptosis, and its silencing effectively increase the incidence of ferroptosis. Furthermore, SIRT1-SIRT3 axis silencing was accompanied by changes in PINK1, Parkin, P62/SQSTM1 and LC3 expression. PINK1 silencing significantly increased the incidence of ferroptosis, while resveratrol (Res) and/or honokiol (HKL) effectively reversed the outcome. Conclusion: Abnormalities in the SIRT1-SIRT3 axis promote MIRI through ferroptosis caused by silencing the PINK1/Parkin signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Cuproptosis, the most recently identified and regulated cell death, depends on copper ions in vivo. Copper regulates the pathogenesis of Idiopathic pulmonary fibrosis (IPF), but the mechanism of action underlying cuproptosis in IPF remains unclear. Methods: We identified three cuproptosis patterns based on ten cuproptosisrelated genes using unsupervised consensus clustering. We quantified these patterns using a PCA algorithm to construct a cuproptosis score. ssGSEA and the Cibersort algorithm assessed the immune profile of IPF patients. GSEA and GSVA were used to analyze the functional differences in different molecular patterns. Drug susceptibility prediction based on cuproptosis scores and meaningful gene markers was eventually screened in combination with external public data sets,in vitro experiments and our cases. Results: Of the three types of cuproptosis-related clusters identified in the study, patients in the clusterA, geneclusterB, and score-high groups showed improved prognoses. Moreover, each cluster exhibited differential immune characteristics, with the subtype showing a poorer prognosis associated with an immune overreaction. Cuproptosis score can be an independent risk factor for predicting the prognosis of IPF patients. GSEA showed a significant functional correlation between the score and cuproptosis. The genes AKAP9, ANK3, C6orf106, LYRM7, and MBNL1, were identified as prognostic-related signatures in IPF patients. The functional role of immune regulation in IPF was further explored by correlating essential genes with immune factors. Also, the nomogram constructed by cumulative information from gene markers and cuproptosis score showed reliable clinical application. Conclusions: Cuproptosis patterns differ significantly in the prognosis and immune characteristics of IPF patients. The cuproptosis score and five gene signatures can provide a reliable reference in the prognosis and diagnosis of IPF [ABSTRACT FROM AUTHOR]

Background: Gorlin-Goltz's syndrome (GGS) is an extremely rare autosomal dominant disorder showing a high penetrance and variable expressivity. Gorlin-Goltz's syndrome is an infrequent multisystemic disease, which is usually characterized by numerous basal cell carcinomas, odontogenic keratocysts (OKCs), and musculoskeletal malformations along with neurological, ophthalmic, endocrine, and genital manifestations. There are also multiple manifestations in the domain of ENT and patient may primarily present to an ENT clinician with one of the diverse clinical involvements. Case presentation: We report one such infrequent case of a 24-year-old male patient who presented with an oroantral fistula at our tertiary health care center and was diagnosed to have Gorlin-Goltz's syndrome. The diagnosis was made in our patient by the presence of 4 major and 2 minor criteria. Conclusion: Early diagnosis and management of GGS helps to prevent long-term sequelae including malignancy and oro-maxillofacial deformation. The constellation of symptoms of such rare disorders should be promptly recognized and a high index of suspicion should be maintained. This case report is an appraisal of the diagnosis and management of GGS from an otolaryngological perspective and is being reported here for extreme rarity and clinical interest. [ABSTRACT FROM AUTHOR]

Pyroptosis, a novel form of programmed cell death (PCD) discovered after apoptosis and necrosis, is characterized by cell swelling, cytomembrane perforation and lysis, chromatin DNA fragmentation, and the release of intracellular proinflammatory contents, such as Interleukin (IL) 8, IL-1β, ATP, IL-1α, and high mobility group box 1 (HMGB1). Our understanding of pyroptosis has increased over time with an increase in research on the subject: gasdermin-mediated lytic PCD usually, but not always, requires cleavage by caspases. Moreover, new evidence suggests that pyroptosis induction in tumor cells results in a strong inflammatory response and significant cancer regression, which has stimulated great interest among scientists for its potential application in clinical cancer therapy. It’s worth noting that the side effects of chemotherapy and radiotherapy can be triggered by pyroptosis. Thus, the intelligent use of pyroptosis, the double-edged sword for tumors, will enable us to understand the genesis and development of cancers and provide potential methods to develop novel anticancer drugs based on pyroptosis. Hence, in this review, we systematically summarize the molecular mechanisms of pyroptosis and provide the latest available evidence supporting the antitumor properties of pyroptosis, and provide a summary of the various antitumor medicines targeting pyroptosis signaling pathways. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is a malignancy of the inner epithelial lining of the uterus. While early-stage EC is often curable through surgery, the management of advanced, recurrent and metastatic EC poses significant challenges and is associated with a poor prognosis. Pyroptosis, an emerging form of programmed cell death, is characterized by the cleavage of gasdermin proteins, inducing the formation of extensive gasdermin pores in the cell membrane and the leakage of interleukin-1b (IL-1b) and interleukin-18 (IL-18), consequently causing cell swelling, lysis and death. It has been found to be implicated in the occurrence and progression of almost all tumors. Recent studies have demonstrated that regulating tumor cells pyroptosis can exploit synergies function with traditional tumor treatments. This paper provides an overview of the research progress made in molecular mechanisms of pyroptosis. It then discusses the role of pyroptosis and its components in initiation and progression of endometrial cancer, emphasizing recent insights into the underlying mechanisms and highlighting unresolved questions. Furthermore, it explores the potential value of pyroptosis in the treatment of endometrial cancer, considering its current application in tumor radiotherapy, chemotherapy, targeted therapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Classical biomarkers have been used to classify clear cell renal cell carcinoma (ccRCC) patients in a variety of ways, and emerging evidences have indicated that cuproptosis is closely related to mitochondrial metabolism, thereby accelerating the development and progression of ccRCC. Nevertheless, the specific relationship between cuproptosis and the prognosis and treatment of ccRCC remains unclear. Methods: We comprehensively integrated several ccRCC patient datasets into a large cohort. Following that, we systematically analyzed multi-omics data to demonstrate the differences between two cuproptosis clusters. Results: We identified two cuproptosis clusters in ccRCC patients. Among the two clusters, cluster 1 patients showed favorable prognosis. We then confirmed the significant differences between the two clusters, including more typical cancer hallmarks were enriched in cluster 2 patients; cluster 2 patients were more susceptible to develop mutations and had a lower level of gistic score and mRNAsi. Importantly, both Tumor Immune Dysfunction and Exclusion analysis and subclass mapping algorithm showed that cuproptosis 1 patients were more susceptible to be responded to immunotherapy. In addition, a prognostic signature was successfully developed and also showed prominent predictive power in response to immunotherapy. Conclusion: As a result of our findings, we were able to classify ccRCC patients according to cuproptosis in a novel way. By constructing the cuproptosis clusters and developing the signature, patients with ccRCC could have a more accurate prognosis prediction and better immunotherapy options. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is a severe liver disease caused by disruptions in the body's immune microenvironment. In the early stages of ALF, Kupffer cells (KCs) become depleted and recruit monocytes derived from the bone marrow or abdomen to replace the depleted macrophages entering the liver. These monocytes differentiate into mature macrophages, which are activated in the immune microenvironment of the liver and polarized to perform various functions. Macrophage polarization can occur in two directions: proinflammatory M1 macrophages and anti-inflammatory M2 macrophages. Controlling the ratio and direction of M1 and M2 in ALF can help reduce liver injury. However, the liver damage caused by pyroptosis should not be underestimated, as it is a caspase-dependent form of cell death. Inhibiting pyroptosis has been shown to effectively reduce liver damage induced by ALF. Furthermore, macrophage polarization and pyroptosis share common binding sites, signaling pathways, and outcomes. In the review, we describe the role of macrophage polarization and pyroptosis in the pathogenesis of ALF. Additionally, we preliminarily explore the relationship between macrophage polarization and pyroptosis, as well as their effects on ALF. [ABSTRACT FROM AUTHOR]

Ferroptosis is a regulatory cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress. Many signaling pathways such as iron metabolism, lipid metabolism, and amino acid metabolism precisely regulate the process of ferroptosis. Ferroptosis is involved in a variety of lung diseases, such as acute lung injury, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Increasing studies suggest that ferroptosis is involved in the development of asthma. Ferroptosis plays an important role in asthma. Iron metabolism disorders, lipid peroxidation, amino acid metabolism disorders lead to the occurrence of ferroptosis in airway epithelial cells, and then aggravate clinical symptoms in asthmatic patients. Moreover, several regulators of ferroptosis are involved in the pathogenesis of asthma, such as Nrf2, heme oxygenase-1, mevalonate pathway, and ferroptosis inhibitor protein 1. Importantly, ferroptosis inhibitors improve asthma. Thus, the pathogenesis of ferroptosis and its contribution to the pathogenesis of asthma help us better understand the occurrence and development of asthma, and provide new directions in asthma treatment. This article aimed to review the role and mechanism of ferroptosis in asthma, describing the relationship between ferroptosis and asthma based on signaling pathways and related regulatory factors. At the same time, we summarized current observations of ferroptosis in eosinophils, airway epithelial cells, and airway smooth muscle cells in asthmatic patients. [ABSTRACT FROM AUTHOR]

Poking palpebral conjunctiva evoked upper-eyelid retraction during ophthalmic surgery. Iatrogenic eyelid ptosis occurred if eyelid branch of lachrymal nerve was sectioned. Mesencephalic trigeminal nucleus (Vme) neurons were labeled when tracer injected into lachrymal nerve innervating eyelid Mueller's muscle. Masseter afferent Vme neurons projecting to oculomotor nucleus (III) was observed in toad and rat, which helps amphibians to stare prey when they open mouth widely to prey. We hypothesized single Vme neurons may have peripheral collaterals to both eyelid and masseter muscles. WGA-594 was injected into upper eyelid, and WGA-488 was simultaneously delivered into ipsilateral masseter muscle in the same rat. Then, double labeled Vme neurons were found under both conventional and confocal microscope. Meanwhile, contact of WGA-594 positive eyelid afferent Vme neurons with WGA-488 labeled masseter afferent ones were observed sometimes. Combined with our previous observation of oculomotor projection Vme neurons, we thought WGA-594/488 double labeled Vme cells, at least some of them, are oculomotor projecting ones. Contact between eyelid and masseter afferent Vme neurons are supposed to be electrotonically coupled, based on a line of previous studies. If exogenous or genetic factors make these Vme neurons misinterpret masseter input as eyelid afferent signals, these Vme neurons might feedforward massages to eyelid retractor motoneurons in the III. Besides, oculomotor projecting Vme neurons might be co-fired by adjacent masseter afferent Vme neurons through electrotonic coupling once the masseter muscle is activated. In these cases, Marcus Gunn Syndrome might occur. This finding leads to a new hypothesis for the Syndrome. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome, which belongs to the pyrin domain containing 3 family of NOD-like receptors, has a significant impact on both the innate and adaptive immune responses. Regulating host immune function and protecting against microbial invasion and cell damage, the NLRP3 inflammasome plays a crucial role. By triggering caspase-1, it facilitates the development of the inflammatory cytokines IL-1β and IL-18, and triggers cell pyroptosis, resulting in cell lysis and demise. Common sterile arthritis includes osteoarthritis (OA), rheumatoid arthritis (RA) and gouty arthritis (GA), all of which manifest as bone destruction and synovial inflammation in a complex inflammatory state, placing a significant medical burden on the families of patients and government agencies. In the past few years, there has been a growing interest in investigating the impact of cell pyroptosis on arthritis development, particularly the widespread occurrence of pyroptosis mediated by the NLRP3 inflammasome. The NLRP3 inflammasome's biological properties are briefly described in this review, along with the presentation of the fundamental processes of pyroptosis resulting from its activation. Furthermore, we provide a summary of the advancements made in studying the NLRP3 inflammasome in various forms of arthritis and enumerate the intervention approaches that target the NLRP3-mediated pyroptosis, either directly or indirectly. These discoveries lay the groundwork for future investigations on medications for arthritis, offering fresh approaches for the clinical identification and treatment of this condition. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. Due to the rise in the incidence rate of RA and the limitations of existing therapies, the search for new treatment strategies for RA has become a global focus. Ferroptosis is a novel programmed cell death characterized by iron-dependent lipid peroxidation, with distinct differences from apoptosis, autophagy, and necrosis. Under the conditions of iron accumulation and the glutathione peroxidase 4 (GPX4) activity loss, the lethal accumulation of lipid peroxide is the direct cause of ferroptosis. Ferroptosis mediates inflammation, oxidative stress, and lipid oxidative damage processes, and also participates in the occurrence and pathological progression of inflammatory joint diseases including RA. This review provides insight into the role andmechanism of ferroptosis in RA and discusses the potential and challenges of ferroptosis as a new therapeutic strategy for RA, with an effort to provide new targets for RA prevention and treatment. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly heterogeneous breast tumor type that is highly malignant, invasive, and highly recurrent. Ferroptosis is a unique mode of programmed cell death (PCD) at the morphological, physiological, and molecular levels, mainly characterized by cell death induced by iron-dependent accumulation of lipid peroxides, which plays a substantial role in a variety of diseases, including tumors and inflammatory diseases. TNBC cells have been reported to display a peculiar equilibrium metabolic profile of iron and glutathione, which may increase the sensitivity of TNBC to ferroptosis. TNBC possesses a higher sensitivity to ferroptosis than other breast cancer types. Ferroptosis also occurred between immune cells and tumor cells, suggesting that regulating ferroptosis may remodel TNBC by modulating the immune response. Many ferroptosis-related genes or molecules have characteristic expression patterns and are expected to be diagnostic targets for TNBC. Besides, therapeutic strategies based on ferroptosis, including the isolation and extraction of natural drugs and the use of ferroptosis inducers, are urgent for TNBC personalized treatment. Thus, this review will explore the contribution of ferroptosis in TNBC progression, diagnosis, and treatment, to provide novel perspectives and therapeutic strategies for TNBC management. [ABSTRACT FROM AUTHOR]

Summary: A 9‐month‐old Thoroughbred colt was presented to the University College Dublin Veterinary Hospital for investigation of suspected neck pain. Clinical signs included severe dullness, bilateral mucopurulent nasal discharge, ptosis of the right eyelid, reduced range of motion of the neck and ataxia. Endoscopy of the medial compartment of both guttural pouches showed fungal‐like plaques, from which Aspergillus was cultured. Laser salpingopharyngeal fistulation was performed under standing sedation and the colt received treatment with oral potassium iodide. The colt developed bacteraemia post‐operatively which resolved after antimicrobial treatment. Serial endoscopic evaluation of the guttural pouches showed complete resolution of fungal plaques 4 months post‐operatively. Minimal neurologic deficits remained 6 months post‐operatively. This report highlights the importance of considering guttural pouch mycosis in young horses and those presenting with reduced range of neck motion and neck pain. It offers support for the use of salpingopharyngostomy as an effective treatment method for guttural pouch mycosis and documents its use in the case of bilateral disease confirmed by fungal culture. It also documents the recovery of a horse from GPM with associated severe neurological signs. [ABSTRACT FROM AUTHOR]

Background: The involvement of ferroptosis in the pathogenesis and progression of various cancers has been well established. However, limited studies have investigated the role of ferroptosis-mediated tumor microenvironment (TME) in skin cutaneous melanoma (SKCM). Methods: By leveraging single-cell RNA sequencing data, the nonnegative matrix factorization (NMF) approach was employed to comprehensively characterize and identify distinct gene signatures within ferroptosis-associated TME cell clusters. Prognostic and treatment response analyses were conducted using both bulk datasets and external cancer cohort to evaluate the clinical implications of TME clusters. Results: This NMF-based analysis successfully delineated fibroblasts, macrophages, T cells, and B cells into multiple clusters, enabling the identification of unique gene expression patterns and the annotation of distinct TME clusters. Furthermore, pseudotime trajectories, enrichment analysis, cellular communication analysis, and gene regulatory network analysis collectively demonstrated significant intercellular communication between key TME cell clusters, thereby influencing tumor cell development through diverse mechanisms. Importantly, our bulk RNA-seq analysis revealed the prognostic significance of ferroptosis-mediated TME cell clusters in SKCM patients. Moreover, our analysis of immune checkpoint blockade highlighted the crucial role of TME cell clusters in tumor immunotherapy, facilitating the discovery of potential immunotherapeutic targets. Conclusions: In conclusion, this pioneering study employing NMF-based analysis unravels the intricate cellular communication mediated by ferroptosis within the TME and its profound implications for the pathogenesis and progression of SKCM. We provide compelling evidence for the prognostic value of ferroptosis-regulated TME cell clusters in SKCM, as well as their potential as targets for immunotherapy. [ABSTRACT FROM AUTHOR]

Ipsilateral mydriasis (IM) is usually not acute. However, the acute occurrence of unilateral dilated pupil may result in acute ischemic stroke. Herein, we present 3 patients with IM, lateral eye deviation, ptosis, and contralateral hemiparesis due to isolated occlusion of the pre-communicating segment of the posterior cerebral artery with preservation of the posterior communicating artery, which was successfully treated by emergent mechanical thrombectomy. In a 3-month follow-up, all patients were independent without any neurological deficits. [ABSTRACT FROM AUTHOR]

Aim: Congenital myasthenic syndromes (CMS) are a rare and diverse group of treatable neuromuscular transmission disorders. Diagnosis is often substantially delayed. This study aimed to identify common symptoms of CMS in children and their manifestation to aid diagnosis and early intervention. Methods: We performed a retrospective cohort study, including 18 children (median age 13 years, range 9 years 5 months–18 years 0 month) with CMS. Data on CMS symptoms and their manifestation were extracted from patients' charts and supplemented with parental telephone interviews. Descriptive analyses were used to identify common symptoms. Results: A median diagnostic delay of 4 years and 7 months (interquartile range: 51 months) was observed. Proximal muscle weakness (100%), ptosis (89%), clumsy gait (82%), difficulty eating solid foods (78%) and recurrent respiratory tract infections (72%) were most common in these patients. Symptoms mostly co‐occurred and frequently had a fluctuating character, aggravated by infections or fatigue. Conclusion: Early referral to diagnose CMS is crucial to enable timely initiation of treatment. Heightened attention to a combination of symptoms related to muscle weakness, rather than individual symptoms, should support paediatricians in flagging these neuromuscular disorders. Medical history taking should be tailored to parents' perceptions, asking questions about recognisable symptoms of muscle weakness. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression. Methods: A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer. Results: Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti‐tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy. Conclusions: Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer cases. Neferine is used as a traditional Chinese medicine with many pharmacological effects, including antitumor properties; however, it has not been reported whether neferine plays an anticancer role by causing pyroptosis in NSCLC cells. We used two typical lung cancer cell lines, A549 and H1299, and 42 lung cancer tissue samples to investigate the regulatory effects of neferine on TGF‐β and MST1. We also treated lung cancer cells with different concentrations of neferine to study its effects on lung cancer cell survival, migration, invasion, and epithelial–mesenchymal transition (EMT) as well as on pyroptosis. Lentivirus‐mediated gain‐of‐function studies of TGF‐β and MST1 were applied to validate the roles of TGF‐β and MST1 in lung cancer. Next, we used murine transplanted tumor models to evaluate the effect of neferine treatment on the metastatic capacity of lung cancer tissues. With increasing neferine concentration, the viability, migration, invasion, and EMT capacity of A549 and H1299 cells decreased, whereas pyroptosis increased. Neferine repressed TGF‐β expression to modulate the induction of reactive oxygen species (ROS) by MST1. Overexpression of TGF‐β in either in vitro or mouse‐transplanted A549 cells restored the inhibitory effect of neferine on tumor development. Overexpression of MST1 clearly enhanced pyroptosis. Neferine contributed to pyroptosis by regulating MST1 expression through downregulation of TGF‐β to induce ROS formation. Therefore, our study shows that neferine can serve as an adjuvant therapy for NSCLC patients. [ABSTRACT FROM AUTHOR]

Necroptosis has been reported to be involved in cancer progression and associated with cancer prognosis. However, the prognostic values of necroptosis-related genes (NRGs) in hepatocellular carcinoma (HCC) remain largely unknown. This study aimed to build a signature on the basis of NRGs to evaluate the prognosis of HCC patients. In this study, using bioinformatic analyses of transcriptome sequencing data of HCC (n = 370) from The Cancer Genome Atlas (TCGA) database, 63 differentially expressed NRGs between HCC and adjacent normal tissues were determined. 24 differentially expressed NRGs were found to be related with overall survival (OS). Seven optimum NRGs, determined using Lasso regression and multivariate Cox regression analysis, were used to construct a new prognostic risk signature for predicting the prognosis of HCC patients. Then survival status scatter plots and survival curves demonstrated that the prognosis of patients with high-Riskscore was worse. The prognostic value of this 7-NRG signature was validated by the International Cancer Genome Consortium (ICGC) cohort and a local cohort (Wenzhou, China). Notably, Riskscore was defined as an independent risk factor for HCC prognosis using multivariate cox regression analysis. Immune infiltration analysis suggested that higher macrophage infiltration was found in patients in the high-risk group. Finally, enhanced 7 NRGs were found in HCC tissues by immunohistochemistry. In conclusion, a novel 7-NRG prognostic risk signature is generated, which contributes to the prediction in the prognosis of HCC patients for the clinicians. [ABSTRACT FROM AUTHOR]

Background: It is widely acknowledged that cisplatin-induced nephrotoxicity hinders its efficacy during clinical therapy. Effective pharmaceutical interventions for cisplatin-induced acute kidney injury (Cis-AKI) are currently lacking. Prior studies have implicated the chemokine CX3CL1 in the development of lipopolysaccharide-induced AKI; however, its specific role in Cis-AKI remains uncertain. This research aimed to comprehensively characterize the therapeutic impact and mechanism of CX3CL1 inhibition on Cis-AKI. Methods: This study employed an in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes. Kidney pathological changes were assessed using hematoxylin–eosin (HE) and Periodic-Schiff (PAS) staining. Transcriptome changes in mouse kidney tissue post-cisplatin treatment were analyzed through RNA sequencing (RNA-seq) datasets. Evaluation parameters included the expression of inflammatory markers, intracellular free iron levels, ferroptosis-related proteins—solute carrier family 7 member 11 (SLC7A11/XCT) and glutathione peroxidase 4 (GPX4)—as well as lipid peroxidation markers and mitochondrial function proteins. Mitochondrial morphological changes were visualized through transmission electron microscopy. The impact of CX3CL1 on the glucose-regulated protein 78/eukaryotic translation initiation factor 2A/CCAAT enhancer binding protein-homologous protein (GRP78/eIF2α/CHOP) and hypoxia-inducible factor 1-alpha/heme oxygenase-1 (HIF1A/HO-1) pathways in Cis-AKI was assessed via Western Blot and Immunofluorescence experiments, both in vivo and in vitro. Results: Kidney CX3CL1 levels were elevated following cisplatin injection in wild-type (WT) mice. Cisplatin-treated CX3CL1-Knockout mice exhibited reduced renal histological changes, lowered blood creatinine (Cre) and blood urea nitrogen (BUN) levels, and decreased expression of inflammatory mediators compared to cisplatin-treated WT mice. RNA-seq analysis revealed the modulation of markers associated with oxidative stress and lipid metabolism related to ferroptosis in the kidneys of mice with Cis-AKI. Both the in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes demonstrated that CX3CL1 inhibition could mitigate ferroptosis. This effect was characterized by alleviated intracellular iron overload, malondialdehyde (MDA) content, and reactive oxygen species (ROS) production, alongside increased glutathione/glutathione disulfide ratio, superoxide dismutase (SOD), XCT, and GPX4 activity. CX3CL1 inhibition also ameliorated mitochondrial dysfunction and upregulated expression of mitochondrial biogenesis proteins-uncoupling protein (UCP), mitofusin 2 (Mfn2), and peroxisome proliferators-activated receptor γ coactivator l-alpha (PGC1α)-both in vivo and in vitro. Furthermore, CX3CL1 inhibition attenuated cisplatin-induced endoplasmic reticulum (ER) stress in podocytes. Notably, CX3CL1 inhibition reduced cisplatin-induced expression of HIF-1α and HO-1 in vivo and in vitro. Conclusion: Our findings suggest that CX3CL1 inhibition exerts therapeutic effects against Cis-AKI by suppressing podocyte ferroptosis. [ABSTRACT FROM AUTHOR]

Background: Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. Methods: The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. Results: Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. Conclusions: ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells. [ABSTRACT FROM AUTHOR]

Blepharoptosis is a recognized cause of reversible vision loss and a non-specific indicator of neurological issues, occasionally heralding life-threatening conditions. Currently, diagnosis relies on human expertise and eyelid examination, with most existing Artificial Intelligence algorithms focusing on eyelid positioning under specialized settings. This study introduces a deep learning model with convolutional neural networks to detect blepharoptosis in more realistic conditions. Our model was trained and tested using high quality periocular images from patients with blepharoptosis as well as those with other eyelid conditions. The model achieved an area under the receiver operating characteristic curve of 0.918. For validation, we compared the model's performance against nine medical experts—oculoplastic surgeons, general ophthalmologists, and general practitioners—with varied expertise. When tested on a new dataset with varied image quality, the model's performance remained statistically comparable to that of human graders. Our findings underscore the potential to enhance telemedicine services for blepharoptosis detection. [ABSTRACT FROM AUTHOR]

Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation of lipid peroxides, provides a novel avenue for delving into the intersection of cellular metabolism, oxidative stress, and disease pathology. We have witnessed a mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological and pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, and traumatic tissue injuries. By unraveling the intricate underpinnings of the molecular machinery, pivotal contributors, intricate signaling conduits, and regulatory networks governing ferroptosis, researchers aim to bridge the gap between the intricacies of this unique mode of cellular death and its multifaceted implications for health and disease. In light of the rapidly advancing landscape of ferroptosis research, we present a comprehensive review aiming at the extensive implications of ferroptosis in the origins and progress of human diseases. This review concludes with a careful analysis of potential treatment approaches carefully designed to either inhibit or promote ferroptosis. Additionally, we have succinctly summarized the potential therapeutic targets and compounds that hold promise in targeting ferroptosis within various diseases. This pivotal facet underscores the burgeoning possibilities for manipulating ferroptosis as a therapeutic strategy. In summary, this review enriched the insights of both investigators and practitioners, while fostering an elevated comprehension of ferroptosis and its latent translational utilities. By revealing the basic processes and investigating treatment possibilities, this review provides a crucial resource for scientists and medical practitioners, aiding in a deep understanding of ferroptosis and its effects in various disease situations. [ABSTRACT FROM AUTHOR]