Serum levels of leptin, ghrelin putative peptide YY-3 in patients with fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) are a severe developmental condition resulting from exposure to alcohol during pregnancy. The aim of this study was to examine the concentrations of hormones involved in appetite regulation-ghrelin, leptin, and putative peptide YY-3 (PYY)-in the serum of individuals with FASD. Additionally, we investigated the relationship between these hormone levels and clinical indicators. We conducted an enzyme-linked immunosorbent assay on samples collected from 62 FASD patients and 23 individuals without the condition. Our results revealed a significant decrease in leptin levels among FASD patients compared to the control group (5.124 vs. 6.838 ng/mL, p = 0.002). We revealed no statistically significant differences in the levels of other hormones studied (ghrelin and PYY). Comparisons of hormone levels were also conducted in three subgroups: FAS, neurobehavioral disorders associated with prenatal alcohol exposure and FASD risk, as well as by sex. Assignment to FASD subgroups indicated changes only for leptin. Sex had no effect on the levels of hormones. Moreover, the levels of leptin showed a negative correlation with cortisol levels and a positive correlation with BMI and proopiomelanocortin. Alterations in appetite regulation can contribute to the improper development of children with FASD, which might be another factor that should be taken into consideration in the proper treatment of patients.

[Porphyromonas gingivalis infection facilitates immune escape of esophageal cancer by enhancing YTHDF2-mediated Fas degradation].

OBJECTIVE: To investigate the effect of Porphyromonas gingivalis (Pg) infection on immune escape of oesophageal cancer cells and the role of YTHDF2 and Fas in this regulatory mechanism. METHODS: We examined YTHDF2 and Fas protein expressions in esophageal squamous cell carcinoma (ESCC) tissues with and without Pg infection using immunohistochemistry and in Pg-infected KYSE150 cells using Western blotting. The interaction between YTHDF2 and Fas was investigated by co-immunoprecipitation (Co-IP). Pg-infected KYSE150 cells with lentivirus-mediated YTHDF2 knockdown were examined for changes in expression levels of YTHDF2, cathepsin B (CTSB), Fas and FasL proteins, and the effect of E64 (a cathepsin inhibitor) on these proteins were observed. After Pg infection and E64 treatment, KYSE150 cells were co-cultured with human peripheral blood mononuclear cells (PBMCs), and the expressions of T cell-related effector molecules were detected by flow cytometry. RESULTS: ESCC tissues and cells with Pg infection showed significantly increased YTHDF2 expression and lowered Fas expression. The results of Co-IP demonstrated a direct interaction between YTHDF2 and Fas. In Pg-infected KYSE150 cells with YTHDF2 knockdown, the expression of CTSB was significantly reduced while Fas and FasL expressions were significantly increased. E64 treatment of KYSE150 cells significantly decreased the expression of CTSB without affecting YTHDF2 expression and obviously increased Fas and FasL expressions. Flow cytometry showed that in Pg-infected KYSE150 cells co-cultured with PBMCs, the expressions of Granzyme B and Ki67 were significantly decreased while PD-1 expression was significantly enhanced. CONCLUSION: Pg infection YTHDF2-dependently regulates the expression of Fas to facilitate immune escape of esophageal cancer and thus promoting cancer progression, suggesting the key role of YTHDF2 in regulating immune escape of esophageal cancer.

[ADAS and automation-a relevant contribution to maintaining mobility of older drivers?] / Fahrerassistenzsysteme und automatisiertes Fahren ­ ein relevanter Beitrag zum Erhalt der Mobilität im Alter?

Driving is the most important and safest form of mobility for the majority of senior citizens. However, physical and mental performance gradually decline with age, which can lead to more problems, critical situations or even accidents. Vehicle technology innovations such as advanced driver assistance systems (ADAS) have the potential to increase the road safety of older people and maintain their individual mobility for as long as possible.This overview article aims to identify ADAS that have the greatest potential to reduce the number of accidents involving older drivers. For this purpose, the accident and damage occurrence as well as the driving behaviour and compensation strategies of older people are examined in more detail. Suitable ADAS should compensate for typical driver errors, reduce information deficiencies and have a high level of acceptance. For older drivers, emergency braking, parking assistance, navigation, intersection assistance and distance speed control systems as well as systems for detecting blind spots and obstacles appear to be particularly suitable.Some of the disadvantages of ADAS are the lack of market penetration, acceptance problems and interface designs that have not yet been optimally adapted to the needs of older users. For older drivers in particular, it appears to be a priority to develop coherent and integrated solutions in the sense of cooperative assistance instead of pushing ahead with high and full automation with many system limits and exceptions, which can place high demands on attention, for example if the vehicle has to be taken over in a critical situation.

Association between fatty acid intake and age-related macular degeneration: a meta-analysis.

Objective: The association of age-related macular degeneration (AMD) with the intake of high and low fatty acids (FAs), respectively, remains controversial. To this end, we performed a comprehensive meta-analysis of all the existing studies on the association of various intake levels of FA subtypes with AMD to determine these associations. Methods: A systematic search of PubMed, Web of Science, Cochrane Library, and EMBASE databases was conducted from inception to September 2023. To compare the highest and lowest groups, odds ratio (OR) with 95% confidence intervals (CIs) was analyzed with a random-effects model/fixed-effects model. Results: A high intake of omega-3 LCPUFAs (OR:0.67; 95%CI:[0.51, 0.88]; p = 0.004), DHA (OR:0.80; 95%CI:[0.70, 0.90]; p < 0.001), EPA (OR:0.91; 95%CI:[0.86, 0.97]; p = 0.004), and simultaneous intake of DHA and EPA (OR:0.79; 95%CI:[0.67, 0.93]; p = 0.035) significantly reduced the risk of overall AMD. Conversely, a high intake of trans-FAs (OR: 2.05; 95%CI: [1.29, 3.25]; p = 0.002) was significantly related to an increased risk of advanced AMD compared to the low-intake group. The subgroup analysis results are shown in the articles. Conclusion: Increasing dietary intake of omega-3 LCPUFAs, specifically DHA, and EPA, or the simultaneous intake of DHA and EPA, is significantly associated with a reduced risk of overall AMD. Various subtypes of omega-3 also have a significant association with a reduced risk of different stages of AMD. The high intake of trans-fatty acids (TFAs) is significantly and positively correlated with the risk of advanced AMD. This could further support the idea that consuming foods rich in omega-3 LCPUFAs and reducing consumption of foods rich in TFAs may prevent AMD. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023467227.

Caspase-8-mediated inflammation but not apoptosis drives death of retinal ganglion cells and loss of visual function in glaucomaa.

Background-: Glaucoma is a complex multifactorial disease where apoptosis and inflammation represent two key pathogenic mechanisms. However, the relative contribution of apoptosis versus inflammation in axon degeneration and death of retinal ganglion cells (RGCs) is not well understood. In glaucoma, caspase-8 is linked to RGC apoptosis, as well as glial activation and neuroinflammation. To uncouple these two pathways and determine the extent to which caspase-8-mediated inflammation and/or apoptosis contributes to the death of RGCs, we used the caspase-8 D387A mutant mouse (Casp8 DA/DA ) in which a point mutation in the auto-cleavage site blocks caspase-8-mediated apoptosis but does not block caspase-8-mediated inflammation. Methods-: Intracameral injection of magnetic microbeads was used to elevate the intraocular pressure (IOP) in wild-type, Fas deficient Faslpr, and Casp8 DA/DA mice. IOP was monitored by rebound tonometry. Two weeks post microbead injection, retinas were collected for microglia activation analysis. Five weeks post microbead injection, visual acuity and RGC function were assessed by optometer reflex (OMR) and pattern electroretinogram (pERG), respectively. Retina and optic nerves were processed for RGC and axon quantification. Two- and five-weeks post microbead injection, expression of the necrosis marker, RIPK3, was assessed by qPCR. Results-: Wild-type, Faslpr, and Casp8 DA/DA mice showed similar IOP elevation as compared to saline controls. A significant reduction in both visual acuity and pERG that correlated with a significant loss of RGCs and axons was observed in wild-type but not in Faslpr mice. The Casp8 DA/DA mice displayed a significant reduction in visual acuity and pERG amplitude and loss of RGCs and axons similar to that in wild-type mice. Immunostaining revealed equal numbers of activated microglia, double positive for P2ry12 and IB4, in the retinas from microbead-injected wild-type and Casp8 DA/DA mutant mice. qPCR analysis revealed no induction of RIPK3 in wild-type or Casp8 DA/DA mice at two- or five-weeks post microbead injection. Conclusions-: Our results demonstrate that caspase-8-mediated extrinsic apoptosis is not involved in the death of RGCs in the microbead-induced mouse model of glaucoma implicating caspase-8-mediated inflammation, but not apoptosis, as the driving force in glaucoma progression. Taken together, these results identify the caspase-8-mediated inflammatory pathway as a potential target for neuroprotection in glaucoma.

Low-dose doxorubicin loaded extracellular vesicles combined Fas/FasL pathway-mediated chemo-sensitization and immunotherapy against tumor.

The clinical application of doxorubicin (DOX) is mainly restricted by its serious side effects, poor drug delivery efficiency, and limited immunogenic death (ICD) effect. To improve DOX-based chemotherapy and ameliorate its adverse effects, we utilized 3LL cell-derived extracellular vesicles to encapsulate DOX and sodium nitroprusside (SNP) to obtain DOX/SNP@CM, which could effectively target the tumor site by harnessing the inherent homologous targeting property of tumor cell membranes. DOX performed its role on chemotherapy, and SNP successfully respond to the intracellular GSH to continuously generate nitric oxide (NO). The in situ-produced NO upregulated the Fas expression on the tumor cell surface, thereby sensitizing the Fas/FasL pathway-mediated tumor cell apoptosis of DOX. Furthermore, NO also boosted the intratumoral infiltration of cytotoxic T cells by promoted ICD effect towards tumor cells. Importantly, the anti-tumor immunity tightly cooperated with Fas/FasL mediated tumor cell apoptosis by NO-mediated manipulation on Fas/FasL interaction, collectively making DOX/SNP@CM exert significant tumor growth inhibition with low-dose DOX. Remarkably, DOX and SNP both are widely used clinical medicines, ensuring DOX/SNP@CM a potential opportunity for future practical applications.

Survivin: A key apoptosis inhibitor in COVID-19 infection and its implication for treatment protocol.

While the relationship between cellular apoptosis and proliferation rates in COVID patients remains underexplored in existing literature, various viruses are known to impact these fundamental process to modulate response to infection. This paper aims to assess apoptosis and proliferation rates in individuals recently infected with Coronavirus, both before and after vaccination, comparing them with healthy controls. Peripheral blood cells from newly diagnosed COVID-19 patients revealed a significant increase in proliferation and apoptosis levels in fresh lymphocytes and granulocytes compared to healthy donors. Notably, as none of the patients were under corticosteroid therapy or cytotoxic drugs, the study underscores the critical role of white blood (WBC) apoptosis in viral pathogenesis, potentially contributing significantly to COVID-19's pathogenicity. Elevated levels of soluble Fas ligand (FaSL) and the pro-inflatmmatory cytokine IL-38 were identified in COVID-19 patients, indicating potential immune dysregulation. Furthermore, individual who received the vaccine or recovered from COVID-19 exhibited higher survivin rates, suggesting a protective role for survivin in migitating lung damage. These findings suggest the prospect of developing a strategy to prevent WBC apoptosis, offering potential benefits in averting lymphopenia associated with severe COVID-19 ouctomes.

FAS(APO), DAMP, and AKT Phosphoproteins Expression Predict the Development of Nosocomial Infection After Pediatric Burn Injury.

Pediatric burn injuries are a leading cause of morbidity with infections being the most common acute complication. Thermal injuries elicit a heightened cytokine response while suppressing immune function; however, the mechanisms leading to this dysfunction are still unknown. Our aim was to identify extracellular proteins and circulating phosphoprotein expression in the plasma after burn injury to predict the development of nosocomial infection (NI). Plasma was collected within 72 hours after injury from sixty-four pediatric burn subjects; of these, eighteen went on to develop a NI. Extracellular damage associated molecular proteins (DAMPs), FAS(APO), and protein kinase b (AKT) signaling phosphoproteins were analyzed. Subjects who went on to develop a NI had elevated high mobility group box 1 (HMGB1), heat shock protein 90 (HSP90), and FAS expression than those who did not develop a NI after injury (NoNI). Concurrently, phosphorylated (p-) AKT and mammalian target of rapamycin (p-mTOR) were elevated in those subjects who went on to develop a NI. Quadratic discriminant analysis revealed distinct differential profiles between NI and NoNI burn subjects using HSP90, FAS, and p-mTOR. The area under the receiver-operator characteristic curves displayed significant ability to distinguish between these two burn subject cohorts. These findings provide insight into predicting the signaling proteins involved in the development of NI in pediatric burn patients. Further these proteins show promise as a diagnostic tool for pediatric burn patients at risk of developing infection while additional investigation may lead to potential therapeutics to prevent NI.

FASTKD1 as a diagnostic and prognostic biomarker for STAD: Insights into m6A modification and immune infiltration.

Fas-activated serine/threonine kinase domain 1 (FASTKD1), a known modulator of mitochondrial-mediated cell death and survival processes, has garnered attention for its potential role in various biological contexts. However, its involvement in gastric cancer remains unclear. Thus, the present study aimed to investigate the relationship between FASTKD1 expression and key factors, including clinicopathological characteristics, immune infiltration and m6A modification in stomach adenocarcinoma (STAD). The expression of FASTKD1 was analyzed in STAD and normal adjacent tissues to assess its association with clinicopathological characteristics and survival prognosis. Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used in this study. Additionally, the findings were validated through immunohistochemical staining. Co-expression analysis of FASTKD1 was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and LinkedOmics database analysis. An in-depth analysis was conducted using databases, such as Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), GEO and TCGA to explore the potential correlation between FASTKD1 expression and immune infiltration and m6A modification in STAD. The results revealed that FASTKD1 was significantly upregulated across different tumor types, including STAD. Notably, FASTKD1 was able to distinguish between tumor and normal tissue samples with accuracy. Furthermore, the expression levels of FASTKD1 were significantly associated with clinical stage and survival. Through GO/KEGG enrichment analysis and GSEA, it was revealed that the genes co-expressed with FASTKD1 were active in a variety of biological processes. Within the TIMER, GEPIA and TCGA databases, a notable inverse correlation was observed between FASTKD1 expression and the abundance of immune cell subsets. Notably, significant correlations were established between FASTKD1 and m6A modification genes, YTHDF1 and LRPPRC, in both TCGA and GEO datasets. In conclusion, FASTKD1 may serve a significant role in m6A modification and immune infiltration processes, making it a potentially valuable diagnostic and prognostic biomarker in STAD.

Discovery of Loureirin analogues with colorectal cancer suppressive activity via regulating cell cycle and Fas death receptor.

Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were designed with the inspiration of Loureirin, a DHC extracted from Resina Draconis, and synthesized by classical Claisen-Schmidt reactions. Afterwards the reduction reactions were carried out to obtain the corresponding DHCs. Cytotoxicity assay indicated chalcones and DHCs possessed selective cytotoxicity against colorectal cancer (CRC) cells. The preliminary structure-activity relationships (SAR) of these compounds suggested the α, ß-unsaturated ketone of the chalcones were crucial for the anticancer activity. Interestingly, compounds 3d and 4c exhibited selective anticancer activity against CRC cell line HCT116 with IC50s of 8.4 and 17.9 µM but not normal cell. Moreover, 4c could also inhibit the migration and invasion of CRC cells. Mechanism investigations showed 4c could induce cell cycle G2/M arrest by regulating cell cycle-associated proteins and could also up-regulate Fas cell surface death receptor. The virtual docking further pointed out that compounds 3d and 4c could nicely bind to the Fas/FADD death domain complex (ID: 3EZQ). Furthermore, silencing of Fas significantly enhanced the proliferation of CRC cells and attenuated the cytotoxicity induced by 4c. These results suggested 4c exerted its anticancer activity possibly regulating cell cycle and Fas death receptor. In summary, this study investigated the anticancer activity and mechanism of Loureirin analogues in CRC, suggesting these compounds may warrant further investigation as promising anticancer drug candidates for the treatment of CRC.

Interleukin-10 induces TNF-driven apoptosis and ROS production in salivary gland cancer cells.

Treatment resistance after chemo-/immunotherapy occurs in patients with head and neck squamous cell cancers (HNSCs), including salivary gland cancers (SGCs). Interleukin-10 (IL-10), a cytokine with pro- and anti-cancer effects, has an unclear impact on HNSC/SGC cells. We show that HNSC patients exhibiting high expression of IL-10 and its receptor IL-10Rα experience have prolonged overall survival. Immunoreactive IL-10 was low in ductal cells of human SGC biopsies. Human (A253) and murine WR21-SGC cells expressed IL-10Rß, but only A253 cells expressed IL-10 and IL-10Rα. The addition of recombinant IL-10 impaired SGC cell proliferation and induced apoptosis in vitro. N-acetylcysteine restored IL-10-induced reactive oxygen species (ROS) production but did not prevent IL-10-mediated viability loss. Mechanistically, recIL-10 delayed cell cycle progression from G0/G1 to the S phase with cyclin D downregulation and upregulation of NF-kB. IL-10 increased tumor necrosis factor-α (TNF-α) in A253 and WR21 and FasL in WR21 cells. Neutralizing antibodies against TNF-α and NF-kB inhibition restored SGC proliferation after IL-10 treatment, emphasizing the critical role of TNF-α and NF-kB in IL-10-mediated anti-tumor effects. These findings underscore the potential of IL-10 to impede SGC cell growth through apoptosis induction, unraveling potential therapeutic targets for intervention in salivary gland carcinomas.

Looking for ALPS: The value of a combined assessment of biochemical markers.

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder caused by defect of the extrinsic apoptotic pathway. The current diagnostic criteria combine clinical features and typical biomarkers but have not been the object of clear international consensus. METHODS: We conducted a retrospective study on pediatric patients who were investigated for autoimmune cytopenia and/or lymphoproliferation at the CHU Sainte-Justine Hospital over 10 years. Patients were screened using the combination of TCRαß+ CD4- CD8- "double negative" (DN) T cells and soluble plasmatic FAS ligand (sFASL). RESULTS: Among the 398 tested patients, the median sFASL and DN T cells were 200 ng/mL and 1.8% of TCRαß+ T cells, respectively. sFASL was highly correlated with vitamin B12 levels. We identified five patients diagnosed with ALPS for whose sFASL and vitamin B12 levels were the more discriminating biomarkers. While ALPS diagnostic criteria had high sensibility, their predictive value remained low. CONCLUSION: sFASL level can efficiently discriminate patients with ALPS when using the appropriate thresholds. Our study highlights the need for an international consensus to redefine the place and threshold of biological biomarkers for ALPS diagnosis.

Structural characteristics and in vitro starch digestibility of oil-modified cooked rice with varied addition manipulations.

Lipid has crucial applications in improving the quality of starchy products during heat processing. Herein, the influence of lipid modification and thermal treatment on the physicochemical properties and starch digestibility of cooked rice prepared with varied addition manipulations was investigated. Rice bran oil (RO) and medium chain triglyceride oil (MO) manipulations were performed either before (BC) or after cooking (AC). GC-MS was applied to determine the fatty acid profiles. Nutritional quality was analyzed by quantifying total phenolics, atherogenic, and thrombogenic indices. All complexes exhibited higher surface firmness, a soft core, and less adhesive. FTIR spectrum demonstrated that the guest component affected some of the dense structural attributes of V-amylose. The kinetic constant was in the range between 0.47 and 0.86 min-1 wherein before mode presented a higher value. The lowest glucose release was observed in the RO_BC sample, whereas the highest complexing index was observed in the RO_AC sample, indicating that the dense molecular configuration of complexes that could resist enzymatic digestion was more critical than the quantity of complex formation. Despite the damage caused by mass and heat transfer, physical barrier, intact granule forms, and strengthened dense structure were the central contributors affecting the digestion characteristics of lipid-starch complexes.

FasL impacts Tgfb signaling in osteoblastic cells.

Fas ligand (FasL, CD178) belongs to classical apoptotic molecules, however, recent evidence expands the spectrum of FasL functions into non-apoptotic processes which also applies for the bone. Tgfb subfamily members (Tgfb1, Tgfb2, Tgfb3) represent major components in osteogenic pathways and extracellular matrix. Their possible association with FasL has not yet been investigated but can be postulated. To test such a hypothesis, FasL deficient (gld) calvaria-derived cells were examined with a focus on the expression of Tgfb receptor ligands. The qPCR analysis revealed significantly increased expression of Tgfb1, Tgfb2 and Tgfb3 in gld cells. To check the vice versa effect, the gld cells were stimulated by soluble FasL. As a consequence, a dramatic decrease in expression levels of all three ligands was observed. This phenomenon was also confirmed in IDG-SW3 (osteoblastic cells of endochondral origin). TFLink gateway identified Fosl2 as an exclusive candidate of FasL capable to impact expression of all three Tgfb ligands. However, Fosl2 siRNA did not cause any significant changes in expression of Tgfb ligands. Therefore, the upregulation of the three ligands is likely to occur separately. In this respect, we tested the only exclusive candidate transcription factor for Tgfb3, Prrx1. Additionally, an overlapping candidate for Tgfb1 and Tgfb2, Mef2c capable to modulate expression of sclerostin, was examined. Prrx1 as well as Mef2c were found upregulated in gld samples and their expression decreased after addition of FasL. The same effect of FasL treatment was observed in the IDG-SW3 model. Taken together, FasL deficiency causes an increase in the expression of Tgfb ligands and stimulation by FasL reduces Tgfb expression in osteoblastic cells. The candidates mediating the effect comprise Prrx1 for Tgfb3 and Mef2c for Tgfb1/2. These results indicate FasL as a novel cytokine interfering with Tgfb signaling and thus the complex osteogenic network. The emerging non-apoptotic functions of FasL in bone development and maintenance should also be considered in treatment strategies such as the anti-osteoporotic factor.

Fas Ligand enhances vessel maturation and inhibits vascular leakage associated with age-related macular degeneration.

Neovascular age-related macular degeneration (AMD), results from choroidal neovascularization (CNV), retinal edema and loss of photoreceptors. Previous studies suggested that Fas Ligand (FasL) on retinal pigment epithelial cells inhibited CNV by inducing apoptosis of infiltrating Fas+ vascular endothelial cells. However, induction of apoptosis depends on membrane-bound (mFasL) while the FasL cleavage product (sFasL) is neuroprotective. To better understand how FasL regulates the development of CNV, we used a mouse model of laser CNV to evaluate the development of CNV in mice with a FasL cleavage site mutation (ΔCS) and can only express the membrane-bound form of FasL. There was no significant difference in CNV size and area of vascular leakage in homozygous FasLΔCS/ΔCS mice when compared to wild type mice. Unexpectedly, heterozygous FasLΔCS/WT mice developed significantly less vascular leakage and showed accelerated neovessel maturation. However, CNV was not prevented in heterozygous FasLΔCS/WT mice if the Fas receptor was deleted in myeloid cells (FasLΔCS/+ Fasflox/flox CreLysM). Thus, FasL-mediated CNV inhibition depends on the extent of FasL cleavage, and on FasL engagement of Fas+ myeloid cells. Moreover, accelerated neovessel maturation prevents vascular leakage in AMD.

Platelets Induce Cell Apoptosis of Cardiac Cells via FasL after Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Cell apoptosis in the myocardium plays an important role in ischemia and reperfusion (I/R) injury, leading to cardiac damage and dysfunction. Platelets are major players in hemostasis and play a crucial role in vessel occlusion, inflammation, and cardiac remodeling after I/R. Here, we studied the impact of platelets on cell apoptosis in the myocardium using a close-chest mouse model of AMI. We found caspase-3-positive resident cardiac cells, while leukocytes were negative for caspase-3. Using two different mouse models of thrombocytopenia, we detected a significant reduction in caspase-3 positive cells in the infarct border zone after I/R injury. Further, we identified platelet FasL to induce cell apoptosis via the extrinsic pathway of Fas receptor activation of target cells. Mechanistically, hypoxia triggers platelet adhesion to FasR, suggesting that platelet-induced apoptosis is elevated after I/R. Platelet-specific FasL knock-out mice showed reduced Bax and Bcl2 expression, suggesting that platelets modulate the intrinsic and extrinsic pathways of apoptosis, leading to reduced infarct size after myocardial I/R injury. Thus, a new mechanism for how platelets contribute to tissue homeostasis after AMI was identified that should be validated in patients soon.

The Association of Death Receptors and TGF-ß1 Expression in Urothelial Bladder Cancer and Their Prognostic Significance.

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-ß1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-ß1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-ß1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-ß1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-ß1 and indicates independent prognostic significance of high FAS and TGF-ß1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.

The dehydration-responsive protein PpFAS1.3 in moss Physcomitrium patens plays a regulatory role in lipid metabolism.

Moss plants appear in the early stages of land colonization and possess varying degrees of dehydration tolerance. In this study, a protein called PpFAS1.3 was identified, which contains a fasciclin 1-like domain and is essential for the moss Physcomitrium patens' response to short-term rapid dehydration. When the FAS1.3 protein was knocked out, leafyshoots showed a significant decrease in tolerance to rapid dehydration, resulting in accelerated water loss and increased membrane leakage. Phylogenetic analysis suggests that PpFAS1.3 and its homologous proteins may have originated from bacteria and are specifically found in non-vascular plants like mosses and liverworts. As a dehydration-related protein, FAS1.3 plays a significant role in regulating lipid metabolism, particularly in the synthesis of free fatty acids (FFA) and the metabolism of two phospholipids, PC and PA. This discovery highlights the close connection between PpFAS1.3 and lipid metabolism, providing new insights into the molecular mechanisms underlying plant adaptation to stresses.

Ficus hirta Vahl. alleviate LPS induced apoptosis via down-regulating of miR-411 in orange-spotted grouper (Epinephelus coioides) spleen cell.

Ficus hirta Vahl. (FhV) has been shown to have antimicrobial and antiviral efficacy. To further ascertain the pharmacological properties of FhV., and to search for alternatives to antibiotics. An in vitro experiment was carried out to evaluate what influence FhV. would have on LPS-induced apoptosis. In this study, Fas, an apoptosis receptor, was cloned, which included a 5'-UTR of 39 bp, an ORF of 951 bp, a protein of 316 amino acids, and a 3'-UTR of 845 bp. EcFas was most strongly expressed in the spleen tissue of orange-spotted groupers. In addition, the apoptosis of fish spleen cells induced by LPS was concentration-dependent. Interestingly, appropriate concentrations of FhV. alleviated LPS-induced apoptosis. Inhibition of miR-411 further decreased the inhibitory effect of Fas on apoptosis, which reduced Bcl-2 expression and mitochondrial membrane potential, enhanced the protein expression of Bax and Fas. More importantly, the FhV. could activate miR-411 to improve this effect. In addition, luciferase reporter assays showed that miR-411 binds to Fas 3'-UTR to inhibit Fas expression. These findings provide evidence that FhV. alleviates LPS-induced apoptosis by activating miR-411 to inhibit Fas expression and, therefore, provided possible strategies for bacterial infections in fish.