Chitosan based smart polymer composites: Fabrication and pH-Responsive behavior for bio-medical applications.

This research aimed to synthesize Chitosan/PVA-blank and a series of Cs/PVA/Sepolite based pH-sensitive membranes using a solution casting process. The synthesized Cs/PVA-blank and Cs/PVA/Sep based membranes were investigated via SEM, FTIR, XRD, and TGA techniques. The SEM results of Cs/PVA/Sep based membrane reveal that the hydrolytic stability and strength were improved in acidic and basic media owing to the incorporation of sepiolite content into chitosan. The characteristic band at 3741 cm-1 in the FTIR spectra of the Cs/PVA/Sep membrane confirmed the successful synthesis. The obtained XRD results showed higher d-spacing for Cs/PVA/Sep membranes as compared to the Cs/PVA-blank membranes owing to the intercalation of chitosan in the interlayer spacing of the sepiolite. The obtained TGA results show higher thermally stability for Cs/PVA/Sep membrane as compared to the Cs/PVA-blank sample due to the interaction of sepiolite content with the chitosan matrix. The obtained hydrolytic and swelling studies revealed that the Cs/PVA/Sep membrane displayed enhanced stability in basic and neutral media while showing minimum swelling in an acidic medium. The water uptake ability was checked for Cs/PVA/-blank and Cs/PVA/Sep-60% membrane and the results exhibited that the Cs/PVA/-blank membrane had maximum water uptake value as compared to the Cs/PVA/Sep-60% membrane. While those with a considerable amount of filler had the lowest water uptake values. As Sepolite content increased, the water uptake % values decreases because of weakness in H-bonding (of hydrophilic groups) and due to intercalation in Sepolite layers during polymer formation.

STING activation promotes inflammatory response and delays skin wound healing in diabetic mice.

Sustained inflammatory responses delay wound repair in diabetic skin. The stimulator of interferon genes (STING) plays a vital role in the innate immune responses. However, its function in diabetic skin wound repair, and the underlying mechanism remains unclear. Here, we reported that STING activation is a pathogenic marker that correlates with delayed wound repair in diabetic skin. Firstly, we found that STING expression is enhanced in the epidermis of STZ induced diabetes mouse model and db/db mouse model. Consistently, we also found that STING expression was upregulated in keratinocytes with the high-glucose (HG) treatment. Moreover, silencing of STING accelerated wound healing in vitro. In vivo, inhibition of STING by c176 inhibited inflammatory response in the epidermis and accelerated wound healing in diabetic skin. In addition, we found that autophagy dysfunction is correlated with the expression of STING in epidermis of diabetic mice. Induction of autophagy by rapamycin significantly reduced STING expression in keratinocytes. Collectively, these results indicated that defects of autophagy might lead to the activation of STING and finally delay the diabetic wound healing.

Receptor activity-modifying protein 1 regulates mouse skin fibroblast proliferation via the Gαi3-PKA-CREB-YAP axis.

BACKGROUND: Skin innervation is crucial for normal wound healing. However, the relationship between nerve receptors and wound healing and the intrinsic mechanism remains to be further identified. In this study, we investigated the role of a calcitonin gene-related peptide (CGRP) receptor component, receptor activity-modifying protein 1 (RAMP1), in mouse skin fibroblast (MSF) proliferation. METHODS: In vivo, Western blotting and immunohistochemical (IHC) staining of mouse skin wounds tissue was used to detect changes in RAMP1 expression. In vitro, RAMP1 was overexpressed in MSF cell lines by infection with Tet-On-Flag-RAMP1 lentivirus and doxycycline (DOX) induction. An IncuCyte S3 Live-Cell Analysis System was used to assess and compare the proliferation rate differences between different treatment groups. Total protein and subcellular extraction Western blot analysis, quantitative real-time-polymerase chain reaction (qPCR) analysis, and immunofluorescence (IF) staining analysis were conducted to detect signalling molecule expression and/or distribution. The CUT & RUN assay and dual-luciferase reporter assay were applied to measure protein-DNA interactions. RESULTS: RAMP1 expression levels were altered during skin wound healing in mice. RAMP1 overexpression promoted MSF proliferation. Mechanistically, total Yes-associated protein (YAP) and nuclear YAP protein expression was increased in RAMP1-overexpressing MSFs. RAMP1 overexpression increased inhibitory guanine nucleotide-binding protein (G protein) α subunit 3 (Gαi3) expression and activated downstream protein kinase A (PKA), and both elevated the expression of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and activated it, promoting the transcription of YAP, elevating the total YAP level and promoting MSF proliferation. CONCLUSIONS: Based on these data, we report, for the first time, that changes in the total RAMP1 levels during wound healing and RAMP1 overexpression alone can promote MSF proliferation via the Gαi3-PKA-CREB-YAP axis, a finding critical for understanding RAMP1 function, suggesting that this pathway is an attractive and accurate nerve target for skin wound treatment. Video Abstract.

Effects of category learning strategies on recognition memory.

Extant research has shown that previously acquired categorical knowledge affects recognition memory, and that differences in category learning strategies impact classification accuracy. However, it is unknown whether different learning strategies also have downstream effects on subsequent recognition memory. The present study investigates the effect of two unidimensional rule-based category learning strategies - learning (a) with or without explicit instruction, and (b) with or without supervision - on subsequent recognition memory. Our findings suggest that acquiring categorical knowledge increased both hits (Experiments 1 and 2) and false-alarms (Experiment 1) for category-congruent items regardless of the particular strategy employed in initially learning these categories. There were, however, small processing speed advantages during recognition memory for both explicit instruction and supervised practice relative to neither (Experiment 2). We discuss these findings in the context of how prior knowledge influences recognition memory, and in relation to similar findings showing schematic effects on episodic memory.

Thresholded single-photon underwater imaging and detection.

Optical underwater target imaging and detection have been a tough but significant challenge in deep-sea exploration. Distant reflected signals drown in various underwater noises due to strong absorption and scattering, resulting in degraded image contrast and reduced detection range. Single-photon feature operating at the fundamental limit of the classical electromagnetic waves can broaden the realm of quantum technologies. Here we experimentally demonstrate a thresholded single-photon imaging and detection scheme to extract photon signals from the noisy underwater environment. We reconstruct the images obtained in a high-loss underwater environment by using photon-limited computational algorithms. Furthermore, we achieve a capability of underwater detection down to 0.8 photons per pulse at Jerlov type III water up to 50 meters, which is equivalent to more than 9 attenuation lengths. The results break the limits of classical underwater imaging and detection and may lead to many quantum-enhanced applications, like air-to-sea target tracking and deep-sea optical exploration.

CD271 promotes STZ-induced diabetic wound healing and regulates epidermal stem cell survival in the presence of the pTrkA receptor.

Diabetes mellitus (DM) often causes delayed wound healing in patients, which can lead to limb loss, disability, and even death. Many conventional therapeutic strategies have been proposed, but there is still no effective therapy for DM wounds. This study aimed to explore the effects of CD271 and phosphorylated tyrosine kinase receptor A (pTrkA) on the migration and proliferation abilities of epidermal stem cells (eSCs) and on the activation of DM wound healing. We investigated the interventional effects of CD271-overexpressing eSC (CD271 eSC) treatment and pTrkA inhibition (through k252a treatment) on delayed wound healing using mice with streptozotocin-induced DM. The migration and proliferation abilities of control eSCs, CD271 eSCs, and k252a-treated CD271 eSCs were observed under high-glucose conditions. Decreases in CD271 and increases in pTrkA were observed in DM mouse skin compared with control mouse skin; in addition, the rate of wound closure in DM mice was promoted by CD271 eSC treatment but delayed by pTrkA inhibition. Furthermore, the CD271 eSC migration and proliferation were greater than of control eSCs. Compared with that of CD271 eSCs, the number of CD271+k252a eSCs decreased significantly under high-glucose conditions. In parallel, the expression levels of the pERK, pAkt, and pJNK pathways increased in CD271 eSCs and decreased in CD271+k252a eSCs under high glucose. Our findings demonstrate that CD271 and pTrkA affect DM wound closure by promoting the eSC migration and proliferation. This mechanism involving the pERK, pAkt, and pJNK pathways might be a new therapeutic target for the treatment of delayed wound re-epithelialization in DM.

p75 neurotrophin receptor regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A.

Myofibroblasts are characterized by de novo expression of α-smooth muscle actin (α-SMA) and play a key role in tissue repair and remodeling. In addition to TGF-ß1, recent studies have shown that nerve growth factor (NGF) has effects on myofibroblast differentiation and collagen synthesis. However, the regulatory mechanism remains poorly defined. NGF effects are mediated by the specific expression of the NGF neurotrophic tropomyosin-receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR). Using NIH/3T3 fibroblast cell lines, we examined the induction of myofibroblast differentiation stimulated by NGF. Our findings showed that p75NTR was in keeping with the expression of α-SMA. Herein, we investigated the role of p75NTR in NGF-induced myofibroblast differentiation and collagen synthesis in these cells using lentivirus transfection to overexpress and knock down. Our results showed that p75NTR was preferentially expressed and was sufficient to induce actin cytoskeleton remodeling, which was required for NGF-induced α-SMA expression. Furthermore, NGF induced nuclear translocation of MRTF-A, an effect that was regulated by p75NTR, and required for α-SMA and collagen-I expression in myofibroblasts. Using a novel MRTF-A pathway inhibitor, CCG-203971, we further demonstrated the requirement of MRTF-A nuclear localization and activity in NGF-induced α-SMA expression. In conclusion, we conclude that p75NTR regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A. Regulation of NGF-p75NTR interactions represents a promising therapy for fibrotic disorders.

Ultrasonography Superior Over Visual Assessment in Evaluation of Wound Healing After Dermabrasion.

BACKGROUND: Dermabrasion as one kind of treatment for partial thickness wounds is controversial. Visual assessment as the main way to evaluate the healing process of burn wounds is also inaccurate. In this study we try to explore whether dermabrasion accelerates healing in wounds of partial thickness and determine a reliable way to evaluate epithelialization. MATERIALS AND METHODS: Eight female Bama minipigs were anesthetized, and eighteen partial thickness wounds (circle, 4.0 cm2, symmetrically located at both sides of the spine) were produced on each. Wounds on the left side underwent dermabrasion (group D), and wounds on the right side did not (group N). All wounds were covered with allogenic skin (premade). The healing processes of the wounds were observed through three different ways, which included visual assessment, ultrasonography, and histological observation. The epithelialization rate (ER) for each day was plotted together to form a healing curve, by which theoretical mean healing times could be determined ("healed" was classified as ER = 95%). RESULTS: Through visual assessment, the healing times of group D and group N were 13.6 and 18.0 d, respectively. Using ultrasonography, wounds of group D and group N healed at 5.0 and 10.4 d, respectively. Through histological observation, full epithelialization was seen at 5.0 d in group D and at 10.2 d in group N. The healing curves based on visual assessment deviated far from those based on ultrasonography and histological observations, the two of which were almost duplicated. CONCLUSIONS: Earlier epithelialization could be seen in wounds of partial thickness burns after dermabrasion. It would be more accurate and reliable to monitor the epithelialization process through ultrasonography than visual assessment.

Effective treatment for hypertrophic scar with dual-wave-length PDL and Nd:YAG in Chinese patients.

There are several ways to prevent and treat hypertrophic scars. In recent years, lasers have been quite extensively used in treating scars. For example, Pulsed Dye Laser (PDL) and Intense Pulsed Light (IPL) can accelerate mutation of scar, whereas non-ablative and ablative fractional laser can improvescar texture. Dual-wave-length laser treatment is extensively used for blood vessel diseases but is rarely used and less reported for treatment of hypertrophic scars. Our study focuses on the efficacy and safety of dual-wave-length PDL and Nd:YAG in treatment of hypertrophic scars. Twenty-five patients in our study complaining of hypertrophic scars were treated with combined PDL/Nd:YAG laser at 4-6 weeks intervals. Following this, the patients and observers assessed these scars by using Patient Scar Assessment Scale (PSAS) and Observer Scar Assessment Scale (OSAS). The resultsshowed that hypertrophic scar was significantly improved after several laser treatments, and no severe adverse effects were observed. Considering the safety and satisfactory effects of dual-wave-length laser treatment, it can be regarded as a good method for treating hypertrophic scars. This study clearly demonstrates that combined PDL/Nd:YAG laser treatment is an effective, safe and well-tolerated treatment option for hypertrophic scars.

Do framing effects debunk moral beliefs?

May argues that framing effects do not undermine moral beliefs, because they affect only a minority of moral judgments in small ways. We criticize his estimates of the extent of framing effects on moral judgments, and then we argue that framing effects would cause trouble for moral judgments even if his estimates were correct.

Discovery of leucokinin-like neuropeptides that modulate a specific parameter of feeding motor programs in the molluscan model, Aplysia.

A better understanding of neuromodulation in a behavioral system requires identification of active modulatory transmitters. Here, we used identifiable neurons in a neurobiological model system, the mollusc Aplysia, to study neuropeptides, a diverse class of neuromodulators. We took advantage of two types of feeding neurons, B48 and B1/B2, in the Aplysia buccal ganglion that might contain different neuropeptides. We performed a representational difference analysis (RDA) by subtraction of mRNAs in B48 versus mRNAs in B1/B2. The RDA identified an unusually long (2025 amino acids) peptide precursor encoding Aplysia leucokinin-like peptides (ALKs; e.g. ALK-1 and ALK-2). Northern blot analysis revealed that, compared with other ganglia (e.g. the pedal-pleural ganglion), ALK mRNA is predominantly present in the buccal ganglion, which controls feeding behavior. We then used in situ hybridization and immunohistochemistry to localize ALKs to specific neurons, including B48. MALDI-TOF MS on single buccal neurons revealed expression of 40 ALK precursor-derived peptides. Among these, ALK-1 and ALK-2 are active in the feeding network; they shortened the radula protraction phase of feeding motor programs triggered by a command-like neuron. We also found that this effect may be mediated by the ALK-stimulated enhancement of activity of an interneuron, which has previously been shown to terminate protraction. We conclude that our multipronged approach is effective for determining the structure and defining the diverse functions of leucokinin-like peptides. Notably, the ALK precursor is the first verified nonarthropod precursor for leucokinin-like peptides with a novel, marked modulatory effect on a specific parameter (protraction duration) of feeding motor programs.

How and when does a used (vs. unused) account affect consumption behavior?

How does spending from a used (vs. unused) account affect consumption behavior? An account is used when some resources of that account have been used (e.g., $90 has been used on a gift card that originally had $100). An account is unused when no resources of that account have been used (e.g., no money has been used on a gift card that has $10). Across seven studies (N = 8,667), we find that people are more likely to spend resources from a used account than otherwise equivalent resources from an unused account. This is because people engage in within-account comparisons, comparing the remaining resources in the account with what the account originally had, leading them to value the remaining resources less in a used account. We demonstrate the robustness of the effect of a used (vs. unused) account across several domains, including gift cards, checking accounts, and credit card reward points. Further, we demonstrate a boundary condition of the effect, revealing that the proportion of the account remaining moderates the subsequent consumption. Lastly, we generalize this effect from consumption to charitable giving. The findings provide insights into how policymakers, companies, and individuals may consider leveraging the perception of an account being used or unused to curb expenses and encourage charitable giving. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effects of Pregnancy-Onset Asthma on Perinatal Outcomes: A Retrospective Cohort Study.

BACKGROUND: It is unknown whether women with pregnancy-onset asthma are predisposed to worse pregnancy outcomes compared with women with pre-pregnancy asthma. OBJECTIVE: To explore whether pregnancy-onset asthma leads to worse perinatal outcomes compared with pre-pregnancy asthma. METHODS: Women who were discharged with a diagnosis of asthma and gave birth to a live singleton were included in this retrospective cohort analysis. Women were separated into groups based on whether the asthma was diagnosed during or before pregnancy. We compared clinical characteristics, perinatal outcomes, and asthma exacerbations (AEs) between groups. RESULTS: A total of 335 women were included in this study, 39 of whom (11.6%) had pregnancy-onset asthma and 296 had pre-pregnancy asthma. All pregnant women in the pregnancy-onset group experienced AEs during pregnancy. The proportion of chronic hypertension, chronic hypertension with superimposed preeclampsia, and spontaneous preterm births in the pregnancy-onset group was significantly higher than that in the pre-pregnancy asthma group. After adjusting for age, body mass index, onset of asthma during pregnancy, and severity of AEs through multivariate analysis, pregnancy-onset asthma was an independent risk factor for spontaneous preterm birth (adjusted odds ratio = 7.71; 95% CI, 1.30-46.12) and severe AE was an independent risk factor for gestational hypertension and preeclampsia (adjusted odds ratio = 3.58; 95% CI, 1.30-9.87). CONCLUSIONS: During pregnancy, pregnancy-onset asthma in women is associated with an exacerbation of the condition. Obstetricians should be vigilant for signs of asthma onset during pregnancy. Other health care providers should watch for symptoms of gestational hypertension and preeclampsia in pregnant women with preexisting or new-onset asthma.

Propolis alleviates ulcerative colitis injury by inhibiting the protein kinase C - transient receptor potential cation channel subfamily V member 1 - calcitonin gene-related peptide/substance P (PKC-TRPV1-CGRP/SP) signaling axis.

This study investigated the protective effect of water-soluble propolis (WSP) on colonic tissues in ulcerative colitis (UC) and the role of the protein kinase C - transient receptor potential cation channel subfamily V member 1 - calcitonin gene-related peptide/substance P (PKC-TRPV1-CGRP/SP) signaling pathway. Male SD rats were divided into a control group, a UC model group, various WSP groups (Low-WSP, Medium-WSP, and High-WSP) with UC, and a salazosulfapyridine (SASP) positive control group with UC. After UC was established, the WSP and SASP groups were treated with WSP or SASP, respectively, for 7 d. Each day, body weight measurements were obtained, and the disease activity index (DAI) was recorded by observing fecal characteristics and blood in the stool. After the experiment, hematoxylin and eosin (HE) colonic tissue staining was performed to observe pathological changes, western blotting and immunohistochemistry were performed to detect PKC, TRPV1, CGRP, and SP expression in colonic tissues, and laser confocal microscopy was performed to observe the fluorescence colocalization of PKC/TRPV1, TRPV1/CGRP, and TRPV1/SP. HE staining showed significant colonic tissue structure disruption and inflammatory infiltration in the UC group. Western blotting and immunohistochemistry showed that the expression of PKC, TRPV1, CGRP, and SP in the colonic tissues of the UC group increased significantly compared with that of the control group. Compared with the UC group, the expression of PKC, TRPV1, CGRP, and SP in colonic tissues was significantly reduced in the High-WSP, Medium-WSP, and SASP groups. Immunofluorescence showed the colocalized expression of PKC/TRPV1, TRPV1/CGRP, and TRPV1/SP proteins in the colon tissue of the UC group was significantly reduced after WSP and SASP interventions compared with that of the control group. The results suggest that the mechanism of UC alleviation by propolis may inhibit the PKC-TRPV1-CGRP/SP signaling pathway and the release of inflammatory mediators, thus alleviating inflammation.

P75NTR regulates autophagy through the YAP-mTOR pathway to increase the proliferation of interfollicular epidermal cells and promote wound healing in diabetic mice.

Wound healing is delayed in diabetic patients. Increased autophagy and dysfunction of interfollicular epidermal (IFE) cells are closely associated with delayed healing of diabetic wounds. Autophagy plays an important role in all stages of wound healing, but its role in diabetic wound healing and the underlying molecular mechanisms are not clear. Here, we found that diabetic mice had delayed wound healing and increased autophagy in wounds compared with normal mice and that chloroquine, an inhibitor of autophagy, decreased the level of autophagy, improved the function of IFE cells, and accelerated wound healing in diabetic mice. Treatment of IFE cells with advanced glycosylation end products (AGEs) resulted in increased microtubule-associated protein chain (LC3) expression and decreased prostacyclin-62 (P62) expression, indicating increased autophagy in AGE-treated IFE cells. Moreover, P75NTR reduced autophagy in IFE cells in the presence of AGEs and significantly increased the proliferation of IFE cells. In addition, P75NTR participated in regulating autophagy in IFE cells and in wounds in diabetic mice through the YAP-mTOR signalling pathway, which increased the functional activity of the cells and the healing rate of wounds in diabetic mice. Thus, our study suggests that P75NTR protects IFE cells against AGEs by affecting autophagy and accelerating wound healing in diabetic mice, providing a basis for understanding the role of autophagy in diabetic wound healing.

Research progress on and molecular mechanism of vacuum sealing drainage in the treatment of diabetic foot ulcers.

Diabetic foot ulcers (DFUs) are common chronic wounds and a common complication of diabetes. The foot is the main site of diabetic ulcers, which involve small and medium-sized arteries, peripheral nerves, and microcirculation, among others. DFUs are prone to coinfections and affect many diabetic patients. In recent years, interdisciplinary research combining medicine and material science has been increasing and has achieved significant clinical therapeutic effects, and the application of vacuum sealing drainage (VSD) in the treatment of DFUs is a typical representative of this progress, but the mechanism of action remains unclear. In this review, we integrated bioinformatics and literature and found that ferroptosis is an important signaling pathway through which VSD promotes the healing of DFUs and that System Xc-GSH-GPX4 and NAD(P)H-CoQ10-FSP1 are important axes in this signaling pathway, and we speculate that VSD is most likely to inhibit ferroptosis to promote DFU healing through the above axes. In addition, we found that some classical pathways, such as the TNF, NF-κB, and Wnt/ß-catenin pathways, are also involved in the VSD-mediated promotion of DFU healing. We also compiled and reviewed the progress from clinical studies on VSD, and this information provides a reference for the study of VSD in the treatment of DFUs.

Constructing Efficient CuO-Based CO Oxidation Catalysts with Large Specific Surface Area Mesoporous CeO2 Nanosphere Support.

CeO2 is an outstanding support commonly used for the CuO-based CO oxidation catalysts due to its excellent redox property and oxygen storage-release property. However, the inherently small specific surface area of CeO2 support restricts the further enhancement of its catalytic performance. In this work, the novel mesoporous CeO2 nanosphere with a large specific surface area (~190.4 m2/g) was facilely synthesized by the improved hydrothermal method. The large specific surface area of mesoporous CeO2 nanosphere could be successfully maintained even at high temperatures up to 500 °C, exhibiting excellent thermal stability. Then, a series of CuO-based CO oxidation catalysts were prepared with the mesoporous CeO2 nanosphere as the support. The large surface area of the mesoporous CeO2 nanosphere support could greatly promote the dispersion of CuO active sites. The effects of the CuO loading amount, the calcination temperature, mesostructure, and redox property on the performances of CO oxidation were systematically investigated. It was found that high Cu+ concentration and lattice oxygen content in mesoporous CuO/CeO2 nanosphere catalysts greatly contributed to enhancing the performances of CO oxidation. Therefore, the present mesoporous CeO2 nanosphere with its large specific surface area was considered a promising support for advanced CO oxidation and even other industrial catalysts.

Baroreflex activation therapy for heart failure with reduced ejection fraction: A comprehensive systematic review and meta-analysis.

Background: In recent years, baroreflex activation therapy (BAT) has been utilized to treat heart failure with reduced ejection fraction (HFrEF). However, the supporting literature on its efficacy and safety is still limited. This investigation elucidates the effects of BAT in HFrEF patients to provide a reference for future clinical applications. Methods: This investigation follows Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. Relevant investigations on the use of BAT in HFrEF patients were searched and selected from 5 databases, including Web of Science, MEDLINE, PubMed, Embase, and Cochrane Library, from inception to December 2022. The methodological quality of eligible articles was assessed via the Cochrane risk of bias tool, and for meta-analysis, RevMan (5.3) was used. Results: Randomized controlled trials comprising 343 participants were selected for the meta-analysis, which revealed that in HFrEF patients, BAT enhanced the levels of LVEF (MD: 2.97, 95 % CI: 0.53 to 5.41), MLHFQ (MD: -14.81, 95 % CI: -19.57 to -10.06) and 6MWT (MD: 68.18, 95 % CI: 51.62 to 84.74), whereas reduced the levels of LVEDV (MD: -15.79, 95 % CI: -32.96 to 1.37) and DBP (MD: -2.43, 95 % CI: -4.18 to -0.68). Conclusion: It was concluded that BAT is an efficient treatment option for HFrEF patients. However, to validate this investigation, further randomized clinical trials with multiple centers and large sample sizes are needed.

YAP promotes the healing of ischemic wounds by reducing ferroptosis in skin fibroblasts through inhibition of ferritinophagy.

The impaired healing of chronic wounds is often attributed to the ischemic and hypoxic microenvironment, leading to increased cell death. Ferroptosis, a novel form of cell death unveiled in recent years, could potentially be linked with the process of wound healing. In this study, we explored the significance and mechanism of ferroptosis in ischemic wounds. Using transmission electron microscopy, Western blot, flow cytometry, immunofluorescence, and glutathione (GSH) assay, we observed that the death of primary mouse skin fibroblasts induced by oxygen and glucose deprivation (OGD) was associated with ferroptosis. Specifically, we observed elevated intracellular Fe2+ and lipid peroxidation levels and decreased GSH levels in vitro, indicative of ferroptosis. Importantly, we found that ferroptosis in OGD-treated skin fibroblasts was dependent on autophagy, as the autophagy inhibitor chloroquine phosphate (CHQ) significantly reduced ferroptosis induced by OGD. Moreover, our study revealed that NCOA4-mediated ferritinophagy significantly contributed to the occurrence of ferroptosis induced by OGD in skin fibroblasts. Additionally, we identified the involvement of YAP in the regulation of ferritinophagy, with YAP suppressing NCOA4 expression in OGD-treated skin fibroblasts, thereby reducing ferroptosis. Furthermore, in ischemic wound models in mice, both inhibitors of ferroptosis and autophagy promoted wound healing, while a YAP inhibitor, verteporfin, delayed wound healing. In conclusion, these findings indicate that ferroptosis, regulated by YAP through ferritinophagy inhibition, presents a novel mechanism responsible for the delayed healing of ischemic wounds. Understanding this process could offer promising therapeutic targets to improve wound healing in ischemic conditions.

Metabolic Recoding of NSUN2-Mediated m5C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m5C-ENO1 Positive Feedback Loop.

The RNA modification, 5-methylcytosine (m5C), has recently gained prominence as a pivotal post-transcriptional regulator of gene expression, intricately intertwined with various tumorigenic processes. However, the exact mechanisms governing m5C modifications during the onset and progression of colorectal cancer (CRC) remain unclear. Here, it is determined that the m5C methyltransferase NSUN2 exhibits significantly elevated expression and exerts an oncogenic function in CRC. Mechanistically, NSUN2 and YBX1 are identified as the "writer" and "reader" of ENO1, culminating in the reprogramming of the glucose metabolism and increased production of lactic acid in an m5C-dependent manner. The accumulation of lactic acid derived from CRC cells, in turn, activates the transcription of NSUN2 through histone H3K18 lactylation (H3K18la), and induces the lactylation of NSUN2 at the Lys356 residue (K356), which is crucial for capturing target RNAs. Together, these findings reveal an intriguing positive feedback loop involving the NSUN2/YBX1/m5C-ENO1 signaling axis, thereby bridging the connection between metabolic reprogramming and epigenetic remodeling, which may shed light on the therapeutic potential of combining an NSUN2 inhibitor with immunotherapy for CRC.