Protective effects and molecular mechanisms of Litopenaeus vannamei treated with l-arginine/l-lysine against myofibrillar proteins oxidation and quality degradation during freeze-thaw cycles.

The storage and processing of Litopenaeus vannamei are often challenged by the freeze-thaw (F-T) cycle phenomenon. This study delved into the influence of pretreatment with l-arginine (Arg) and l-lysine (Lys) on the myofibrillar proteins oxidation and quality of shrimp subjected to F-T cycles. Arg and Lys pretreatment notably improved water-holding capacity (WHC), textural integrity as well as the myofibrillar structure of the shrimps. A lesser reduction in the amounts of immobile and bound water was found in the amino acid-treated groups, and the oxidation of lipids and proteins were both decelerated. Molecular simulation results indicated that Arg and Lys could form hydrogen and salt-bridge bonds with myosin, enhancing the stability of Litopenaeus vannamei. The study concludes that Arg and Lys are effective in alleviating the adverse effects of F-T cycles on the quality of Litopenaeus vannamei, and provides a new solution for the quality maintenance during storage and processing.

Overview of the PRMT6 modulators in cancer treatment: Current progress and emerged opportunity.

Protein Arginine Methyltransferase 6 (PRMT6) is a Type I PRMT enzyme that plays a role in the epigenetic regulation of gene expression by methylating histone and non-histone proteins. It is also involved in various cellular processes, including alternative splicing, DNA repair, and cell signaling. Furthermore, PRMT6 exerts multiple effects on cellular processes such as growth, migration, invasion, apoptosis, and drug resistance in various cancers, positioning it as a promising target for anti-tumor therapeutics. In this review, we initially provide an overview of the structure and biological functions of PRMT6, along with its association with cancer. Subsequently, we focus on recent progress in the design and development of modulators targeting PRMT6. This includes a comprehensive review of PRMT6 inhibitors (isoform-selective and non-selective), dual-target inhibitors based on PRMT6, PRMT6 covalent inhibitors, and PRMT6-targeting hydrophobic tagging (HyT) degraders, from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and the clinical status of these modulators. Finally, we also provided the challenges and prospective directions for PRMT6 targeting drug discovery in cancer therapy.

Associations of plasma arginine, homoarginine, and ADMA/SDMA levels with risk of ischemic stroke: A nested case-control study.

BACKGROUND AND AIMS: Previous studies have linked aberrant nitric oxide (NO) metabolism with vascular diseases. Although arginine, homoarginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) are involved in NO metabolic pathways, their associations with ischemic stroke (IS) remain unclear. METHODS AND RESULTS: We conducted a case-control study nested within the Prospective Follow-up Study on Cardiovascular Morbidity and Mortality in China (PFS-CMMC) (2013-2018, n = 16,457; median follow-up time: 5.3 y), which included 321 incident cases of IS and 321 controls matched by age and sex. Plasma arginine, homoarginine, ADMA/SDMA were measured by ultrahigh performance liquid chromatography-tandem mass spectrometry. Conditional logistic regression analyses were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) for the association between the plasma metabolites and IS risk. After adjustment for body mass index, educational attainment, smoking, hypertension, hyperlipidemia, diabetes, and family history of stroke, the OR of IS risk for the highest versus the lowest quartile was 2.46 (95% CI: 1.39-4.35, P trend = 0.004) for homoarginine and 2.22 (95% CI: 1.24-3.97, P trend = 0.003) for ADMA/SDMA. Spline regression analyses indicated positive dose-response relationships of homoarginine and ADMA/SDMA with the IS risk (both P for linearity <0.05). No significant association was observed between plasma arginine and IS risk. CONCLUSIONS: Elevated plasma levels of homoarginine and ADMA/SDMA were associated with a higher risk of IS. Our novel findings suggest a role of NO metabolism in the pathogenesis of IS.

Mechanistic Insights on Metformin and Arginine Implementation as Repurposed Drugs in Glioblastoma Treatment.

As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients' life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes with coexisting nemaline myopathy: a case report.

BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and nemaline myopathy are two rare genetic conditions. We report the first case reported in world literature with coexistence of both these rare disorders. CASE PRESENTATION: A 11-year-old previously healthy Sri Lankan male child, product of a nonconsanguineous marriage with normal development presented with acute onset short lasting recurring episodes of right-sided eye deviation with impaired consciousness. In between episodes he regained consciousness. Family history revealed a similar presentation in the mother at 36 years of age. Examination was significant for short stature and proximal upper and lower limb weakness. His plasma and cerebrospinal fluid lactate were elevated. Magnetic resonance imaging brain had evidence of an acute infarction in the right occipital territory. Sanger sequencing for common mitochondrial variants of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes confirmed this diagnosis. Whole exome sequencing revealed pathogenic compound heterozygous variants in NEB gene implicating in coexisting nemaline myopathy. Acute presentation was managed with supportive care, antiepileptics, and mitochondrial supplementation. Currently he is stable on daily supplementation of arginine and limb-strengthening physiotherapy. He is being monitored closely clinically and with serum lactate level. CONCLUSION: Genetic diseases are rare. Coexistence of two genetic conditions is even rarer. Genetic confirmation of diagnosis is imperative for prediction of complications, accurate management, and genetic counseling.

Behavioral and hormonal responses in the defensive repertoire during provocation in captive monocled cobra (Naja kaouthia).

The hooding behavior exhibited by cobras is a distinct defensive mechanism against predators, encompassing both visual and auditory displays. This behavior can be triggered by natural predators or humans. Considering that human provocation may potentially stimulate the hypothalamic-pituitary-adrenal (HPA) axis, the present study aimed to determine the pattern of the HPA axis response following human provocation-induced hooding behavior (PV) and provide a detailed analysis of the behavioral PV displays. Our primary hypothesis was that a 5-minute PV could activate the HPA axis to a degree comparable to that in the restraint-induced stress model (RS). The PV, RS-1 (1-minute), and RS-5 (5-minute) restraint models indeed activated the HPA axis. However, the pattern of plasma corticosteroid (CORT), but not arginine vasotocin, in the PV group differed from that in the RS-1 and RS-2 groups. The present study revealed the behavioral components of the PV. The first component appeared to be related to an increase in apparent size that is an intimidation display, while the second hissing and striking component consisted of a bluff charge. Moreover, no correlation was observed between the pattern of plasma CORT and any specific PV display. Finally, the body temperature (Tb) of cobras from RS-5 gradually increased, while the Tb of cobras from PV (5 min) remained unchanged. In conclusion, the activation of the HPA axis emerges as the main physiological response after human provocation. Within 5 min of provocation, the cobras' hooding behavior comprised two display components that were not related to the pattern of plasma CORT.

Adipocyte-secreted PRELP promotes adipocyte differentiation and adipose tissue fibrosis by binding with p75NTR to activate FAK/MAPK signaling.

Adipocyte-secreted factors intricately regulate adipose tissue function, and the underlying molecular mechanisms are only partially understood. However, the function of PRELP, which is a key component of the extracellular matrix (ECM) in adipocytes, remains largely unknown. In this study, we demonstrate that PRELP was upregulated in both obese humans and mice, which exhibited a positive correlation with metabolic disorders. PRELP knockout could resist HFD-induced obesity and inhibit adipocyte differentiation. PRELP knockout improved glucose tolerance, insulin sensitivity and alleviated adipose tissue fibrosis. Mechanistically, PRELP was secreted into the ECM and bound to the extracellular domain of its receptor p75NTR in adipocytes, which further activated the FAK/MAPK (JNK, p38 MAPK, ERK1/2) signaling pathway, promoting adipocyte differentiation and exacerbating adipocyte fibrosis. Adipocyte PRELP plays a pivotal role in regulating obesity and adipose tissue fibrosis through an autocrine manner, and PRELP may be a therapeutic target for obesity and its related metabolic disorders.

A novel class of potent antiangiogenic and antioxidant pyrazoles: synthesis, bioactivity, docking and ADMET studies.

Aim: Angiogenesis is the hallmark of cancer progression driven by VEGF/VEGFR-2 signalling pathway, inhibition of which could be a solution to tackle the progression of tumour cells and thus arresting their growth.Materials & methods: A novel class of pyrazoles was synthesized using arginine and dibromo ketones. Antiangiogenic activity was performed by in vivo yolk sac method. Antioxidant activity was evaluated by hydroxyl and superoxide radical scavenging assays. Docking studies were performed to determine the pyrazoles' binding potential with VEGFR-2 receptor and VEGF tyrosine kinase. ADMET properties were calculated using SwissADME and admetSAR for drug-likeness.Results: Compounds 5a-e showed significant antiangiogenic effects. Compound 5f exhibited effective hydroxyl and superoxide radical scavenging activities. Docking results confirmed the potential binding efficiency with VEGFR-2 receptor over VEGF tyrosine kinase, thus, functioning as competitive-inhibitors. ADMET studies revealed that the compounds possess favourable drug-like qualities.Conclusion: This study presents a novel class of pyrazoles as promising antioxidant and antiangiogenic agents with favourable drug-likeness properties.

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An Internally Attached Aptameric Graphene Nanosensor for Sensitive Vasopressin Measurement in Critical Patient Monitoring.

This paper presents an aptameric graphene nanosensor for rapid and sensitive measurement of arginine vasopressin (AVP) toward continuous monitoring of critical care patients. The nanosensor is a field-effect transistor (FET) with monolayer graphene as the conducting channel and is functionalized with a new custom-designed aptamer for specific AVP recognition. Binding between the aptamer and AVP induces a change in the carrier density in the graphene and resulting in measurable changes in FET characteristics for determination of the AVP concentration. The aptamer, based on the natural enantiomer D-deoxyribose, possess optimized kinetic binding properties and is attached at an internal position to the graphene for enhanced sensitivity to low concentrations of AVP. Experimental results show that this aptameric graphene nanosensor is highly sensitive (with a limit of detection of 0.3 pM and a resolution of 0.1 pM) to AVP, and rapidly responsive (within 90 s) to both increasing and decreasing AVP concentration changes. The device is also reversable (within 4%), repeatable (within 4%) and reproducible (within 5%) in AVP measurements.

Muscle protein catabolism and splanchnic arginine consumption drive arginine dysregulation during Pseudomonas Aeruginosa induced early acute sepsis in swine.

Human sepsis is characterized by increased protein breakdown and changes in arginine and citrulline metabolism. However, it is unclear whether this is caused by changes in transorgan metabolism. We therefore studied in a Pseudomonas aeruginosa induced pig sepsis model the changes in protein and arginine related metabolism on whole body (Wb) and transorgan level. We studied 22 conscious pigs for 18 hours during sepsis, induced by infusing live bacteria (Pseudomonas aeruginosa) or after placebo infusion (control). We used stable isotope tracers to measure Wb and skeletal muscle protein synthesis and breakdown, as well as Wb, splanchnic, skeletal muscle, hepatic and portal drained viscera (PDV) arginine and citrulline disposal and production rates. During sepsis, arginine Wb production (p=0.0146), skeletal muscle release (p=0.0035) and liver arginine uptake were elevated (p=0.0031). Wb de novo arginine synthesis, citrulline production, and transorgan PDV release of citrulline, glutamine and arginine did not differ between sepsis and controls. However, Wb (p<0.0001) and muscle (p<0.001) protein breakdown were increased, suggesting that the enhanced arginine production is predominantly derived from muscle breakdown in sepsis. In conclusion, live-bacterium sepsis increases muscle arginine release and liver uptake, mirroring previous pig endotoxemia studies. In contrast to observations in humans, acute live-bacterium sepsis in pigs does not change citrulline production or arterial arginine concentration. We therefore conclude that the arginine dysregulation observed in human sepsis is possibly initiated by enhanced protein catabolism and splanchnic arginine catabolism, while decreased arterial arginine concentration and citrulline metabolism may require more time to fully manifest in patients.

Effects of arginine intake during weight training on blood variables.

This experiment studied the effect of arginine intake on blood pressure and blood variables during weight training in 20 men in their 20s. The resistance exercise program was performed 3 times a week at 60% of one repetition maximum for 8 weeks. The arginine intake group consumed 1,000 mg of arginine 2 tablets per day before weight training for 8 weeks. The placebo group was instructed to consume two of placebo with water, the same as the arginine intake group. After 8 weeks, the day after the end of the resistance exercise program, systolic pressure, diastolic pressure, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, muscle mass, and maximum muscle strength were measured. In changes in systolic blood pressure, the arginine intake group was 118.20±2.40 mmHg, showed a statistically significant decrease compared to the placebo group. Triglyceride in the arginine intake group was 112.62±2.40 mg/dL, showing a statistically significant decrease compared to the placebo group. Based on these results, arginine intake during resistance exercise is judged to have a positive effect on lowering blood pressure, and is also believed to reduce triglycerides, a blood lipid variable, so it is thought to function as a supplement during exercise.

Testosterone treatment impacts the intestinal microbiome of transgender individuals.

Medical modulation of sex hormone levels is a cornerstone of treatment for many conditions that impact well-being, including cancer, fertility/infertility, gender dysphoria, and chronic metabolic diseases such as diabetes and obesity. The microbial residents of the intestine, known as the microbiota, interact with sex hormones in the intestine, and there is correlative evidence that this interaction is bidirectional. Based on these published findings, we hypothesized that transgender individuals receiving exogenous testosterone as part of their gender-affirming medical treatment might undergo changes in their intestinal microbiome. To test this, we collected 26 stool samples from nine individuals before and up to 8 months after initiation of treatment with exogenous testosterone and subjected these samples to metagenomic analysis. While no species were significantly associated with the duration of testosterone therapy, pathways that generate glutamate increased in abundance, while those that consume glutamate decreased. Glutamate is a precursor of arginine, and testosterone is known to increase levels of arginine and its metabolites in the plasma. We hypothesize that testosterone increases the uptake of glutamate by enterocytes, thus decreasing access of the microbiota to this amino acid. While this pilot study establishes the impact of testosterone therapy on the intestinal microbiome, a more comprehensive study is necessary to establish the impact of testosterone-driven metagenomic shifts on the stool metatranscriptome, the stool metabolome, and the plasma metabolome.IMPORTANCEThe human intestine is inhabited by a large community of microbes known as the microbiome. Members of the microbiome consume the diet along with their human host. Thus, the metabolomes of the host and microbe are intricately linked. Testosterone alters the plasma metabolome. In particular, plasma levels of arginine and its metabolites and testosterone are positively correlated. To investigate the impact of exogenous testosterone on the microbiome, we analyzed the stool metagenomes of transgender individuals before and after the initiation of testosterone treatment. In this pilot project, we found a modest impact on the microbiome community structure but an increase in the abundance of metabolic pathways that generate glutamate and spare glutamate consumption. We propose that the host uses glutamate to generate arginine, decreasing the amount available for the microbiome.

Modulation of empathic abilities by the interplay between estrogen receptors and arginine vasopressin.

This review examines the complex interactions between estrogen receptors α and ß (ERα and ERß) and arginine vasopressin (AVP), delving into their significant roles in modulating empathy, a critical psychological component in human social dynamics. Empathy, integrating affective and cognitive elements, is anchored in neural regions like the amygdala and prefrontal cortex. ERα and ERß, pivotal in estrogen regulation, influence neurotransmitter dynamics and neural network activities, crucial for empathic development. AVP, key in regulating water balance, blood pressure, and social behaviors, interplays with these receptors, profoundly impacting empathic responses. The study highlights that ERα predominantly enhances empathy, especially affective empathy, by stimulating AVP synthesis and release. In contrast, ERß may diminish empathy in certain contexts by suppressing AVP expression and activity. The intricate interplay, homeostatic balance, and mutual conversion between ERα and ERß in AVP regulation are identified as challenging yet crucial areas for future research. These findings provide essential insights into the neurobiological underpinnings of empathy, offering new avenues for therapeutic interventions in social cognitive disorders and emotional dysregulation.

Therapeutic potential of arginine deprivation therapy for gliomas: a systematic review of the existing literature.

Background: Arginine deprivation therapy (ADT) hinders glioma cells' access to nutrients by reducing peripheral blood arginine, showing great efficacy in various studies, which suggests it as a potentially promising treatment for glioma. The aim of this systematic review was to explore the mechanism of ADT for gliomas, the therapeutic effect based on existing research, and possible combination therapies. Methods: We performed a systematic literature review of PubMed, ScienceDirect and Web of Science databases according to PRISMA guidelines, searching for articles on the efficacy of ADT in glioma. Results: We identified 17 studies among 786 search results, among which ADT therapy mainly based on Arginine free condition, Arginine Deiminase and Arginase, including three completed clinical trials. ADT therapy has shown promising results in vivo and in vitro, with its safety confirmed in clinical trials. In the early phase of treatment, glioblastoma (GBM) cells develop protective mechanisms of stress and autophagy, which eventually evolve into caspase dependent apoptosis or senescence, respectively. The immunosuppressive microenvironment is also altered by arginine depletion, such as the transformation of microglia into a pro-inflammatory phenotype and the activation of T-cells. Thus, ADT therapy demonstrates glioma-killing effect in the presence of a combination of mechanisms. In combination with various conventional therapies and investigational drugs such as radiotherapy, temozolomide (TMZ), cyclin-dependent kinase inhibitors (CDK) inhibitors and autophagy inducers, ADT therapy has been shown to be more effective. However, the phenomenon of drug resistance due to re-expression of ASS1 rather than stem cell remains to be investigated. Conclusion: Despite the paucity of studies in the literature, the available data demonstrate the therapeutic potential of arginine deprivation therapy for glioma and encourage further research, especially the exploration of its combination therapies and the extrapolation of what we know about the effects and mechanisms of ADT from other tumors to glioma.

Effect of a thiohydantoin salt derived from l-Arginine on Leishmania amazonensis and infected cells: Insights from biological effects to molecular docking interactions.

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania and is responsible for more than 1 million new cases and 70,000 deaths annually worldwide. Treatment has high costs, toxicity, complex and long administration time, several adverse effects, and drug-resistant strains, therefore new therapies are urgently needed. Synthetic compounds have been highlighted in the medicinal chemistry field as a strong option for drug development against different diseases. Organic salts (OS) have multiple biological activities, including activity against protozoa such as Leishmania spp. This study aimed to investigate the in vitro leishmanicidal activity and death mechanisms of a thiohydantoin salt derived from l-arginine (ThS) against Leishmania amazonensis. We observed that ThS treatment inhibited promastigote proliferation, increased ROS production, phosphatidylserine exposure and plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid body accumulation, autophagic vacuole formation, cell cycle alteration, and morphological and ultrastructural changes, showing parasites death. Additionally, ThS presents low cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), and sheep erythrocytes. ThS in vitro cell treatment reduced the percentage of infected macrophages and the number of amastigotes per macrophage by increasing ROS production and reducing TNF-α levels. These results highlight the potential of ThS among thiohydantoins, mainly related to the arginine portion, as a leishmanicidal drug for future drug strategies for leishmaniasis treatment. Notably, in silico investigation of key targets from L. amazonensis, revealed that a ThS compound from the l-arginine amino acid strongly interacts with arginase (ARG) and TNF-α converting enzyme (TACE), suggesting its potential as a Leishmania inhibitor.

Arginine on immune function and post-operative obstructions in colorectal cancer patients: a meta-analysis.

BACKGROUND: The aim of this study is to investigate the impact of arginine on immune function and postoperative complications in colorectal cancer (CRC) patients. METHODS: We conducted a comprehensive search to identify eligible RCTs in various databases, such as PubMed, Cochrane Library, EMBASE, Web of Science, MEDLINE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP Medicine Information System (VIP), and Chinese Biomedical Database (CBM). This study aimed to examine IgA, IgG, and IgM levels as well as CD4+ and CD8+ counts as well as the CD4+/CD8+ ratio. Anastomotic leaking, length of stay (LOS), and surgical site infection (SSI) were included as secondary outcomes. Stata (StataCorp, version 14.0) was utilized for data analysis. To ensure the results were reliable, we used meta-regression, sensitivity analysis, and publication bias analysis. RESULTS: A total of 24 publications (including 1883 patients) out of 681 that were retrieved fulfilled the inclusion criteria. The arginine group showed notable improvements in humoral immunity, with gains in IgA (SMD=0.45, 95% CI: 0.30-0.60), IgG (SMD=0.80, 95% CI: 0.64-0.96), and IgM (SMD=0.66, 95% CI: 0.39-0.93). With regards to cellular immunity, the arginine group exhibited a substantial increase in the CD4+ T cell count (SMD = 1.03, 95% CI: 0.67-1.38) compared to the control group. However, the CD4+/CD8+ ratio decreased significantly (SMD=1.37, 95% CI: 0.88-1.86) in the same arginine group, indicating a change in the balance between these two cell types. Additionally, the CD8+ T cell count showed a notable decrease (SMD=-0.70, 95% CI: -1.09 to -0.32) in the arginine group when compared to the control group. Anastomotic leakage was also considerably lower in the arginine group (SMD=-0.05, 95% CI: -0.08 to -0.02), the rate of SSIs was lower (RR = -0.02, 95% CI: -0.05-0), and the length of time patients spent in the hospital was shorter (SMD=-0.15, 95% CI: -0.38 to -0.08). CONCLUSIONS: After radiation treatment for CRC, arginine improves immune function and decreases the risk of infection problems. TRIAL REGISTRATION: Registration with PROSPERO for this meta-analysis is number CRD42024520509.

Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression.

In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant-7 (ARV7) is clinically the most relevant and has a distinct 3' untranslated region (3'UTR) compared to the AR full-length variant, suggesting a unique post-transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3'UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine-rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.

Enhanced Tumor-Targeted Delivery of Arginine-Rich Peptides via a Positive Feedback Loop Orchestrated by Piezo1/integrin ß1 Signaling Axis.

Peptide-based drugs hold great potential for cancer treatment, and their effectiveness is driven by mechanisms on how peptides target cancer cells and escape from potential lysosomal entrapment post-endocytosis. Yet, the mechanisms remain elusive, which hinder the design of peptide-based drugs. Here hendeca-arginine peptides (R11) are synthesized for targeted delivery in bladder carcinoma (BC), investigated the targeting efficiency and elucidated the mechanism of peptide-based delivery, with the aim of refining the design and efficacy of peptide-based therapeutics. It is demonstrated that the over-activated Piezo1/integrin ß1 (ITGB1) signaling axis significantly facilitates tumor-targeted delivery of R11 peptides via macropinocytosis. Furthermore, R11 peptides formed hydrogen bonds with integrin ß1, facilitating targeting and penetration into tumor cells. Additionally, R11 peptides protected integrin ß1 from lysosome degradation, promoting its recycling from cytoplasm to membrane. Moreover, this findings establish a positive feedback loop wherein R11 peptides activate Piezo1 by increasing membrane fusion, promoting Ca2+ releasing and resulting in enhanced integrin ß1-mediated endocytosis in both orthotopic models and clinical tissues, demonstrating effective tumor-targeted delivery. Eventually, the Piezo1/integrin ß1 signaling axis promoted cellular uptake and transport of peptides, establishing a positive feedback loop, promoting mechanical delivery to cancer and offering possibilities for drug modification in cancer therapy.

Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.

BACKGROUND: The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. METHODS: To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids. RESULTS: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models. CONCLUSIONS: The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.

l-Arginine-Loaded Oxidized Isabgol/Chitosan-Based Biomimetic Composite Scaffold Accelerates Collagen Synthesis, Vascularization, and Re-epithelialization during Wound Healing in Diabetic Rats.

Impaired wound healing in diabetic wounds is common due to infection, inflammation, less collagen synthesis, and vascularization. Diabetic wound healing in patients is still a challenge and needs an ideal wound dressing to treat and manage diabetic wounds. Herein, an efficacious wound dressing biomaterial was fabricated by cross-linking oxidized isabgol (Oisab) and chitosan (Cs) via trisodium trimetaphosphate and Schiff base bonds. l-Arginine (l-Arg) was incorporated as a bioactive substance in the Oisab + Cs scaffold to promote cell adhesion, cell proliferation, collagen synthesis, and vascularization. The fabricated scaffolds showed microporous networks in the scanning electron microscopy analysis. The scaffold also possessed excellent hemocompatibility. In vitro studies using fibroblasts (L929 and human dermal fibroblast cells) confirmed the cytocompatibility of these scaffolds. The results of the in vivo chicken chorioallantoic membrane assay confirmed the proangiogenic activity of the Oisab + Cs + l-Arg scaffolds. The wound-healing potential of these scaffolds was studied in streptozotocin-induced diabetic rats. This in vivo study showed that the period of epithelialization in the Oisab + Cs + l-Arg scaffold-treated wounds was 21.67 ± 1.6 days, which was significantly faster than the control (30.33 ± 2.5 days). Histological and immunohistochemical studies showed that the Oisab + Cs + l-Arg scaffolds significantly accelerated the rate of wound contraction by reducing inflammation, improving collagen synthesis, and promoting neovascularization. These findings suggest that the Oisab + Cs + l-Arg scaffolds could be beneficial in treating diabetic wounds in clinical applications.