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Charge microenvironment and bioactivity of in situ-formed PEG-RGD dual hydrogel dressings promote wound healing.
J Mater Chem B
Chuanjie He, Yulin Wang, Xinyu Fang +10 more
Healing of large skin wounds involves a complex biological process with overlapping phases, facing challenges from fibroblast proliferation, immune response, and extracellular matrix (ECM) remolding. Hydrogel dressings serve as temporary barriers protecting injured tissue from exogenous infections while providing an advantageous microenvironment for cellular regeneration. However, traditionally molded hydrogels through catalyzed or triggered crosslinking into fixed size and strength prior to treatment struggle to integrate tightly with irregular wound surfaces, leading to dressing detachment and wound exposure in areas with high curvature and mobility. Here, we designed CGRGDGC peptide enantiomers, incorporating with 4 arm-PEG-maleimide, to in situ form functional and morphologically matching dual-phasic hydrogel dressing. In situ elastic hydrogel dressing forms within 10 min after applying, with a storage modulus of 1300 Pa and internal porous networks. The peptide incorporation increased the surface potential to ∼370 mV, twice that of PEG hydrogels. The bioactive L-peptide hydrogel exhibited strongest immunomodulation and skin regeneration enhancement, while the non-bioactive D-peptide hydrogel also showed significant promotion compared to the PEG hydrogel. We demonstrated that both the charge microenvironment and bioactivity of hydrogel dressing regulate the immune response and promote wound healing after skin injury. This research provides novel insights and strategies showing that non-ligand peptide sequences achieve biological functions by modulating molecular potential and that adjusting the charge microenvironment and incorporating bioactive peptides through peptide phase introduction enhance skin regeneration.
Post-stress modulation of the HPA and melanocortin systems alleviates migraine-like behaviors in mice.
Cephalalgia
Ya-Yu Hu, Hao-Ruei Mei, Shruti Sankar +4 more
BackgroundStress is a major trigger for migraine attacks. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) to maintain homeostasis, and migraine attacks may occur as an adverse effect of this response. We previously demonstrated in a mouse model that inhibiting corticosterone (CORT) synthesis by administering metyrapone before stress prevented stress-induced migraine-like behaviors. Given the unpredictable nature of stressors and their onset or termination, it is critical to better understand the adaptive and maladaptive effects of the HPA stress response. Here, we aimed to evaluate the effects of HPA axis modulation following the end of stress exposure.MethodsRepeated stress induces migraine-like behaviors and priming to sodium nitroprusside (SNP) in mice. Metyrapone (to inhibit CORT synthesis), CORT (to evaluate its effects after exogenous administration), and adrenocorticotropic hormone (ACTH) (to test the effects of a hormone upstream to CORT) were administered post-stress. Additionally, α-melanocyte-stimulating hormone (α-MSH, an ACTH cleavage product) and tetrahydroisoquinoline (THIQ), a melanocortin 4 receptor (MC4R) agonist, were administered to examine melanocortin receptor involvement. Facial hypersensitivity was assessed via von Frey testing and grimace scoring was used to evaluate non-evoked pain. Serum CORT levels were measured in both control and stressed mice following ACTH administration.ResultsWe examined post-stress HPA axis modulation on stress-induced facial hypersensitivity. Metyrapone reduced acute-phase hypersensitivity and reduced priming to SNP, suggesting sustained synthesis of CORT after stress plays a role in development of migraine-like behavior. Surprisingly, both CORT and ACTH treatments at 1- and 24-h post-stress alleviated stress-induced behaviors and priming. To determine if ACTH effects were mediated by an elevation in circulating CORT, metyrapone was administered before the ACTH injection. Metyrapone increased the ACTH reversal of stress effects on facial hypersensitivity. Furthermore, post-stress ACTH injections significantly increased serum CORT levels within 30 min. In addition to ACTH effects on CORT levels, ACTH effects could be mediated by the melanocortin system. Post-stress administration of α-MSH or the MC4R agonist THIQ, reduced migraine-like behaviors.ConclusionsThere is a complex relationship between stress, the HPA axis, and melanocortin signaling, in the effects of repeated stress exposure on migraine-like behaviors. In the early post-stress response phase, there are contributions from both CORT and MC4R signaling in the maintenance of behavioral effects. These findings suggest that targeting the HPA axis and MC4R after stress may be a potential therapeutic approach for stress-induced migraine attacks.
Stress and high fat diet reconfigure the active translatome of CeA-NPY neurons.
Mol Metab
Chi Kin Ip, Lei Zhang, Ramon Tasan +1 more
The interplay between calorie-dense food and chronic stress significantly accelerates obesity development, with neural circuits expressing Neuropeptide Y (NPY) in the central amygdala (CeA) emerging as the key mediator of this process. While these circuits are known to enhance hedonic feeding behavior and promote weight gain, the precise molecular mechanisms regulating NPY neuron activity at the translational level under the combined influence of high fat diet and stress conditions have remained poorly understood.
Plasmacytoid dendritic cells alleviate allergic asthma via airway epithelial cell-dependent thymosin β4 expression.
J Allergy Clin Immunol
Yue Li, Zhengrong Chen, Miaomiao Han +7 more
Plasmacytoid dendritic cells (pDCs) have been previously reported to induce immune tolerance to allergen by inhibiting allergic TH2-cell priming. However, there is limited knowledge on pDC function during the TH2 effector phase of allergic asthma.
Intranasal pramlintide matches intraperitoneal effects on food intake and gastric emptying in mice.
Endocrine
Milena S Almeida, Mariele P Sanches, Natália S Tonet +5 more
Pramlintide is an amylin analog developed as a complementary treatment for diabetes. However, it requires several subcutaneous injections, reducing patients' adherence. Since the intranasal route might be an alternative for drug administration, we evaluated whether intranasal pramlintide treatment exerts comparable actions with intraperitoneal administration.
Lactic acidosis: implications for human exercise performance.
Eur J Appl Physiol
Simeon P Cairns, Michael I Lindinger
During high-intensity exercise a lactic-acidosis occurs with raised myoplasmic and plasma concentrations of lactate- and protons ([lactate-], [H+] or pH). We critically evaluate whether this causes/contributes to fatigue during human exercise. Increases of [lactate-] per se (to 25 mM in plasma, 50 mM intracellularly) exert little detrimental effect on muscle performance while ingestion/infusion of lactate- can be ergogenic. An exercise-induced intracellular acidosis at the whole-muscle level (pHi falls from 7.1-7.0 to 6.9-6.3), incorporates small changes in slow-twitch fibres (pHi ~ 6.9) and large changes in fast-twitch fibres (pHi ~ 6.2). The relationship between peak force/power and acidosis during fatiguing contractions varies across exercise regimes implying that acidosis is not the sole cause of fatigue. Concomitant changes of other putative fatigue factors include phosphate metabolites, glycogen, ions and reactive oxygen species. Acidosis to pHi 6.7-6.6 at physiological temperatures (during recovery from exercise or induced in non-fatigued muscle), has minimal effect on force/power. Acidosis to pHi ~ 6.5-6.2 per se reduces maximum force (~12%), slows shortening velocity (~5%), and lowers peak power (~22%) in non-fatigued muscles/individuals. A pre-exercise induced-acidosis with ammonium chloride impairs exercise performance in humans and accelerates the decline of force/power (15-40% initial) in animal muscles stimulated repeatedly in situ. Raised [H+]i and diprotonated inorganic phosphate ([H2PO4-]i) act on myofilament proteins to reduce maximum cross-bridge activity, Ca2+-sensitivity, and myosin ATPase activity. Acidosis/[lactate-]o attenuates detrimental effects of large K+-disturbances on action potentials and force in non-fatigued muscle. We propose that depressive effects of acidosis and [H2PO4-]i on myofilament function dominate over the protective effects of acidosis/lactate- on action potentials during fatigue. Raised extracellular [H+]/[lactate-] do not usually cause central fatigue but do contribute to elevated perceived exertion and fatigue sensations by activating group III/IV muscle afferents. Modulation of H+/lactate- regulation (via extracellular H+-buffers, monocarboxylate transporters, carbonic anhydrase, carnosine) supports a role for intracellular acidosis in fatigue. In conclusion, current evidence advocates that severe acidosis in fast-twitch fibres can contribute to force/power fatigue during intense human exercise.
Living myocardial slices as a model for testing cardiac pro-reparative gene therapies.
Mol Ther
Rocco Caliandro, Azra Husetić, Merel L Ligtermoet +5 more
Available models currently adopted for preclinical studies in the cardiovascular field either fail to recapitulate human cardiac physiology or are extremely expensive and time-consuming. Translational research would greatly benefit from the development of novel models that reflect the native mature phenotype of the human heart while being cost and time effective. Living myocardial slices (LMSs) have emerged as a novel, powerful ex vivo tool for translational research. Although the number of studies adopting LMSs is rapidly increasing, this model remains largely under-characterized. In this study, we make use of LMSs and compare them to a murine model to deliver the cardioprotective factor zinc finger E box-binding homeobox 2 (ZEB2), a transcription factor known to exert cardioprotective effects after ischemic injury and promote the secretion of pro-angiogenetic factors thymosin beta-4 (TMSB4) and prothymosin alpha (PTMA). Our data show that viral-mediated delivery of these factors induced similar cardiomyocyte gene expression changes in LMS and mouse models. We also show that the delivery of these pro-angiogenic factors enhances an angiogenic response in both models, indicating that LMSs are a suitable alternative to mice for studying the effects of gene transfer in various cardiac cell types.
Plasma levels of biomarkers associated with vasodilation and neuroinflammation in pediatric patients with head trauma and their relationship with clinical characteristics of patients.
Childs Nerv Syst
Yasemin Baranoglu Kilinc, Yasar Dagistan, Erkan Kilinc
Traumatic brain injury in children can lead to lifelong sequelae and disabilities. Identifying the mediators of the neuroinflammatory process resulting from head trauma is of great importance. We therefore explored the plasma levels of neurogenic inflammatory and vasodilator peptides in children with head trauma and their relationship with the clinical characteristics of the patients.
Complexity of the Hypothalamic Oxytocin System and its Involvement in Brain Functions and Diseases.
Neurosci Bull
Xiao Cui, Lei Xiao
Oxytocin is classically termed a 'prosocial neuropeptide' because of its evolutionarily conserved role in promoting affiliative behaviors. Endogenous oxytocin is mainly synthesized by hypothalamic oxytocin neurons and signals through oxytocin receptors (OxtRs). Recent studies with cell type-specific and circuit-specific interrogation have uncovered that oxytocin signals exert pleiotropic neuromodulatory effects through anatomically widespread axonal projections and ubiquitously distributed OxtRs. Dysfunctions of oxytocin signals are closely relevant to brain disorders/diseases. While intranasal oxytocin administration has been demonstrated to be one potential strategy to alleviate some brain disorders/diseases, such as autism, obesity, and anxiety, conflicting clinical outcomes highlight the imperative for precision-targeted neuromodulation strategies. Dissecting the molecular, cellular, and neural circuitry mechanisms underlying oxytocinergic modulation is a prerequisite to achieving this goal. This review provides an overview of the current understanding of the oxytocin system in terms of anatomical structure, neuronal modulation, and signal pathways, and discusses the modulatory roles of oxytocin in social, feeding, emotional, and sensory-related brain functions and brain diseases.
Evaluation and Treatment of Patients With Hypothalamic Hypogonadism.
Obstet Gynecol Surv
Rachel Himel, David Keefe
The prevalence of eating disorders has more than doubled in the past 20 years, now affecting more than 28 million people in the United States. With eating disorders on the rise, a review of the ways in which disordered eating can present, as well as the impact on patients' gynecological health and fertility, is relevant as these causes often have reversible origins with early intervention and treatment.
Thymosin alpha 1 alleviates inflammation and prevents infection in patients with severe acute pancreatitis through immune regulation: a systematic review and meta-analysis.
Front Immunol
Yong Tian, Jiaqi Yao, Yihan Ma +4 more
Immune and inflammatory disorders are part of the complex pathophysiological processes that exacerbate severe acute pancreatitis (SAP) and subsequent infection. Thymosin alpha 1 (Tα1) is an important immunomodulatory agent in clinical practice, but there is a lack evidence to prove its effectiveness in improving the condition of SAP patients. In this study, we aimed to evaluate the efficacy in meta-analysis.
Advancing antihypertensive drug development.
Br J Pharmacol
Fay Pu, Yanrong Liu, Fozia Zahir Ahmed +3 more
Hypertension affects more than a billion individuals worldwide and remains a major cause of cardiovascular morbidity and mortality. Despite advances in therapies, optimal blood pressure control remains elusive for many patients because of treatment resistance, adverse effects, and adherence challenges. This review highlights innovative approaches in hypertension management. Aldosterone synthase inhibitors (ASIs) and non-steroidal mineralocorticoid receptor antagonists improve blood pressure control and offer cardiorenal benefits while reducing adverse effects including hyperkalaemia. Endothelin receptor antagonists show promise in resistant hypertension by addressing vasoconstrictive pathways. RNA-based therapies, like zilebesiran, provide a novel approach to suppress angiotensinogen, offering durable antihypertensive effects with less frequent dosing. Additional advances include AT2 receptor agonists, ACE2/Angiotensin-(1-7)/MAS receptor activators and NAD+ boosting compounds, which target key mechanisms of vascular dysfunction and ageing-related hypertension. Gut microbiome-targeted therapies and fixed-dose combination pills are also discussed for their potential to enhance blood pressure control and patient adherence. These emerging therapies not only aim to lower blood pressure but also address underlying pathophysiological mechanisms, offering a precision-focussed approach to treatment. By critically analysing these developments, this review provides insights into how novel strategies can overcome existing challenges in hypertension management, reduce the global disease burden and improve patient outcomes.
2'-Fucosyllactose synbiotics with Bifidobacterium bifidum to improve intestinal transcriptional function and gut microbiota in constipated mice.
Food Res Int
Yi Shan, Miaomiao Zheng, Weiwei Liang +2 more
Probiotics, prebiotics, and synbiotics are potential therapeutic options for constipation. However, the synergistic effects and underlying mechanisms of 2'-fucosyllactose (2'-FL) and Bifidobacterium bifidum (B. bifidum) in ameliorating constipation remain unclear. In this study, constipated mice were treated 2'-FL combined with B. bifidum, and their effects were evaluated based on defecation performance, gastrointestinal regulatory peptide levels, intestinal inflammation, and barrier function. Transcriptomics and 16S rRNA sequencing were performed to assess gene expression and gut microbiota composition, respectively. The results demonstrated that 2'-FL + B. bifidum enhanced intestinal secretion of gastrin and substance P while suppressed vasoactive intestinal peptide, improving defecation parameters. Furthermore, 2'-FL + B. bifidum significantly reduced the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 while increasing IL-10 levels. It also upregulated intestinal tight junction proteins (ZO-1, Claudin-1, and Occludin) and reduced serum markers of intestinal permeability (D-lactic acid, enterotoxin, and diamine oxidase). Transcriptomic analysis revealed that 2'-FL + B. bifidum upregulated genes related to the immune system processes, signaling pathways, ABC transporters, glycolysis/gluconeogenesis, and butanoate metabolism. Furthermore, our results demonstrated that 2'-FL + B. bifidum could regulate the composition of the gut microbiota in constipated mice, promoting the growth of beneficial intestinal bacteria, such as Akkermansia, Bifidobacterium, and Parabacteroides. In summary, 2'-FL + B. bifidum alleviates constipation in mice by regulating intestinal transcriptional profiles and the gut microbiota composition. This study provides theoretical support for the development and application of synbiotics containing 2'-FL and B. bifidum.
Injectable Thymosin β4-Modified Hyaluronic Acid Hydrogel with Exosomes for Stem Cell Homing and Neuronic-Angiogenic-Osteogenic Coupled Cranial Repair.
ACS Nano
Yanhai Xi, Zhen Zhang, Zixuan Zhao +7 more
Accelerating angiogenesis, neurogenesis, and in situ stem cell recruitment at the site of bone defects is critical for bone regenerative repair. Bone marrow mesenchymal stem cell (BMSC) exosomes are cell-free therapeutic agents with bone-enhancing effects. Thymosin β4 (Tβ4) is a short peptide known for its key role in tissue repair and angiogenesis. In this study, we successfully developed a multifunctional injectable Exo@Tβ4/HAMA hydrogel platform by grafting Tβ4 onto methylmalonic anhydride-modified hyaluronic acid (HAMA) via photo-cross-linking and then encapsulating BMSC-derived exosomes. In vitro results demonstrated that the Exo@Tβ4/HAMA hydrogel exhibited improved mechanical properties, favorable biocompatibility, and the ability to significantly recruit BMSCs. Additionally, it showed superior vasculogenic effects on HUVECs and osteogenic differentiation potentials on BMSCs. In vivo studies revealed that the hydrogel successfully promoted both neurogenesis, angiogenesis, and new bone formation. It also facilitated osteogenesis through the ERK1/2-dependent RUNX2 signaling pathway. Our results suggest that this hydrogel platform exerts a robust multisystemic regulatory effect, fostering rat bone repair through the synergistic promotion of in situ stem cell recruitment, angiogenesis, neurogenesis, and osteogenesis. As a simple-to-prepare and multifunctional integrated bone graft, this hydrogel platform holds a significant promise in establishing a conducive microenvironment for optimal bone healing.
Evidence-Based Recommendations for Managing Atopic Dermatitis in Pediatric Patients: A Systematic Review and Meta-Analysis From the Pediatric Dermatology Special Interest Group of IADVL.
Int J Dermatol
Rahul Mahajan, Rashmi Sarkar, Maitreyee Panda +10 more
Atopic dermatitis (AD) is the most common inflammatory skin disease in the pediatric age group, affecting 15%-20% of children globally. Initial treatment modes include hydration, occlusive topical medicines, antimicrobial treatment, phototherapy, and systemic immune suppressants in the case of severe to moderate refractory AD. However, there is a lack of head-to-head studies on the choice of topical and systemic therapies for moderate to severe AD in the pediatric age group.
Acute Compartment Syndrome and Intra-Abdominal Hypertension, Decompression, Current Pharmacotherapy, and Stable Gastric Pentadecapeptide BPC 157 Solution.
Pharmaceuticals (Basel)
Predrag Sikiric, Sven Seiwerth, Anita Skrtic +16 more
In this study, pharmacotherapies of abdominal compartment syndrome (ACS) and intra-abdominal hypertension (IAH) in animal studies were reviewed from the perspective of ACS/IAH as failed cytoprotection issues, as non-specific injuries, and from the point of view of the cytoprotection concept as resolution. Therefore, this review challenges the unresolved theoretical and practical issues of severe multiorgan failure, acknowledged significance in clinics, and resolving outcomes (i.e., open abdomen). Generally, the reported agents not aligned with cytoprotection align with current pharmacotherapy limitations and have (non-)confirmed effectiveness, mostly in only one organ, mild/moderate IAH, prophylactic application, and provide only a tentative resolution. Contrarily, stable gastric pentadecapeptide BPC 157 therapy, as a novel and relevant cytoprotective mediator having pleiotropic beneficial effects, simultaneously resolves many targets, resolving established disturbances, specifically compression/ischemia (grade III and grade IV), and decompression/advanced reperfusion. BPC 157 therapy rapidly activates collateral bypassing pathways, and, in ACS and IAH, and later, in reperfusion, there is a "bypassing key" (i.e., azygos vein direct blood flow delivery). This serves to counteract multiorgan and vessel failure, including lesions and hemorrhages in the brain, heart, lung, liver, kidney and gastrointestinal tract, thrombosis, peripherally and centrally, intracranial (superior sagittal sinus), portal and caval hypertension and aortal hypotension, occlusion/occlusion-like syndrome, advanced Virchow triad circumstances, and free radical formation acting as a membrane stabilizer and free radical scavenger. Likewise, not only in ACS/IAH resolving, but also in other occlusion/occlusion-like syndromes, this "bypassing key" could be an effect of the essential endothelial cytoprotective capacity of BPC 157 and a particular modulatory effect on the NO-system, and a rescuing impact on vasomotor tone.
Stable Gastric Pentadecapeptide BPC 157 as a Therapy and Safety Key: A Special Beneficial Pleiotropic Effect Controlling and Modulating Angiogenesis and the NO-System.
Pharmaceuticals (Basel)
Predrag Sikiric, Sven Seiwerth, Anita Skrtic +13 more
Although approached through many concepts, the pleiotropic healing issue, specifically, maintaining/reestablishing tissue integrity, remains a central challenge in pharmacology, particularly when the process is misdirected or not properly controlled. Robert and Szabo's concept of cytoprotection holds that innate cell (epithelial (Robert), endothelial (Szabo)) integrity and protection/maintenance/reestablishment in the stomach is translated to other organ therapy (cytoprotection → organoprotection) via the cytoprotection agent's effect. Therefore, we defend stable gastric pentadecapeptide BPC 157 therapy's efficacy and pleiotropic beneficial effects, along with its high safety (LD1 not achieved), against speculation of its negative impact, speculation of angiogenesis toward tumorigenesis, increased NO and eNOS, damaging free radical formation, and neurodegenerative diseases (Parkinson's disease and Alzheimer's disease). Contrarily, in wound healing and general healing capabilities, as reviewed, as a cytoprotective agent and native cytoprotection mediator, BPC 157 controls angiogenesis and the NO-system's healing functions and counteracts the pathological presentation of neurodegenerative diseases in acknowledged animal models (i.e., Parkinson's disease and Alzheimer's disease), and it presents prominent anti-tumor potential in vivo and in vitro. BPC 157 resolved cornea transparency maintenance, cornea healing "angiogenic privilege" (vs. angiogenesis/neovascularization/tumorigenesis), and it does not produce corneal neovascularization but rather opposes it. Per Folkman's concept, it demonstrates an anti-tumor effect in vivo and in vitro. BPC 157 exhibits a distinctive effect on the NO-level (increase vs. decrease), always combined with the counteraction of free radical formation, and, in mice and rats, BPC 157 therapy counteracts Parkinson's disease-like and Alzheimer's disease-like disturbances. Thus, BPC 157 therapy means targeting angiogenesis and NO's cytotoxic and damaging actions but maintaining, promoting, or recovering their essential protective functions.
Key Factors Influencing Caries Development in Preschoolers: A Focus on Socio-Demographic, Maternal Health, and Salivary Biomarkers in 3-Year-Olds.
Med Sci Monit
Branislava Stojkovic, Marija Igic, Tatjana Jevtovic Stoimenov +7 more
BACKGROUND The study examined and compared the significance of sociodemographic, oral health behavior, and maternal factors, as well as salivary pH and salivary levels of human neutrophil peptide 1 (HNP-1), human b defensin 2 (hBD-2), and human cathelicidin (LL-37) as early caries predictors in 3-year-olds. MATERIAL AND METHODS A 1-year observational prospective study was conducted. The study included 165 caries-free children aged 36-48 months and their mothers. At baseline data were collected through a questionnaire for mothers and clinical examination of the children. For certain children (N=35), unstimulated saliva samples were collected to determine salivary pH using a digital portable pH meter and salivary levels of HNP-1, hBD-2, and LL-37 peptides using ELISA. After 12 months, caries incidence was determined. The caries-predictive significance of factors was estimated by logistic regression analysis. RESULTS After 1 year, caries was diagnosed in 29.1% of the children. Univariate logistic regression analysis revealed that the potentially most significant caries predictors in 3-year-olds were debris index >1 (OR 6.324, P<0.001), breastfeeding duration (OR 1.017, P=0.001), lack of a personal dentist (OR 2.454, P=0.012), and poor dental health of the mother (OR 10.521, P<0.001). The multivariate model confirmed that these variables are the potentially most significant caries predictors in 3-year-olds. CONCLUSIONS This 1-year study showed that the most significant early caries predictors in 3-year-olds are debris index, breastfeeding length, lack of a personal dentist, and poor dental health of mothers. The tested salivary parameters did not show caries-predictive significance.
Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis.
Cell
Marie H Solheim, Sima Stroganov, Weiyi Chen +13 more
Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin's anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.
Tβ4-exosome-loaded hemostatic and antibacterial hydrogel to improve vascular regeneration and modulate macrophage polarization for diabetic wound treatment.
Mater Today Bio
Hua Yu, Bin Wang, Zihao Li +16 more
Diabetic wounds often exhibit delayed healing due to compromised vascular function and intensified inflammation. In this study, we overexpressed Thymosin β4 (Tβ4) in Adipose-Derived Stem Cells (ADSCs) to produce Exosomes (Exos) rich in Tβ4. We then utilized a dual photopolymerizable hydrogel composed of Hyaluronic Acid Methacryloyl (HAMA) and Poly-L-lysine Methacryloyl (PLMA) for the sustained release of Tβ4-Exos on diabetic wounds. The results showed that Tβ4-Exos could stimulate angiogenesis and collagen synthesis, and mitigate inflammation in diabetic wounds by promoting the polarization of M1-type macrophages and inhibiting that of M2-type macrophages. Furthermore, Tβ4-Exos was found to activate the PI3K/AKT/mTOR/HIF-1a signaling pathway, thereby enhancing vascular proliferation. In summary, the sustained release of Tβ4-Exos in HAMA-PLMA (HP) hydrogel and the management of inflammation through the upregulation of the HIF-1a pathway and modulation of macrophage polarization in vascular proliferation significantly accelerated the healing process of diabetic wounds.