Fibroblasts and endothelial cells interplay drives hypertrophic scar formation: Insights from in vitro and in vivo models.

Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co-culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF-ß. Additionally, a suspended co-culture multicellular spheroid model revealed molecular-level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro-angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF-ß, IL-17, Wnt, Notch, PI3K-Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts-endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.

Transplantation of human placental chorionic plate-derived mesenchymal stem cells for repair of neurological damage in neonatal hypoxic-ischemic encephalopathy.

JOURNAL/nrgr/04.03/01300535-202409000-00035/figure1/v/2024-01-16T170235Z/r/image-tiff Neonatal hypoxic-ischemic encephalopathy is often associated with permanent cerebral palsy, neurosensory impairments, and cognitive deficits, and there is no effective treatment for complications related to hypoxic-ischemic encephalopathy. The therapeutic potential of human placental chorionic plate-derived mesenchymal stem cells for various diseases has been explored. However, the potential use of human placental chorionic plate-derived mesenchymal stem cells for the treatment of neonatal hypoxic-ischemic encephalopathy has not yet been investigated. In this study, we injected human placental chorionic plate-derived mesenchymal stem cells into the lateral ventricle of a neonatal hypoxic-ischemic encephalopathy rat model and observed significant improvements in both cognitive and motor function. Protein chip analysis showed that interleukin-3 expression was significantly elevated in neonatal hypoxic-ischemic encephalopathy model rats. Following transplantation of human placental chorionic plate-derived mesenchymal stem cells, interleukin-3 expression was downregulated. To further investigate the role of interleukin-3 in neonatal hypoxic-ischemic encephalopathy, we established an in vitro SH-SY5Y cell model of hypoxic-ischemic injury through oxygen-glucose deprivation and silenced interleukin-3 expression using small interfering RNA. We found that the activity and proliferation of SH-SY5Y cells subjected to oxygen-glucose deprivation were further suppressed by interleukin-3 knockdown. Furthermore, interleukin-3 knockout exacerbated neuronal damage and cognitive and motor function impairment in rat models of hypoxic-ischemic encephalopathy. The findings suggest that transplantation of hpcMSCs ameliorated behavioral impairments in a rat model of hypoxic-ischemic encephalopathy, and this effect was mediated by interleukin-3-dependent neurological function.

The application of microwaves in axillary hyperhidrosis: Curative effect observation of a pathological examination over 1 year.

BACKGROUND: In Asia, axillary hyperhidrosis is a frequent problem for many people, and the consequent excessive sweating can seriously affect many aspects of daily life and even lead to mental disorders. Microwave therapy is a new, non-invasive treatment method for axillary hyperhidrosis, whose energy and long-term effectiveness still needs to be clinically validated. OBJECTIVE: The aim of this study was to evaluate the clinical efficacy, safety, histological changes, and psychological status of microwave devices in the treatment of axillary hyperhidrosis and osmidrosis. METHOD: We conducted a prospective self-controlled study in a top-tier Chinese hospital. After a 5/5 energy treatment session, a skin biopsy was taken to observe histological changes both before and after treatment. An iodine starch test was used to determine the sweating range. We evaluated symptoms of improved efficacy using the Hyperhidrosis Disease Severity Scale (HDSS) and assessed changes in life status with the DLQI. In the case of concurrent underarm odor, odor-5, VAS, and Young-Jin Park grading were used to assess odor relief. The effect of odor on psychology was assessed by using a psychological status symptom checklist (scl-90). The study period was 1 year. RESULTS: We observed 20 patients in this study. Of those, 90% met the primary treatment endpoint of a decrease in axillary hyperhidrosis symptomatology to below grade 2 on the HDSS score (p < 0.001). Furthermore, 75% of patients achieved a treatment endpoint of at least 50% reduction in VAS (p < 0.001). 70% of patients achieved a treatment endpoint of at least 50% reduction in odor-5 (p < 0.001). The iodine starch test showed that the region decreased 99% from the baseline to 12 months after follow-up had ended (p < 0.001). Eight patients volunteered to undergo histological examination; their average light density of immunohistochemistry decreased from 1.04 (0.4-2.11) to 0.07 (0.04-0.46; p < 0.05). The immunohistochemical positive number for sweat glands was initially 104 (59.75-132.5) but was 41.5 (29.75-62) after the procedure. None of the patients experienced any serious adverse reactions. CONCLUSION: The treatment demonstrated high effectiveness, safety, and short-lived adverse reactions.

Voluntary running wheel exercise induces cognitive improvement post traumatic brain injury in mouse model through redressing aberrant excitation regulated by voltage-gated sodium channels 1.1, 1.3, and 1.6.

Traumatic brain injury (TBI) leads to disturbed brain discharge rhythm, elevated excitability, anxiety-like behaviors, and decreased learning and memory capabilities. Cognitive dysfunctions severely affect the quality of life and prognosis of TBI patients, requiring effective rehabilitation treatment. Evidence indicates that moderate exercise after brain injury decreases TBI-induced cognitive decline. However, the underlying mechanism remains unelucidated. Our results demonstrate that TBI causes cognitive impairment behavior abnormalities and overexpression of Nav1.1, Nav1.3 and Nav1.6 proteins inside the hippocampus of mice models. Three weeks of voluntary running wheel (RW) exercise treatments before or/and post-injury effectively redressed the aberrant changes caused by TBI. Additionally, a 10% exercise-conditioned medium helped recover cell viability, neuronal sodium current and expressions of Nav1.1, Nav1.3 and Nav1.6 proteins across cultured neurons after injury. Therefore, the results validate the neuroprotection induced by voluntary RW exercise treatment before or/and post-TBI. The RW exercise-induced improvement in cognitive behaviors and neuronal excitability could be associated with correcting the Nav1.1, Nav1.3, and Nav1.6 expression levels. The current study proves that voluntary exercise is an effective treatment strategy against TBI. The study also highlights novel potential targets for rehabilitating TBI, including the Navs proteins.

Notch4 participates in mesenchymal stem cell-induced differentiation in 3D-printed matrix and is implicated in eccrine sweat gland morphogenesis.

Background: Eccrine sweat gland (SG) plays a crucial role in thermoregulation but exhibits very limited regenerative potential. Although SG lineage-restricted niches dominate SG morphogenesis and benefit SG regeneration, rebuilding niches in vivo is challenging for stem cell therapeutic applications. Hence, we attempted to screen and tune the critical niche-responding genes that dually respond to both biochemical and structural cues, which might be a promising strategy for SG regeneration. Methods: An artificial SG lineage-restricted niche consisting of mouse plantar dermis homogenates (i.e. biochemical cues) and 3D architecture (i.e. structural cues) was built in vitro by using an extrusion-based 3D bioprinting approach. Mouse bone marrow-derived mesenchymal stem cells (MSCs) were then differentiated into the induced SG cells in the artificial SG lineage-restricted niche. To decouple biochemical cues from structural cues, the transcriptional changes aroused by pure biochemical cues, pure structural cues and synergistic effects of both cues were analyzed pairwise, respectively. Notably, only niche-dual-responding genes that are differentially expressed in response to both biochemical and structural cues and participate in switching MSC fates towards SG lineage were screened out. Validations in vitro and in vivo were respectively conducted by inhibiting or activating the candidate niche-dual-responding gene(s) to explore the consequent effects on SG differentiation. Results: Notch4 is one of the niche-dual-responding genes that enhanced MSC stemness and promoted SG differentiation in 3D-printed matrix in vitro. Furthermore, inhibiting Notch4 specifically reduced keratin 19-positive epidermal stem cells and keratin 14-positive SG progenitor cells, thus further delaying embryonic SG morphogenesis in vivo. Conclusions: Notch4 not only participates in mouse MSC-induced SG differentiation in vitro but is also implicated in mouse eccrine SG morphogenesis in vivo.

Reduced Expression of Voltage-Gated Sodium Channel Beta 2 Restores Neuronal Injury and Improves Cognitive Dysfunction Induced by Aß1-42.

Voltage-gated sodium channel beta 2 (Nav2.2 or Navß2, coded by SCN2B mRNA), a gene involved in maintaining normal physiological functions of the prefrontal cortex and hippocampus, might be associated with prefrontal cortex aging and memory decline. This study investigated the effects of Navß2 in amyloid-ß 1-42- (Aß1-42-) induced neural injury model and the potential underlying molecular mechanism. The results showed that Navß2 knockdown restored neuronal viability of Aß1-42-induced injury in neurons; increased the contents of brain-derived neurotrophic factor (BDNF), enzyme neprilysin (NEP) protein, and NEP enzyme activity; and effectively altered the proportions of the amyloid precursor protein (APP) metabolites including Aß42, sAPPα, and sAPPß, thus ameliorating cognitive dysfunction. This may be achieved through regulating NEP transcription and APP metabolism, accelerating Aß degradation, alleviating neuronal impairment, and regulating BDNF-related signal pathways to repair neuronal synaptic efficiency. This study provides novel evidence indicating that Navß2 plays crucial roles in the repair of neuronal injury induced by Aß1-42 both in vivo and in vitro.

The Impact of Environmental Regulation, Industrial Structure, and Interaction on the High-Quality Development Efficiency of the Yellow River Basin in China from the Perspective of the Threshold Effect.

High-quality development efficiency can comprehensively measure the development quality of a region. This study constructed the SE-SBM Model and measured the quality development efficiency of the Yellow River Basin from 2010 to 2019. In panel regression, the periodic effects of industrial structure, environmental regulation, and their interaction terms on the efficiency of high-quality development are analyzed. From the perspective of the threshold effect, we explore the possible threshold of interaction to change the efficiency of high-quality development. The results show: (1) From 2010 to 2019, the high-quality development efficiency of the Yellow River Basin's watershed segment showed a gradient development trend. (2) In panel regression, the interaction terms positively impact the whole basin's high-quality development efficiency. However, for different sub-basins, the impact of the core explanatory variable on the efficiency of high-quality development is different. (3) The Yellow River basin has a single significant threshold in the threshold regression. From the perspective of the sub-basin, the upper and lower reaches of the Yellow River have a single significant threshold. There is no threshold in midstream. Based on the research results, the article puts forward relevant suggestions, such as reasonably improving regional imports and exports and introducing high-quality foreign capital, which can provide a basis for relevant departments.

Corrigendum: Vi4-miR-185-5p-Igfbp3 Network Protects the Brain From Neonatal Hypoxic Ischemic Injury via Promoting Neuron Survival and Suppressing the Cell Apoptosis.

[This corrects the article DOI: 10.3389/fcell.2020.529544.].

AQP4 knockout promotes neurite outgrowth via upregulating GAP43 expression in infant rats with hypoxic-ischemic brain injury.

Neonatal hypoxic-ischemic encephalopathy (NHIE) induces severe cerebral damage and neurological dysfunction, with seldom effective therapy. Aquaporin-4 (AQP4) is involved in aggravating brain damage induced by NHIE. This study aimed to investigate the role of AQP4 underlying the pathogenesis of NHIE. Neonatal Sprague-Dawley rats were used to establish neonatal hypoxic-ischemic (HI) models, and the expression of AQP4 in the cortex, hippocampus, and lung tissues was detected by real-time quantitative polymerase chain reaction as well as Western blot. Primary cortical neurons were cultured for the oxygen-glucose deprivation (OGD) model, and siRNA was used to silence the expression of AQP4. Immunostaining of Tuj1 was performed to observe the axonal growth. CRISPER/Cas9 technology was used to knock out AQP4. The results demonstrated that AQP4 was upregulated in the cortex, hippocampus, and lung tissues in neonatal rats with HI and OGD neurons. Besides, silencing AQP4 promoted axonal growth of OGD neurons, and AQP4 knockout notably improved long-term neurobehavioral impairment. Furthermore, GAP43 was found closely correlated with AQP4 via GeneMANIA prediction. Significant downregulation of GAP43 was induced in OGD neurons, while AQP4 knockout markedly upregulated its expression in rats. This indicated that the depletion of AQP4 may enhance axonal regeneration and promote the long-term neurobehavioral recovery associated with the upregulation of GAP43 expression.

Role of surfactant protein C in neonatal genetic disorders of the surfactant system: A case report.

RATIONALE: Respiratory distress syndrome (RDS) refers to the symptoms of progressive dyspnea and respiratory failure in newborns shortly after birth. The clinical and genetic characteristics of patients with neonatal RDS have not been extensively reported. PATIENT CONCERNS: A infant was in critical condition with repeated paroxysmal blood oxygen decline. Oxygen inhalation and noninvasive ventilator-assisted breathing relief were not effective. The etiology was unclear, and there was no family history of lung disease. Surface-active substance replacement therapy and positive pressure-assisted ventilation support were ineffective. DIAGNOSIS: The infant was clinically diagnosed with RDS. Genetic tests revealed a heterozygous missense mutation in the c.168 surfactant protein C (SFTPC) gene. INTERVENTIONS: Tracheal intubation was performed with invasive ventilator-assisted breathing, pulmonary surfactant was administered. Supportive treatment for liver protection and administration of a cardiotonic diuretic, vasodilator, human immunoglobulin (intravenous infusion), fresh frozen plasma, and suspended red blood cells were performed. OUTCOMES: The infant showed poor responses to respiratory and circulatory support, antibiotic treatment, and other treatment methods. The patient was discharged from hospital against the advice of us, cut off from us. The long-term prognosis of the patient after discharge remains unknown. LESSONS: SFTPC gene mutations may be an important risk factor for the development of common lung diseases. Because of the important roles of surfactant functions and metabolism, mutations in these genes can affect the production and function of pulmonary surfactant, leading to severe lung disease in term newborns.

Single-cell RNA sequencing reveals B cell-related molecular biomarkers for Alzheimer's disease.

In recent years, biomarkers have been integrated into the diagnostic process and have become increasingly indispensable for obtaining knowledge of the neurodegenerative processes in Alzheimer's disease (AD). Peripheral blood mononuclear cells (PBMCs) in human blood have been reported to participate in a variety of neurodegenerative activities. Here, a single-cell RNA sequencing analysis of PBMCs from 4 AD patients (2 in the early stage, 2 in the late stage) and 2 normal controls was performed to explore the differential cell subpopulations in PBMCs of AD patients. A significant decrease in B cells was detected in the blood of AD patients. Furthermore, we further examined PBMCs from 43 AD patients and 41 normal subjects by fluorescence activated cell sorting (FACS), and combined with correlation analysis, we found that the reduction in B cells was closely correlated with the patients' Clinical Dementia Rating (CDR) scores. To confirm the role of B cells in AD progression, functional experiments were performed in early-stage AD mice in which fibrous plaques were beginning to appear; the results demonstrated that B cell depletion in the early stage of AD markedly accelerated and aggravated cognitive dysfunction and augmented the Aß burden in AD mice. Importantly, the experiments revealed 18 genes that were specifically upregulated and 7 genes that were specifically downregulated in B cells as the disease progressed, and several of these genes exhibited close correlation with AD. These findings identified possible B cell-based AD severity, which are anticipated to be conducive to the clinical identification of AD progression.

Panax notoginseng saponin attenuates the hypoxic-ischaemic injury in neonatal rats by regulating the expression of neurotrophin factors.

Neonatal hypoxic-ischaemic (HI) injury is a serious complication of neonatal asphyxia and the leading cause of neonatal acute death and chronic neurological injury, and the effective therapeutic method is lacking to improve patients' outcomes. We reported in this study that panax notoginseng saponin (PNS) may provide a treatment option for HI. HI model was established using neonatal Sprague-Dawley rats and then intraperitoneally injected with different dosage of PNS, once a day for 7 days. Histological staining and behavioural evaluations were performed to elucidate the pathological changes and neurobehavioural variation after PNS treatment. We found PNS administration significantly reduced the infarct volume of brain tissues and improved the autonomous activities of neonatal rats, especially with higher dosage. PNS treatment at 40 mg/kg reduced neuronal damage, suppressed neuronal apoptosis and depressed astroglial reactive response. Moreover, the long-term cognitive and motor functions were also improved after PNS treatment at 40 mg/kg. Importantly, PNS treatment elevated the levels of BDNF and TrkB but decreased the expression of p75NTR both in the cortex and hippocampus of HI rats. The therapeutic efficacy of PNS might be correlated with PNS-activated BDNF/TrkB signalling and inactivation of p75NTR expression, providing a novel potential therapy for alleviating HI injury.

BDNF promotes neuronal survival after neonatal hypoxic-ischemic encephalopathy by up-regulating Stx1b and suppressing VDAC1.

Neonatal hypoxic-ischemic encephalopathy (HIE), is a major cause of neurologic disorders in terms of neonates, with the unclear underlying mechanisms. In the study, triphenyl tetrazolium chloride (TTC) staining and Zea-longa score were performed to examine the neurologic damage in hypoxia and ischemia (HI) rats. The results showed that HI induced obviously infarct and serious neurologic impairment in neonatal rats. Then, protein chip was applied to detect the differential expression genes in cortex and hippocampus and found the brain-derived neurotrophic factor (BDNF) down-regulated both in cortex and hippocampus. Moreover, low expression of BDNF after HI in right cortex and hippocampus was validate by immunohistochemistry (IHC) and Western Blotting (WB). Afterwards, overexpressing and interfering HSV vector were produced, then verified by immunofluorescent staining and real-time quantitative polymerase chain reaction (qRT-PCR). The results of Tuj1 staining indicated that overexpression of BDNF could promote axonal regeneration and inhibit neuron swelling, whereas BDNF interference take an opposite effect after Oxygen glucose deprivation (OGD) injury. Finally, the interaction network among BDNF and associated proteins as examined by Genemania and confirmed by qRT-PCR. We found that the expression of VDAC1 was decreased and Stx1b was increased when BDNF overexpressing, which indicated that BDNF promoted neurite regrowth after OGD might be related to downregulation of VDAC1 and upregulation of Stx1b. Our results might provide novel strategy for the treatment of neurological defects induced by cerebral ischemia and hypoxia.

Effect of Sutellarin on Neurogenesis in Neonatal Hypoxia-Ischemia Rat Model: Potential Mechanisms of Action.

To investigate the therapeutic efficacy of Scutellarin (SCU) on neurite growth and neurological functional recovery in neonatal hypoxic-ischemic (HI) rats. Primary cortical neurons were cultured to detect the effect of SCU on cell viability of neurons under oxygen-glucose deprivation (OGD). Double immunofluorescence staining of Tuj1 and TUNEL then observed the neurite growth and cell apoptosis in vitro,and double immunofluorescence staining of NEUN and TUNEL was performed to examine the neuronal apoptosis and cell apoptosis in brain tissues after HI in vivo. Pharmacological efficacy of SCU was also evaluated in HI rats by neurobehavioral tests, triphenyl tetrazolium chloride staining, Hematoxylin and eosin staining and Nissl staining. Astrocytes and microglia expression in damaged brain tissues were detected by immunostaining of GFAP and Iba1. A quantitative real-time polymerase chain reaction and western blot were applied to investigate the genetic expression changes and the protein levels of autophagy-related proteins in the injured cortex and hippocampus after HI. We found that SCU administration preserved cell viability, promoted neurite outgrowth and suppressed apoptosis of neurons subjected to OGD both in vitroand in vivo. Meanwhile, 20 mg/kg SCU treatment improved neurological functions and decreased the expression of astrocytes and microglia in the cortex and hippocampus of HI rats. Additionally, SCU treatment depressed the elevated levels of autophagy-related proteins and the p75 neurotrophin receptor (p75NTR) in both cortex and hippocampus. This study demonstrated the potential therapeutic efficacy of SCU by enhancing neurogenesis and restoring long-term neurological dysfunctions, which might be associated with p75NTR depletion in HI rats.

Self-contrast study of pinprick therapy combined with super pulse fractional CO2 laser for the treatment of atrophic acne scars.

AIMS: This study is to evaluate the clinical efficacy and safety of a "double-layer" mode of super pulse fractional CO2 laser and a combined treatment of pinprick therapy with fractional CO2 laser for the treatment of atrophic acne scars. METHODS: A split-face and self-contrast method was applied. A total of 20 patients with atrophic acne scars randomly received the above mentioned therapy on the left or right side of the cheek for 3 times with an interval of 3 months. ECCA scores, IVA scores, patients' satisfaction, VAS scores, and adverse reactions were evaluated. RESULTS: Atrophic acne scars on both sides of the cheek were improved obviously. The ECCA scores showed a significant decrease, while IVA scores significantly increased. Compared with the super pulse fractional CO2 laser group, the decrease of ECCA scores, the increase of IVA scores, and the patients' satisfaction were significantly higher and improvement on V-shaped and U-shaped acne scars was significantly better in the combined treatment group. No patients had severe adverse reactions such as blister, infection, or hypertrophic scars. CONCLUSIONS: Super pulse fractional CO2 laser and pinprick treatment combined with fractional CO2 laser are both safe and effective therapy for the treatment of atrophic acne scars.

Vi4-miR-185-5p-Igfbp3 Network Protects the Brain From Neonatal Hypoxic Ischemic Injury via Promoting Neuron Survival and Suppressing the Cell Apoptosis.

Neonatal hypoxic ischemic encephalopathy (HIE) due to birth asphyxia is common and causes severe neurological deficits, without any effective therapies currently available. Neuronal death is an important driving factors of neurological disorders after HIE, but the regulatory mechanisms are still uncertain. Long non-coding RNA (lncRNA) or ceRNA network act as a significant regulator in neuroregeneration and neuronal apoptosis, thus owning a great potential as therapeutic targets in HIE. Here, we found a new lncRNA, is the most functional in targeting the Igfbp3 gene in HIE, which enriched in the cell growth and cell apoptosis processes. In addition, luciferase reporter assay showed competitive regulatory binding sites to the target gene Igfbp3 between TCONS00044054 (Vi4) and miR-185-5p. The change in blood miR-185-5p and Igfbp3 expression is further confirmed in patients with brain ischemia. Moreover, Vi4 overexpression and miR-185-5p knock-out promote the neuron survival and neurite growth, and suppress the cell apoptosis, then further improve the motor and cognitive deficits in rats with HIE, while Igfbp3 interfering got the opposite results. Together, Vi4-miR-185-5p-Igfbp3 regulatory network plays an important role in neuron survival and cell apoptosis and further promote the neuro-functional recovery from HIE, therefore is a likely a drug target for HIE therapy.