Novel phenanthrene/bibenzyl trimers from the tubers of Bletilla striata attenuate neuroinflammation via inhibition of NF-κB signaling pathway.

Five novel (9,10-dihydro) phenanthrene and bibenzyl trimers, as well as two previously identified biphenanthrenes and bibenzyls, were isolated from the tubers of Bletilla striata. Their structures were elucidated through comprehensive analyses of NMR and HRESIMS spectroscopic data. The absolute configurations of these compounds were determined by calculating rotational energy barriers and comparison of experimental and calculated ECD curves. Compounds 5b and 6 exhibited inhibitory effects on LPS-induced NO production in BV-2 cells, with IC50 values of 12.59 ± 0.40 and 15.59 ± 0.83 µmol·L-1, respectively. A mechanistic study suggested that these compounds may attenuate neuroinflammation by reducing the activation of the AKT/IκB/NF-κB signaling pathway. Additionally, compounds 3a, 6, and 7 demonstrated significant PTP1B inhibitory activities, with IC50 values of 1.52 ± 0.34, 1.39 ± 0.11, and 1.78 ± 0.01 µmol·L-1, respectively. Further investigation revealed that compound 3a might inhibit LPS-induced PTP1B overexpression and NF-κB activation, thereby mitigating the neuroinflammatory response in BV-2 cells.

Hair follicle stem cells promote epidermal regeneration under expanded condition.

Skin soft tissue expansion is the process of obtaining excess skin mixed with skin development, wound healing, and mechanical stretching. Previous studies have reported that tissue expansion significantly induces epidermal proliferation throughout the skin. However, the mechanisms underlying epidermal regeneration during skin soft tissue expansion are yet to be clarified. Hair follicle stem cells (HFSCs) have been recognized as a promising approach for epidermal regeneration. This study examines HFSC-related epidermal regeneration mechanisms under expanded condition and proposes a potential method for its cellular and molecular regulation.

B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans.

Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby TH17 cells promote brain leptomeningeal immune cell aggregates, we found that anti-CD20 treatment effectively spared myelin content and prevented myeloid cell activation, oxidative damage, and mitochondrial stress in the subpial gray matter. Anti-CD20 treatment increased B cell survival factor (BAFF) in the serum, cerebrospinal fluid, and leptomeninges of mice with EAE. Although anti-CD20 prevented gray matter demyelination, axonal loss, and neuronal atrophy, co-treatment with anti-BAFF abrogated these benefits. Consistent with the murine studies, we observed that elevated BAFF concentrations after anti-CD20 treatment in patients with RRMS were associated with better clinical outcomes. Moreover, BAFF promoted survival of human neurons in vitro. Together, our data demonstrate that BAFF exerts beneficial functions in MS and EAE in the context of anti-CD20 treatment.

Prediction model for haematoma after tissue expander placement: A retrospective cohort study of 7080 cases over 20 years.

Haematoma is an early complication of tissue expander placement and can lead to infection, capsule contracture and various complications, hindering successful reconstruction. However, no scientific models can accurately predict the risk of haematoma following tissue expansion. Therefore, this study aimed to develop and validate a prediction model for haematoma following tissue expander placement. The medical records of patients who underwent expander placement between 2001 and 2021 were obtained from the clinical database of the Department of Plastic Surgery at the Xijing Hospital. A total of 4579 consecutive patients with 7080 expanders and 179 expanded pocket haematomas were analysed. Multivariate logistic regression analysis identified adult age (P = 0.006), male sex (P < 0.001), scar reconstruction (P = 0.019), perioperative hypertension (P < 0.001), face and neck location (P = 0.002) and activated partial thromboplastin time above the normal range (P < 0.001) as risk factors for haematoma. Therefore, these were included in the prediction model, and a nomogram was constructed. The discrimination of the nomogram was robust (area under the curve: 0.78; 95% confidence interval: 0.72-0.83). Further, the prediction model had a strong fit (Hosmer-Lemeshow test, P = 0.066) and maintained similar discrimination after considering performance optimism (bootstrapped area under the curve: 0.79; 95% confidence interval: 0.73-0.84). This clinical prediction model was created using a generalisable dataset and can be utilised to obtain valid haematoma predictions after expander placement, assisting surgeons in implementing preventive measures or interventions to reduce the occurrence of haematoma.

Activating autophagy promotes skin regeneration induced by mechanical stretch during tissue expansion.

Background: Tissue expansion, a technique in which skin regeneration is induced by mechanical stretch stimuli, is commonly used for tissue repair and reconstruction. In this study, we aimed to monitor the autophagy levels of expanded skin after the application of expansion stimuli and explore the effect of autophagy modulation on skin regeneration. Methods: A rat scalp expansion model was established to provide a stable expanded skin response to mechanical stretch. Autophagy levels at different time points (6, 12, 24, 48 and 72 h after the last expansion) were detected via western blotting. The effect of autophagy regulation on skin regeneration during tissue expansion was evaluated via skin expansion efficiency assessment, western blotting, immunofluorescence staining, TUNEL staining and laser Doppler blood flow imaging. Results: The autophagic flux reached its highest level 48 h after tissue expansion. Activating autophagy by rapamycin increased the area of expanded skin as well as the thicknesses of epidermis and dermis. Furthermore, activating autophagy accelerated skin regeneration during tissue expansion by enhancing the proliferation of cells and the number of epidermal basal and hair follicle stem cells, reducing apoptosis, improving angiogenesis, and promoting collagen synthesis and growth factor secretion. Conversely, the regenerative effects were reversed when autophagy was blocked. Conclusions: Autophagy modulation may be a promising therapeutic strategy for improving the efficiency of tissue expansion and preventing the incidence of the complication of skin necrosis.

The CNK-HYP scaffolding complex promotes RAF activation by enhancing KSR-MEK interaction.

The RAS-MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and the kinases RAF, MEK and ERK. Activation of RAF by RAS is notoriously intricate and remains only partially understood. There are three RAF isoforms in mammals (ARAF, BRAF and CRAF) and two related pseudokinases (KSR1 and KSR2). RAS-mediated activation of RAF depends on an allosteric mechanism driven by the dimerization of its kinase domain. Recent work on human RAFs showed that MEK binding to KSR1 promotes KSR1-BRAF heterodimerization, which leads to the phosphorylation of free MEK molecules by BRAF. Similar findings were made with the single Drosophila RAF homolog. Here we show that the fly scaffold proteins CNK and HYP stabilize the KSR-MEK interaction, which in turn enhances RAF-KSR heterodimerization and RAF activation. The cryogenic electron microscopy structure of the minimal KSR-MEK-CNK-HYP complex reveals a ring-like arrangement of the CNK-HYP complex allowing CNK to simultaneously engage KSR and MEK, thus stabilizing the binary interaction. Together, these results illuminate how CNK contributes to RAF activation by stimulating the allosteric function of KSR and highlight the diversity of mechanisms impacting RAF dimerization as well as the regulatory potential of the KSR-MEK interaction.

Dihydrophenanthro[b]furan derivatives from the tubers of Bletilla striata.

Two pairs of new dihydrophenanthro[b]furan enantiomers blephebibnols G-H (1-2), one new dihydrophenanthro[b]furan derivative blephebibnol I (3), along with four known analogues (4-7), were isolated from the tubers of Bletilla striata. Their structures including the absolute configurations were determined by the combination of spectroscopic data analysis, ECD and NMR calculations. Compounds 1a, 1b, and 2b showed inhibition of NO production in LPS-stimulated BV-2 cells, with IC50 values ranging from 4.11 to 14.65 µM. Further mechanistic study revealed that 1a suppressed the phosphorylation of p65 subunit to regulate the NF-κB signaling pathway. In addition, some compounds displayed selective cytotoxic activities against HCT-116, HepG2, A549, or HGC27 cancer cell lines with IC50 values ranging from 0.1 to 8.23 µM.

The Roles of WNT Signaling Pathways in Skin Development and Mechanical-Stretch-Induced Skin Regeneration.

The WNT signaling pathway plays a critical role in a variety of biological processes, including development, adult tissue homeostasis maintenance, and stem cell regulation. Variations in skin conditions can influence the expression of the WNT signaling pathway. In light of the above, a deeper understanding of the specific mechanisms of the WNT signaling pathway in different physiological and pathological states of the skin holds the potential to significantly advance clinical treatments of skin-related diseases. In this review, we present a comprehensive analysis of the molecular and cellular mechanisms of the WNT signaling pathway in skin development, wound healing, and mechanical stretching. Our review sheds new light on the crucial role of the WNT signaling pathway in the regulation of skin physiology and pathology.

S100 calcium-binding protein A9 promotes skin regeneration through toll-like receptor 4 during tissue expansion.

Background: In plastic surgery, tissue expansion is widely used for repairing skin defects. However, low expansion efficiency and skin rupture caused by thin, expanded skin remain significant challenges in promoting skin regeneration during expansion. S100 calcium-binding protein A9 (S100A9) is essential in promoting wound healing; however, its effects on skin regeneration during tissue expansion remain unclear. The aim of the present study was to explore the role of S100A9 in skin regeneration, particularly collagen production to investigate its importance in skin regeneration during tissue expansion. Methods: The expression and distribution of S100A9 and its receptors-toll-like receptor 4 (TLR-4) and receptor for advanced glycation end products were studied in expanded skin. These characteristics were investigated in skin samples of rats and patients. Moreover, the expression of S100A9 was investigated in stretched keratinocytes in vitro. The effects of S100A9 on the proliferation and migration of skin fibroblasts were also observed. TAK-242 was used to inhibit the binding of S100A9 to TLR-4; the levels of collagen I (COL I), transforming growth factor beta (TGF-ß), TLR-4 and phospho-extracellular signal-related kinase 1/2 (p-ERK1/2) in fibroblasts were determined. Furthermore, fibroblasts were co-cultured with stretched S100A9-knockout keratinocytes by siRNA transfection and the levels of COL I, TGF-ß, TLR-4 and p-ERK1/2 in fibroblasts were investigated. Additionally, the area of expanded skin, thickness of the dermis, and synthesis of COL I, TGF-ß, TLR-4 and p-ERK1/2 were analysed to determine the effects of S100A9 on expanded skin. Results: Increased expression of S100A9 and TLR-4 was associated with decreased extracellular matrix (ECM) in the expanded dermis. Furthermore, S100A9 facilitated the proliferation and migration of human skin fibroblasts as well as the expression of COL I and TGF-ß in fibroblasts via the TLR-4/ERK1/2 pathway. We found that mechanical stretch-induced S100A9 expression and secretion of keratinocytes stimulated COL I, TGF-ß, TLR-4 and p-ERK1/2 expression in skin fibroblasts. Recombined S100A9 protein aided expanded skin regeneration and rescued dermal thinning in rats in vivo as well as increasing ECM deposition during expansion. Conclusions: These findings demonstrate that mechanical stretch promoted expanded skin regeneration by upregulating S100A9 expression. Our study laid the foundation for clinically improving tissue expansion using S100A9.

Ligustrazine-Derived Chalcones-Modified Platinum(IV) Complexes Intervene in Cisplatin Resistance in Pancreatic Cancer through Ferroptosis and Apoptosis.

Developing multitarget platinum(IV) prodrugs is an important strategy to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity. Herein, six novel ligustrazine-derived chalcones-modified platinum(IV) complexes were synthesized and evaluated for their anti-proliferative activities. Among them, 16a displayed higher cytotoxicity toward the tested cancer cell lines and lower cytotoxicity toward the human normal cells than CDDP or the combined group. Mechanistic studies revealed that 16a efficiently induced DNA damage and initiated a mitochondria-dependent apoptosis pathway. Besides, 16a significantly triggered ferroptosis by down-regulating expression levels of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11. Further, 16a obtained superior in vivo anti-tumor efficiency than CDDP in CDDP-resistant pancreatic cancer xenograft models but showed no significant side effects. In summary, our study suggested that 16a acts via a different anti-cancer mechanistic pathway than CDDP and may therefore encompass a novel practical strategy for cancer treatment.

Reconstruction of Hemifacial Congenital Giant Nevus with Pre-expanded Scalp Flaps and Deltopectoral Skin Flaps.

BACKGROUND: The hemifacial congenital giant nevus impacts both physical and mental health of the patients. Excision is typically the most suitable option in these situations, but reconstructing the subsequent surgical defects is always a serious challenge. METHODS: Between February 2012 and January 2021, a retrospective review of 4 patients who suffered from hemifacial congenital giant nevus was conducted, and they were treated by pre-expanded scalp flap and deltopectoral flap simultaneously. All patients receive tissue expansion, nevus resection, expanded skin flap transfer, and pedicle division. RESULTS: Four patients with hemifacial congenital giant nevi were successfully treated with no major complications. One patient with a transferred deltopectoral flap experienced distal necrosis of the flap, and healed after dressing changes. No recurrence of the nevus was found during the follow-up period, and the transferred skin flaps match well with facial skin in contour and color. CONCLUSION: This modified pre-expanded scalp flap combined with a deltopectoral flap provides an easy and reliable way for hemifacial reconstruction in patients with a congenital giant nevus.

Reconstruction of the Deformed Tragus Accompanied by Accessory Auricle.

BACKGROUND: Accessory auricles are common congenital external ear malformations. However, it remains challenging to treat a complicated accessory auricle and reconstruct the involved tragus. OBJECTIVES: In this study the aim was to present a new classification of accessory auricles and the surgical management of each type. METHODS: We retrospectively reviewed the records of 110 patients who underwent accessory auricle surgery. The accessory auricle was classified by 3 types, according to its morphology and relationship with the tragus: Types I, II, and III. The type III accessory auricle was divided into 3 subtypes: IIIa, IIIb, and IIIc. The surgical techniques utilized varied among the different types. RESULTS: The total number of accessory auricles in 110 patients was 149. Type I was the most common type (52.3%), followed by types II (31.5%) and III (16.1%). Among the type III subtypes, type IIIa was observed in 12 (8.1%), type IIIb in 3 (2%), and type IIIc in 9 (6%) ears. None of the patients experienced short-term complications. Three patients (4 ears) showed mild hypertrophic scarring. Three patients (3 ears) showed a smaller tragus than the normal side. The average score for aesthetic outcomes was 3.7 points on a 4-point Likert scale. CONCLUSIONS: Classification of accessory auricles provides guidance for surgery. Different surgical techniques were employed based on the type of accessory auricle. The final incision at the edge of the reconstructed tragus provided an aesthetically pleasing outcome.

Corrigendum: Identification of common Hub genes in human dermal fibroblasts stimulated by mechanical stretch at both the early and late stages.

[This corrects the article DOI: 10.3389/fsurg.2022.846161.].

Macrophage contribution to the survival of transferred expanded skin flap through angiogenesis.

Background: Despite the application of tissue expansion in the reconstruction of significant tissue defects, complications with expanded random-pattern skin flaps remain a major challenge. Insufficient angiogenesis is one of the keys factors in flap ischemia and dysfunction. Macrophages play a key role in promoting tissue angiogenesis, but their effects on expanded flap angiogenesis and the survival of the transferred skin flap are still unknown. Methods: A rat scalp expansion model was established to evaluate the dynamic changes of macrophages in expanded skin. Clodronate liposomes (Clo-lipo) were injected into the expanded scalps to deplete the macrophages, and the expanded scalp flaps with macrophage depletion were orthotopically transferred. The remaining expanded rat scalp flaps were treated with either a macrophage-colony stimulating factor (M-CSF) alone or M-CSF in combination with Clo-lipo and transferred. The number of macrophages, blood perfusion, microvascular densities (MVDs), flap survival, histological changes, and gene expression related to macrophage polarization and angiogenesis were determined with immunofluorescence (IF) staining, full-field laser perfusion imager, hematoxylin and eosin (HE) staining, and quantitative real-time polymerase chain reaction. Results: The number of pan-macrophages significantly increased in the expanded scalp on days 14 and 21 after expander placement. The depletion rate after treatment with Clo-lipo was 29.06%, and the number of macrophages was significantly reduced in the group that underwent Clo-lipo treatment on day 14 before flap transfer (P<0.05). Macrophage depletion resulted in decreased blood perfusion, reduced MVDs, lower expression of factors, and poor survival rate. The recruitment of macrophages with a M-CSF led to higher blood perfusion, increased MVDs, greater expression of angiogenic factors, and better flap survival after flap transfer. Conclusions: Alternatively activated macrophages in the expanded flap could significantly promote angiogenesis, improve blood perfusion, and ultimately increase the flap survival rate. Modulating alternatively activated macrophages may provide a key therapeutic strategy to promote expanded skin flap survival. Our study has provided a basis for clinically improving random-pattern skin flap survival.

Montelukast Attenuates Retraction of Expanded Flap by Inhibiting Capsule Formation around Silicone Expander through TGF-ß1 Signaling.

BACKGROUND: Tissue expansion has tremendous applications in plastic surgery, but flap retraction provides insufficient tissue for use. Inspired by the use of montelukast to suppress capsular contracture, the authors investigated the effects of montelukast on capsule formation around the expander and retraction of the expanded scalp of the rat. METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into control and montelukast groups. In each group, 12 expanded flaps with or without capsules were harvested for histologic and molecular analysis; the six remaining expanded flaps were transferred to repair defects. Myofibroblast and transforming growth factor-ß1 expression in the capsule was determined using immunofluorescence. Capsule ultrastructure was observed using transmission electron microscopy. Related protein expression in the capsules was detected using Western blot analysis. RESULTS: A comparison of control and montelukast groups revealed that areas of the harvested expanded flaps with capsules were greater (2.04 ± 0.11 cm 2 versus 2.42 ± 0.12 cm 2 , respectively; P = 0.04); the retraction rate decreased (41.3% ± 2.16% versus 28.13% ± 2.17%, respectively; P < 0.01). However, the increased areas and decreased retraction disappeared after capsule removal. The number of myofibroblasts declined. Thin, sparse collagen fibers were observed in the capsules. The expression of COL1, COL3, TGF-ß1, EGR1, and phosphorylated ERK1/2 in the capsules decreased. Furthermore, the recipient area repaired by the transferred expanded flap was increased from 4.25 ± 0.39 cm 2 to 6.58 ± 0.31 cm 2 ( P < 0.01). CONCLUSION: Montelukast attenuates retraction of the expanded flap by inhibiting capsule formation through suppressing transforming growth factor-ß1 signaling. CLINICAL RELEVANCE STATEMENT: This study provides novel insights into a method for increasing the area of the expanded flap.

Novel Insights into the Role of Keratinocytes-Expressed TRPV3 in the Skin.

TRPV3 is a non-selective cation channel that is highly expressed in keratinocytes in the skin. Traditionally, keratinocytes-expressed TRPV3 is involved in multiple physiological and pathological functions of the skin, such as itching, heat pain, and hair development. Although the underlying mechanisms by which TRPV3 functions in vivo remain obscure, recent research studies suggest that several cytokines and EGFR signaling pathways may be involved. However, there have also been other studies with opposite results that question the role of TRPV3 in heat pain. In addition, an increasing number of studies have suggested a novel role of TRPV3 in promoting skin regeneration, indicating that TRPV3 may become a new potential target for regulating skin regeneration. This paper not only reviews the role of keratinocytes-expressed TRPV3 in the physiological and pathological processes of itching, heat pain, hair development, and skin regeneration, but also reviews the relationship between TRPV3 gene mutations and skin diseases such as atopic dermatitis (AD) and Olmsted syndrome (OS). This review will lay a foundation for further developing our understanding of the mechanisms by which TRPV3 is involved in itching, heat pain, and hair development, as well as the treatments for TRPV3-related skin diseases.

Endoscopy-assisted versus open tissue expander placement in plastic and reconstructive surgery: a meta-analysis.

Tissue expansion can be used to overcome challenges due to tissue deficiency in plastic and reconstructive surgery; however, the long expansion process is often accompanied by numerous complications. This meta-analysis aimed to determine whether endoscopy-assisted expander placement could decrease complications and shorten treatment time. This study followed the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered in PROSPERO (CRD42021226116). A literature search was performed in eight databases from their inception dates up to 25 August 2021, to identify clinical studies on endoscopy-assisted and/or open tissue expander placement in plastic and reconstructive surgery. Seven studies met the inclusion criteria. In seven studies, 194 underwent endoscopy-assisted expander placement, and 565 underwent open expander placement. The overall complication rate in the endoscopy-assisted group was significantly lower than that in the open group (risk difference (RD) -0.28, 95% confidence interval (CI), -0.38, -0.18, p < .001). Subgroup analysis showed significantly lower incidence rates of hematoma, infection and dehiscence in the endoscopy-assisted group. The complication rate in the head/neck was lower with low heterogeneity (RD, -0.18; 95% CI, -0.26 to -0.09, p < .001; I2 = 0%). The endoscopy-assisted group had shorter surgery time, hospital stay and time to full expansion (weighted mean difference (WMD), -13.97 min, -16.88 h, -27.54 days; 95% CI, -15.85, -12.08 min, -24.36, -9.40 h, -38.85, -16.24 days; both p < .001, respectively). Endoscopy-assisted expander placement may help lower the risk of complications, especially in the head/neck, and reduce surgery time, hospital stay, and time to full expansion. Abbreviations: CI: confidence interval; CNKI: China National Knowledge Infrastructure Database; CSTJ, China Science and Technology Journal Database; NOS: the Newcastle-Ottawa Scale; PRISMA: preferred reporting items for systematic reviews and meta-analyses; RCT: randomized controlled trial; RoB: the cochrane risk-of-bias; RD: risk difference; WMD: weighted mean difference; SE: standard error; SND: standard normal deviate.

Knowledge and vaccination intention of monkeypox in China's general population: A cross-sectional online survey.

BACKGROUND: Public awareness of monkeypox is critical in the fight against this infectious disease. However, at present a survey of the Chinese population on monkeypox is lacking. This study was conducted to compensate for the lack of knowledge and identify a vaccination intention assessment for monkeypox in China. METHODS: The questionnaire comprised 20 items with the following three aspects: basic information, knowledge, and willingness to vaccinate or pay. For this study, 521 valid respondents were recruited. Utilizing logistic regression, the researchers identified the factors related with knowledge and vaccination intentions. RESULTS: The average total score for knowledge of monkeypox was 5.6 (score range 0-10), and 309 (59.3%) participants were categorized as having greater knowledge based on a total score of 6. Most participants (76.4%) were willing to accept a monkeypox vaccination. The average acceptable cost of the monkeypox vaccine was CNY261.2. Factors such as level of education, and working within the healthcare profession were related to monkeypox knowledge. An increased knowledge of monkeypox was related to a higher willingness to vaccinate. Participants who were willing to pay more for vaccines included those with high incomes, who suffered from chronic diseases, and healthcare workers. CONCLUSIONS: The Chinese population had relatively high knowledge of monkeypox and demonstrated a willingness to receive the vaccine.

Hair-Bearing Expanded Scalp Flap for Total Beard Reconstruction in Patients With Chin and Submental Postburn Scars.

BACKGROUND: Loss of beard in adult male caused by severe burn may cause cosmetic and psychological problems for these patients. Reconstruction of the beard with hair-bearing skin flaps in similar color and texture of the surrounding tissues remains a challenge. METHODS: Eight male patients suffered from submental postburn scar and beard loss were treated by using the hair-bearing expanded scalp flap. A 1000 mL nephroid tissue expander was first implanted under the frontal and mid scalp. After a 3 to 4-month tissue expansion, the expanded hair-bearing scalp flap based on bilateral superficial temporal vessels were raised and transferred for beard reconstruction, and the cutaneous pedicles were curled into tubes. Delay and division of the pedicles were performed 3 to 4 weeks after flap transfer. RESULTS: Eight male patients with postburn scar and beard loss were successfully treated with no major complication. One patient suffered from edge necrosis at distal end of the flap and healed after daily dressing change. Chin and submental areas were repaired by expanded scalp flap and total beard was reconstructed at the same time. All donor sites were closed directly without skin grafting. CONCLUSIONS: The modified expanded bipedicled scalp flap provides an easy and reliable way for total beard reconstruction and large-scale submental scars repairment.