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Bone regeneration of critical-sized bone defects (CSBDs) with biomimetic collagen-based aerogels remains a significant challenge due to the oxidative stress on the microenvironment. The excessive oxidative stress could induce apoptosis and dysfunction of host-derived cells. Astaxanthin (ATX) exhibits excellent antioxidant ability to block free radical chain reactions. In the present study, hybrid antioxidant collagen-derived aerogels (ATX-Col aerogels) were fabricated by a simple one-step method through the covalent cross-linking of Col and ATX. The resulting ATX-Col aerogels show porous and interconnected structures due to freeze-drying strategies. The ATX-Col aerogels exhibited excellent biocompatibility and biosafety. Furthermore, ATX-Col aerogels demonstrated favorable antioxidant capacity by eliminating intracellular ROS by activating the NRF2 signaling pathway. Finally, excellent reparative effects in repairing rat cranial defects were observed in ATX-Col aerogels. Taken together, ATX-Col aerogels can accelerate bone regeneration by relieving oxidative stress via the NRF2 signaling pathway and act as a potential bone graft for CSBD. This study provides a simple method of developing antioxidant aerogels for bone regeneration.

A successful case of crossover replantation of the left foot to the stump of the right leg was described. The lower extremities were amputated at different levels. On the left side, there was a complete amputation in the distal part of the lower leg with comminuted fracture of the distal tibia. On the right side, there was a complete amputation in the hindfoot with comminuted fracture of both the talus and calcaneus. Since anatomical replantation was impossible, we performed crossover replantation of the left foot to the right lower leg. At the latest follow-up examination, forty-six months after the accident, the patient walked independently with a prosthesis on the stump of the left leg. Crossover replantation should be considered in bilateral amputations for the salvage of at least one extremity.

It is a widespread and difficult problem that refractory diabetic wounds have a poor local environment and prolonged inflammatory irritation. Tumor cell-derived exosomes play an important role in the development of tumors, as they can promote tumor cell proliferation, migration, and invasion and enhance tumor cell activity. However, tumor tissue-derived exosomes have been less studied, and it is unclear how they affect wound healing. In this study, we extracted tissue-derived exosomes from human oral squamous carcinoma and paracancerous tissue by ultracentrifugation, size exclusion chromatography and ultrafiltration and performed exosome characterization. In vitro, the oral squamous cell carcinoma tissue-derived exosomes (OSCC Ti-Exos) promoted the proliferation and migration of endothelial cells, keratinocytes, and fibroblasts. In addition, in vivo experiments showed that the OSCC Ti-Exos accelerated the healing of diabetic wounds and were safe in mice. In contrast, there was no promoting effect of paracancerous tissue-derived exosomes either in vivo or in vitro. In conclusion, OSCC Ti-Exos promoted the healing of diabetic wounds, demonstrated preliminary biosafety in mice and have promise as therapeutic applications.

Severe soft tissue defects and amputated digits are clinically common injuries. Primary treatments include surgical free flap transfer and digit replantation, but these can fail because of vascular compromise. Postoperative monitoring is therefore crucial for timely detection of vessel obstruction and survival of replanted digits and free flaps. However, current postoperative clinical monitoring methods are labor intensive and highly dependent on the experience of nurses and surgeons. Here, we developed on-skin biosensors for noninvasive and wireless postoperative monitoring based on pulse oximetry. The on-skin biosensor was made of polydimethylsiloxane with gradient cross-linking to create a self-adhesive and mechanically robust substrate that interfaces with skin. The substrate was shown to exhibit appropriate adhesion on one side for both high-fidelity measurements of the sensor and low risk of peeling injury to delicate tissues. The other side demonstrated mechanical integrity to facilitate flexible hybrid integration of the sensor. Validation studies using a model of vascular obstruction in rats demonstrated the effectiveness of the sensor in vivo. Clinical studies indicated that the on-skin biosensor was accurate and more responsive than current clinical monitoring methods in identifying microvascular conditions. Comparisons with existing monitoring techniques, including laser Doppler flowmetry and micro-lightguide spectrophotometry, further verified the sensor’s accuracy and ability to identify both arterial and venous insufficiency. These findings suggest that this on-skin biosensor may improve postoperative outcomes in free flap and replanted digit surgeries by providing sensitive and unbiased data directly from the surgical site that can be remotely monitored.

Background Skin cutaneous melanoma (SKCM) remains the deadliest form of skin cancer. However, mechanism of prognosis of SKCM is not yet clear, and accurate prediction of the prognosis remains difficult. Here, we developed and validated three prognostic risk models based on immune cell infiltration, DNA methylation features, and immune-related genes for SKCM patients.Methods We downloaded the datasets from high-dimensional public databases. Univariate and multivariable Cox regression analysis was performed to develop models based on prognostic tumor-infiltrating immune cells, methylation related DEGs (mrDEGs), and immune-related genes (IRGs). Functional enrichment analysis was performed using clusterProfiler and GSVA R package. Prediction of sensitivity to drugs was conducted using pRRophetic R package. The prognostic value of these models was assessed using survival analysis and receiver operating characteristic curve analysis.Results The immune cell model was constructed based on 5 immune cell subtypes. Nine mrDEGs were identified to develop the methylation model. Furthermore, the prognostic IS model based on 5 IRGs was established. These models showed good performance to predict the prognosis of SKCM patients. The IS and methylation score were demonstrated to be associated with immune cell infiltration, microsatellite instability, and tumor mutational burden in SKCM. Moreover, the IS could predict the sensitivity to drugs and the responsiveness to immunotherapy. Finally, IHC staining of the clinical samples confirmed the increased expression of the prognostic IRGs.Conclusions These risk models based on immune cell infiltration, DNA methylation, and IS could be used to predict the survival of SKCM patients and further to guide treatment decisions.

The refractory diabetic wound has remained a worldwide challenge as one of the major health problems. The impaired angiogenesis phase during diabetic wound healing partly contributes to the pathological process. MicroRNA (miRNA) is an essential regulator of gene expression in crucial biological processes and is a promising nucleic acid drug in therapeutic fields of the diabetic wound. However, miRNA therapies have limitations due to lacking an effective delivery system. In the present study, we found a significant reduction of miR-31-5p expression in the full-thickness wounds of diabetic mice compared to normal mice. Further, miR-31-5p has been proven to promote the proliferation, migration, and angiogenesis of endothelial cells. Thus, we conceived the idea of exogenously supplementing miR-31-5p mimics to treat the diabetic wound. We used milk-derived exosomes as a novel system for miR-31-5p delivery and successfully encapsulated miR-31-5p mimics into milk exosomes through electroporation. Then, we proved that the miR-31-5p loaded in exosomes achieved higher cell uptake and was able to resist degradation. Moreover, our miRNA-exosomal formulation demonstrated dramatically improved endothelial cell functions invitro, together with the promotion of angiogenesis and enhanced diabetic wound healing invivo. Collectively, our data showed the feasibility of milk exosomes as a scalable, biocompatible, and cost-effective delivery system to enhance the bioavailability and efficacy of miRNAs.

According to the Mozena classification system, stage IIb and stage III ingrown toenail cases are considered as severe ones; however, limited options are available for treatment.To lower the recurrence rate and achieve primary intention healing in severe ingrown toenail cases by the modified Howard-Dubois technique.Forty patients were included in this study. In this procedure, a fish-mouth like soft tissue along the nail groove to the tip of the toe was resected, the upper surface of the distal phalanx was flattened and the nail bed matrix was remodelled. The European Quality of Life (EuroQol) questionnaire and Surgical Satisfaction Questionnaire were used to assess the outcomes.There were no recurrences observed during the follow-up period. Healing time from surgery to back to school or work was 10.82 days on an average (range: 7-23 days). According to the results of EuroQol questionnaire, improvements were achieved in the areas of mobility (50%), looking after myself (10%), doing usual activities (35%), having pain or discomfort (95%) and feeling worried, sad, or unhappy (55%). According to the results of Surgical Satisfaction Questionnaire, 38 (95%) patients indicated that they would undergo the surgery again if they 'had to do it all over again' and 36 (90%) patients said that they would recommend the procedure to others.This modified Howard-Dubois technique was an effective, safe and cosmetic alternation for the treatment of ingrown toenail in severe or relapsed cases.

Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications in diabetes. Previous studies have shown that chronic neuroinflammation was associated with DPN. However, further research is needed to investigate the exact immune molecular mechanism underlying the pathogenesis of DPN. Expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened by R software. After functional enrichment analysis of DEGs, a protein–protein interaction (PPI) network analysis was performed. The CIBERSORT algorithm was used to evaluate the infiltration of immune cells in DPN. Next, the least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were applied to identify potential DPN diagnostic markers. Finally, the results were further validated by qRT-PCR. A total of 1308 DEGs were screened in this study. Enrichment analysis identified that DEGs were significantly enriched in immune-related biological functions and pathways. Immune cell infiltration analysis found that M1 and M2 macrophages, monocytes, resting mast cells, resting CD4 memory T cells and follicular helper T cells were involved in the development of DPN. LTBP2 and GPNMB were identified as diagnostic markers of DPN. qRT-PCR results showed that 15 mRNAs, including LTBP2 and GPNMB, were differentially expressed, consistent with the microarray results. In conclusion, LTBP2 and GPNMB can be used as novel candidate molecular diagnostic markers for DPN. Furthermore, the infiltration of immune cells plays an important role in the progression of DPN.

The flexor pollicis longus muscle and flexor digitorum profundus muscle are innervated by the branches of the anterior interosseous nerve (AIN). Therefore, the commonly used methods of restoring the fingers and thumb flexion in lower brachial plexus injury have mainly focused on the AIN. We transferred the brachialis muscle branch of the musculocutaneous nerve (brachialis nerve) to the AIN using the vascularized lateral antebrachial cutaneous nerve (LACN) as a nerve graft to restore the flexion function of the fingers and thumb. This anatomical study was performed in 16 formalin-fixed upper extremities from 8 frozen cadavers. The brachialis nerve and the AIN were dissected. The bridged portion of the transected LACN was not dissected; only the two transected ends of the LACN were dissected, which kept the native blood supply of the intervening graft of the LACN from being destroyed. The diameters of the transected nerve ends of the brachialis nerve, AIN, and proximal and distal ends of the LACN were measured separately. Specimens of the measured nerve tissue were sent for toluidine blue staining, and the number of nerve fibers in each transected nerve branch was counted. The diameters of the brachialis nerve, AIN, and proximal and distal transected ends of LACN were 1.37 SD0.25 mm, 1.54 SD0.14 mm, 2.07 SD0.29, and 1.76 SD0.14 mm, with 1109 SD422, 1318 SD546, 1684 SD327, and 1378 SD667 myelinated nerve fibers, respectively. The fingers and thumb flexion function of the patient recovered gradually from 8 months after surgery. Using the vascularized LACN as an in situ nerve graft to transfer the brachialis nerve to the AIN was a feasible alternative technique to restore the flexion function of fingers and thumb in lower brachial plexus injury.

Diabetes mellitus is one of the most widespread metabolic diseases in the world, and diabetic foot ulcer (DFU), as one of its chronic complications, not only causes a large amount of physiological and psychological pain to patients but also places a tremendous burden on the entire economy and society. Despite significant advances in knowledge on the mechanism and in the treatment of DFU, clinical practice is still not satisfactory, and our understanding of its cellular and molecular pathogenesis is far from complete. Fortunately, progress in studying the roles of long non-coding RNAs (lncRNAs), which play important regulatory roles in the expression of genes at multiple levels, suggests that we can apply them in the early diagnosis and potential targeted intervention of DFU. In this review, we briefly summarize the current knowledge regarding the functional roles and potential mechanisms of reported lncRNAs in regulating DFU.

Background Sestrin2 (SESN2), a stress-inducible protein, has been reported to protect against denervated muscle atrophy through unfolded protein response and mitophagy, while its role in myofiber type transition remains unknown. Methods A mouse sciatic nerve transection model was created to evaluate denervated muscle atrophy. Myofiber type transition was confirmed by western blot, fluorescence staining, ATP quantification, and metabolic enzyme activity analysis. Adeno-associated virus (AAV) was adopted to achieve SESN2 knockdown and overexpression in gastrocnemius. AMPK/PGC-1α signal was detected by western blot and activated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). C2C12 myotubes with rotenone treatment were adopted for in vitro experiments. Results SESN2 was found to be upregulated in denervated skeletal muscles and rotenone-treated C2C12 cells. Knockdown of SESN2 aggravated muscle atrophy and accelerated myofiber type transition from slow-twitch to fast-twitch. Moreover, AMPK/PGC-1α signaling was proven to be activated by SESN2 after denervation, which further induced the expression of hypoxia-inducible factor HIF2α. Exogenous activation of AMPK/PGC-1α signaling could counteract the addition of slow-to-fast myofiber shift caused by SESN2 knockdown and lead to the retainment of muscle mass after denervation. Conclusion Collectively, the present study indicates that SESN2 prevents myofiber type transition from slow-twitch to fast-twitch and preserves muscle mass in denervated atrophy via AMPK/PGC-1α signaling. These findings contribute to a better understanding of the pathogenesis of muscle atrophy and provide novel insights into the role of SESN2 in myofiber type transition.

IntroductionSoft tissue defects of fingers are common in reconstructive plastic surgery, and reconstruction of the defects remains challenging for plastic surgeons. In our study, we reported our experience in finger reconstruction with a medial plantar artery perforator (MPAP) flap, especially using a lobulated MPAP flap for the complex multifinger soft defect.Patients and methodsFrom the period April 2012 to October 2018, 11 patients (9 males and 2 females) with an average age of 44 years old (ranging from 11 to 58) received finger reconstruction with a free MPAP flap. In total, 11 flaps (8 single-lobulated flaps and 3 two-lobulated flaps) were raised from the ipsilateral or contralateral instep area. Trauma and scar contracture caused hand soft tissue loss in all cases.ResultsThe sizes of the flaps ranged from 2×3 to 5×7.5 cm2. All flaps survived intact with no complications. One donor site was closed primarily, and other donor sites were covered with a full-thickness skin graft. The mean follow-up time was 6 months (ranging from 3 to 8 months). During the follow-up period, the patients were satisfied with their appearance without any traces of flap plastic surgery.ConclusionThe MPAP flap is a reliable and acceptable option for the reconstruction of complex soft tissue defects in the finger. Depending on the two branches of the medial plantar artery, the use of the lobulated MPAP flap holds promise in the treatment of multifinger soft tissue defects.

The treatment of diabetic wounds remains challenging due to the excess levels of oxidative stress, vulnerability to bacterial infection, and persistent inflammation response during healing. The development of hydrogel wound dressings with ideal anti-inflammation, antioxidant, and anti-infective properties is an urgent clinical requirement. In the present study, an injectable thermosensitive niobium carbide (Nb

The arrival of surgical robots in high-end medical equipment is a landmark, and the realization of tactile sensation a major challenge in this important cutting-edge research field. Aiming to address this issue, we present ultra-sensitive ionic electronic skin in the form of flexible capacitive pressure sensors, which incorporate multistage bionic microstructures in ion gels for the purpose of monitoring the delicate operations of surgical robots. Significantly, the ionic skin exhibits an ultra-high sensitivity of 9484.3 kPa−1 (

Wounds occur when skin integrity is broken and the skin is damaged. With progressive changes in the disease spectrum, the acute wounds caused by mechanical trauma have been become less common, while chronic wounds triggered with aging, diabetes and infection have become more frequent. Chronic wounds now affect more than 6 million people in the United States, amounting to 10 billion dollars in annual expenditure. However, the treatment of chronic wounds is associated with numerous challenges. Traditional remedies for chronic wounds include skin grafting, flap transplantation, negative-pressure wound therapy, and gauze dressing, all of which can cause tissue damage or activity limitations. Nanobiotechnology - which comprises a diverse array of technologies derived from engineering, chemistry, and biology - is now being applied in biomedical practice. Here, we review the design, application, and clinical trials for nanotechnology-based therapies for chronic wound healing, highlighting the clinical potential of nanobiotechnology in such treatments. By summarizing previous nanobiotechnology studies, we lay the foundation for future wound care via a nanotech-based multifunctional smart system.

With the rapid increase in the incidence of diabetes, non-healing diabetic wounds have posed a huge challenge to public health. Endothelial progenitor cell (EPC) has been widely reported to promote wound repairing, while its number and function were suppressed in diabetes. However, the specific mechanisms and competing endogenous RNA (ceRNA) network of EPCs in diabetes remain largely unknown. Thus, the transcriptome analyses were carried in the present study to clarify the mechanism underlying EPCs dysfunction in diabetes. EPCs were successfully isolated from rats. Compared to the control, diabetic rat-derived EPCs displayed impaired proliferation, migration, and tube formation ability. The differentially expressed (DE) RNAs were successfully identified by RNA sequencing in the control and diabetic groups. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DE mRNAs were significantly enriched in terms and pathways involved in the functions of EPCs and wound healing. Protein-protein interaction networks revealed critical DE mRNAs in the above groups. Moreover, the whole lncRNA-miRNA-mRNA ceRNA network was constructed, in which 9 lncRNAs, 9 mRNAs, and 5 miRNAs were further validated by quantitative real-time polymerase chain reaction. Rno-miR-10b-5p and Tgfb2 were identified as key regulators of EPCs dysfunction in diabetes. The present research provided novel insight into the underlying mechanism of EPCs dysfunction in diabetes and prompted potential targets to restore the impaired functions, thus accelerating diabetic wound healing. KEY MESSAGES: • Compared to the control, diabetic rat-derived EPCs displayed impaired proliferation, migration, and tube formation ability. • The DE RNAs were successfully identified by RNA sequencing in the control and diabetic groups and analyzed by DE, GO, and KEGG analysis. • PPI and lncRNA-miRNA-mRNA ceRNA networks were constructed. • 9 lncRNAs, 9 mRNAs, and 5 miRNAs were further validated by qRT-PCR. • Rno-miR-10b-5p and Tgfb2 were identified as key regulators of EPCs dysfunction in diabetes.

Diabetic foot ulcer is a serious complication in diabetes patients, imposing a serious physical and economic burden to patients and to the healthcare system as a whole. Oxidative stress is thought to be a key driver of the pathogenesis of such ulcers. However, no antioxidant drugs have received clinical approval to date, underscoring the need for the further development of such medications. Hydrogels can be applied directly to the wound site, wherein they function to prevent infection and maintain local moisture concentrations, in addition to serving as a reservoir for the delivery of a range of therapeutic compounds with the potential to expedite wound healing in a synergistic manner. Herein, we synthesized Prussian blue nanoparticles (PBNPs) capable of efficiently scavenging reactive oxygen species (ROS) owing to their ability to mimic the activity of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD). In the context of in vitro oxidative stress, these PBNPs were able to protect against cytotoxicity, protect mitochondria from oxidative stress-related damage, and restore nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway activity. To expand on these results in an in vivo context, we prepared a thermosensitive poly (d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA) hydrogel (PLEL)-based wound dressing in which PBNPs had been homogenously incorporated, and we then used this dressing as a platform for controlled PBNP release. The resultant PBNPs@PLEL wound dressing was able to improve diabetic wound healing, decrease ROS production, promote angiogenesis, and reduce pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels within diabetic wounds. Overall, our results suggest that this PBNPs@PLEL platform holds great promise as a treatment for diabetic foot ulcers.

Microsurgical free tissue transfer is still playing an important role in lower extremity reconstruction. Finding a suitable recipient artery for anastomosis is critical in the microsurgical procedure, especially in an extensive wound, or in a complex trauma combined with vascular injury. From April 2014 to March 2018, we retrospectively reviewed patients with traumatic/post-traumatic, oncologic, and electrical wounds in the lower extremity. Those treated with muscle feeding artery as recipient vessels were included. The latissimus dorsi (LD) muscle free flap, anterior lateral thigh (ALT) perforator free flap, and deep inferior epigastric perforator (DIEP) free flap were raised. The muscle feeding arteries to vastus lateral muscle and to medial head of gastrocnemius muscle, concomitant veins, and great saphenous vein were used as recipient vessels. Injuries included in the study were caused by tumour in 2 cases, car accident in 3 cases, crushing in 3 cases, burns in one case, and electrical injury in one case. The wound size varied from 14 cm × 6 cm to 30 cm × 20 cm. LD, ALT, and DIEP free flaps were used in 6, 3, and 4 patients, respectively. The muscle feeding arteries to medial head of gastrocnemius muscle, to sartorius muscle, and to vastus lateral muscle were used as recipient arteries in 4, 5, and one patient, respectively. Concomitant and great saphenous veins were used as recipient veins in 10 and 4 patients, respectively. Using the muscle feeding artery is feasible to avoid injury to the main artery and facilitate dissection and anastomoses, particularly when the wound is located proximal to the mid-third of the lower leg.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, but the underlying molecular pathogenesis remains unclear. Accumulating evidence indicates that circular RNAs (circRNAs) play vital roles in DPN, while their expressions and functions in Schwann cell (SC) are rarely reported. Here, we performed protein profiling and circRNA sequencing on the peripheral nerves of patients with or without DPN. A total of 265 differentially expressed proteins were identified in DPN by protein profiling, which mainly enrich in myelination according to Gene Ontology analysis. Further, 15637 circRNAs were identified by circRNA sequencing, of which 11 were verified to be dysregulated. Among them, circ_0002538 was found to be downregulated in DPN and chosen for further investigation. Functional experiments revealed that circ_0002538 overexpression promoted SC migration and relieved demyelination in DPN. Mechanistic studies revealed that circ_0002538 could promote PLLP expression by sponging miR-138-5p, while lack of circ_0002538 led to PLLP deficiency, which further suppressed SC migration and caused demyelination. The present research provided novel insights into the pathogenesis of DPN, in which the circ_0002538/miR-138-5p/PLLP axis was suppressed in SCs and hence caused demyelination. These findings expanded the role of circRNAs in DPN and provided potential therapeutic targets for DPN.

Adipose-derived stem cells (ADSCs) can differentiate into Schwann cells (SCs) at the site of nerve injury, where Schwann cell-derived exosomes (SC-Exos) are suspected to exert an induction effect. Our study aimed to induce the differentiation of ADSCs in vitro using SC-Exos and to investigate the mechanisms involved through miRNA sequencing. Subcutaneous fat was used to extract ADSCs. Exosomes were extracted from Schwann cell lines (RSC96) using ultracentrifugation and were able to be taken up by human ADSCs. After 8 days of induction of ADSCs by SC-Exos, phenotypic characteristics were observed by examining the expression of SC markers (S100ß, NGFR, MPZ, GFAP) through RT-qPCR, Western blot and immunofluorescence. The RNA and protein expression levels of S100ß, NGFR, MPZ, and GFAP were found to be significantly higher in the SC-Exo induction group than in the uninduced group, which was also consistent with the immunofluorescence results. Additionally, miRNA sequencing was performed on exosome-induced ADSCs, followed by bioinformatic analysis and validation of the results. According to the sequencing results, there were a total of 94 differentially expressed miRNAs. Bioinformatics analysis indicated that 3506 Gene Ontology terms and 98 Kyoto Encyclopedia of Genes and Genomes pathways were significantly enriched. Ten miRNAs, 5 target mRNAs and elevated expression of the PIK3CD/Akt pathway were validated by RT-qPCR or Western blot, which is consistent with the sequencing results. Our study demonstrates that the utility of SC-Exos is effective in inducing the differentiation of ADSCs into SCs, in which these validated differentially expressed miRNAs exert a vital effect. This work provides a new paradigm via rationally applying Schwann cell-derived exosomes as a promising therapeutic option for repairing peripheral nerve injury.

Clinical work and research on diabetic wound repair remain challenging globally. Although various conventional wound dressings have been continuously developed, the efficacy is unsatisfactory. The effect of drug delivery is limited by the depth of penetration. The sustained release of biomolecules from biological wound dressings is a promising treatment approach to wound healing. An assortment of cell-derived exosomes (exos) have been proved to be instrumental in tissue regeneration, and researchers are dedicated to developing biomolecules carriers with unique properties. Herein, we reported a methacrylate gelatin (GelMA) microneedles (MNs) patch to achieve transdermal and controlled release of exos and tazarotene. Our MNs patch comprising GelMA/PEGDA hydrogel has distinctive biological features that maintain the biological activity of exos and drugs in vitro. Additionally, its unique physical structure prevents it from being tightly attached to the skin of the wound, it promotes cell migration, angiogenesis by slowly releasing exos and tazarotene in the deep layer of the skin. The full-thickness cutaneous wound on a diabetic mouse model was carried out to demonstrate the therapeutic effects of GelMA/PEGDA@T + exos MNs patch. As a result, our GelMA/PEGDA@T + exos MNs patch presents a potentially valuable method for repairing diabetic wound in clinical applications. Graphic Abstract

Injectable and degradable PEG hydrogel was prepared via Michael-type addition between cross-linking monomer 4-arm-PEG-MAL and two cross-linkers of hydrolysis degradable PEG-diester-dithiol and non-degradable PEG-dithiol, and it had a porous structure with the uniform pore size. The biocompatibility assays

Diabetic wound complications are financially costly and difficult to heal in worldwide. Whereas the therapies of diabetic wound, such as wound dressing, endocrine therapy or flap-transplantations, were not satisfied. Based on our previous study of exosome secreted by adipose-derived stem cell (ADSC-exo), we loaded ADSC-exo into the matrix metalloproteinase degradable polyethylene glycol (MMP-PEG) smart hydrogel. Physical and chemical properties of ADSC-exo@MMP-PEG smart hydrogel were tested by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), weight loss examination, etc. As the hydrogel degraded in response to MMP, ADSC-exo was released and subsequently enhanced cell function via Akt signaling. Moreover, treatment with ADSC-exo@MMP-PEG smart hydrogel significantly relieved the H

Diabetes is primarily characterized by hyperglycemia, and its high incidence is often very costly to patients, their families, and national economies. Unsurprisingly, the number and function of endothelial progenitor cells (EPCs) decrease in patients resulting in diabetic wound non-healing. As precursors of endothelial cells (ECs), these cells were discovered in 1997 and found to play an essential role in wound healing. Their function, number, and role in wound healing has been widely investigated. Hitherto, a lot of complex molecular mechanisms have been discovered. In this review, we summarize the mechanisms of how hyperglycemia affects the function and number of EPCs and how the affected cells impact wound healing. We aim to provide a complete summary of the relationship between diabetic hyperglycosemia, EPCs, and wound healing, as well as a better comprehensive platform for subsequent related research.

Gastric cancer (GC) is the second most common cancer and the third most frequent cause of cancer-related deaths in China. E2Fs are a family of transcription factors reported to be involved in the tumor progression of various cancer types; however, the roles of individual E2Fs are still not known exactly in tumor progression of GC. In this study, we examined the expression of E2Fs to investigate their roles in tumor progression in GC patients using multiple databases, including ONCOMINE, GEPIA2, Kaplan-Meier plotter, cBioPortal, Metascape, LinkedOmics, GeneMANIA, STRING and UCSC Xena. We also performed real-time polymerase chain reaction (RT-PCR) to validate the expression levels of individual E2Fs in several GC cell lines. Our results demonstrated that the mRNA levels of E2F1/2/3/5/8 were significantly higher both in GC tissues and cell lines. The expression levels of E2F1 and E2F4 were correlated with poor overall survival (OS), decreased post-progression survival (PPS), and decreased progression-free survival (FP) in patients with GC. However, overexpression of E2F2, E2F5, E2F7 and E2F8 is significantly associated with disease-free survival and overall survival in patients with GC. In addition, higher E2F3 and E2F6 mRNA expression was found to increase GC patients’ OS and PPS. 224 of 415 patients with STAD (54%) had gene mutations that were associated with longer disease-free survival (DFS) but not OS. Cell cycle pathway was closely associated with mRNA level of more than half of E2Fs (E2F1/2/3/7/8). There were close and complicated interactions among E2F family members. Finally, our results indicated the gene expressions of E2Fs had a positive relationship with its copy numbers. Taken together, E2F1/2/3/5/8 can serve as biomarkers for GC patients with high prognostic value for OS of GC patients or therapeutic targets for GC.

The difficulty of wound healing in patients with diabetes mellitus remains a considerable challenge for clinical and scientific research. To address the problem of poor healing that affects chronic wounds in patients with diabetes, we developed an injectable self-healing hydrogel based on chitosan (CS), hyaluronic acid (HA), and kalium γ-cyclodextrin metal organic frameworks (K-γ-CD-MOFs) loaded α-lipoic acid (α-LA) with antibacterial activity and antioxidant performance. In vitro analysis showed that the hydrogel could promote cell proliferation and migration on the basis of Cell Counting Kit-8 (CCK-8) assay and Transwell experiments. Moreover, the addition of α-LA allowed the reversal of oxidative stress-induced cell damage. In vivo analyses were performed involving a full-thickness wound model in diabetic Sprague–Dawley (SD) rats. The hydrogel dressing significantly promoted the wound healing process with better granulation tissue formation and more collagen deposition because of its multifunctional traits, suggesting that it can be an excellent treatment for chronic full-thickness skin wound healing.

As one of the most common pathological processes in the clinic, wound healing has always been an important topic in medical research. Improving the wound healing environment, shortening the healing time and promoting fast and effective wound healing are hot and challenging issues in clinical practice. The nuclear factor‐erythroid–related factor 2 (NFE2L2 or NRF2) signalling pathway reduces oxidative damage and participates in the regulation of anti‐oxidative gene expression in the process of oxidative stress and thus improves the cell protection. Activation of the NRF2 signalling pathway increases the resistance of the cell to chemical carcinogens and inflammation. The signal transduction pathway regulates anti‐inflammatory and antioxidant effects by regulating calcium ions, mitochondrial oxidative stress, autophagy, ferroptosis, pyroptosis and apoptosis. In this article, the role of the NRF2 signalling pathway in wound healing and its research progress in recent years are reviewed. In short, the NRF2 signalling pathway has crucial clinical significance in wound healing and is worthy of further study.

Thumb duplication is one of common anomalies of the hand. Among of Wassel type IV subtypes, type IV-D duplication with a zigzag deformity is most challenging for reconstructing. Several factors may affect the surgical outcomes. This study aimed to present an opening wedge osteotomy at proximal phalangeal neck for treating type IV-D duplication. Data from 14 patients are presented in this study. Eight patients had duplication of the right thumb, and six left thumb. After removal of radial supernumerary thumb, a snug collateral ligament was repaired to correct angular deformity of metacarpophalangeal joint (MCP). Angular deformity of the interphalangeal (IP) joint was corrected by an opening wedge osteotomy at the proximal phalangeal neck. A wedge bone from ablated thumb was grafted to correct the malalignment. IP joint was further stabilized by plication of the ulnar capsule. The relocation of radial part of FPL to the center of distal phalangeal base by use of pull-out suture technique RESULTS: After surgery, the angulations of the IP joints and the MCP joints were improved. Bone union was observed in all patients. According to the Japanese Society for Surgery of the Hand evaluation form, twelve cases were rated good, 2 cases fair. Stability of IP and MCP joints was good in all cases. The active ROM of IP was less in residual thumb than in normal thumb. Small nails were observed in some patients. Although the reconstructed thumbs were smaller than normal counterparts, they were aligned and with stable joints. The opening wedge osteotomy at proximal phalangeal neck could improve realignment of IP joint and prevent reoccurrence of deformity over time. Der Doppeldaumen zählt zu den häufigsten Anomalien der Hand. Von den Subtypen des Typs IV nach Wassel stellt die Duplikation vom Typ IV-D mit Zickzack-Deformität die größte Herausforderung an die Rekonstruktion dar. Mehrere Faktoren können die chirurgischen Ergebnisse beeinflussen. Ziel dieser Studie war es, eine Opening-Wedge-Osteotomie am Hals der proximalen Phalanx zur Behandlung der Duplikation vom Typ IV-D vorzustellen. In dieser Studie werden die Daten von 14 Patienten präsentiert. Bei acht Patienten war der rechte Daumen dupliziert, bei sechs Patienten der linke. Nach Entfernung des radialen überzähligen Daumens wurde zur Korrektur der Winkeldeformität des Metacarpophalangealgelenks (MCP) eine straffe Rekonstruktion des Seitenbandes durchgeführt. Die Winkeldeformität des Interphalangeal(IP)-Gelenks wurde durch eine Opening-Wedge-Osteotomie am Hals der proximalen Phalanx korrigiert. Zur Korrektur der Fehlstellung wurde ein Knochenkeil aus dem abladierten Daumen transplantiert. Das IP-Gelenk wurde durch Raffung der ulnaren Kapsel weiter stabilisiert. Mithilfe der „Pull-Out“-Nahttechnik wurde der radiale Anteil der Sehne des M. flexor pollicis longus zur Mitte der Basis der distalen Phalanx verlagert. Nach der Operation zeigte sich eine Verbesserung der Winkelstellung in den IP-Gelenken und den MCP-Gelenken. Bei allen Patienten wurde eine knöcherne Durchbauung erreicht. Gemäß dem Auswertebogen der Japanischen Gesellschaft für Handchirurgie wurden zwölf Fälle als „gut“ und zwei als „befriedigend“ eingestuft. Die Stabilität der IP- und MCP-Gelenke war bei allen Patienten gut. Der aktive Bewegungsumfang des IP-Gelenks war im verbleibenden Daumen geringer als bei normalen Daumen. Bei einigen Patienten fanden sich verkürzte Nägel. Obwohl die rekonstruierten Daumen kleiner waren als ihre normalen Pendants, zeigten sie eine regelrechte Ausrichtung und stabile Gelenke. Die Opening-Wedge-Osteotomie am Hals der proximalen Phalanx könnte die Neuausrichtung des IP-Gelenks verbessern und rezidivierende Deformitäten im weiteren Verlauf verhindern.

Background aims Tissue engineering technology is a promising therapeutic strategy in peripheral nerve injury. Schwann cells (SCs) are deemed to be a vital component of cell-based nerve regeneration therapies. Many methods for producing SC-like cells derived from adipose-derived stromal cells (ADSCs) have been explored, but their phenotypic and functional characteristics remain unsatisfactory. Methods We investigated whether human ADSCs can be induced to differentiate into mature and stable SC-like cells with the addition of insulin, progestero``ne and glucocorticoids. The phenotypic and functional characteristics of new differentiated ADSCs (modified SC-like cells) were evaluated by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunocytochemistry in vitro. Cells loaded into collagen sponge biomaterials were implanted around transected sciatic nerves with a 10-mm gap in vivo. The axon regrowth and functional recovery of the regenerated nerves were assessed by immunohistochemistry and Walking footprint analysis. Results After differentiation induction, the modified SC-like cells showed significantly up-regulated levels of S100B and P0 and enhanced proliferative and migratory capacities. In addition, the modified SC-like cells showed increased secretion of neurotrophic factors, and their functional characteristics were maintained for more than 3 weeks after removing the induction reagents. The modified SC-like cells exhibited significantly enhanced axon regrowth, myelination and functional recovery after sciatic nerve injury. Conclusions Overall, the results suggest that this modified induction method can induce human ADSCs to differentiate into cells with the molecular and functional properties of mature SCs and increase the promotion of peripheral nerve regeneration.

Diabetic peripheral neuropathy (DPN) is considered to be the most frequent neuropathic complication of diabetes, and severely affects the quality of life of patients. Long noncoding RNAs (lncRNAs) participate in various pathophysiological processes and associate with many diseases. However, the exact impact of lncRNAs on DPN remains obscure. To discover a potential connection, a microarray study was conducted to analyze the expression profiling of lncRNAs and messenger RNAs (mRNAs) in dorsal root ganglia (DRG) from streptozotocin-induced diabetic rats with DPN. As a result, 983 lncRNAs and 1357 mRNAs were aberrantly expressed compared with control samples. Using bioinformatics analyses, we identified 558 Gene Ontology terms and 94 Kyoto Encyclopedia of Genes and Genomes pathways to be significantly enriched. Additionally, the signal-net analysis indicated that integrin receptors, including Itgb3, Itgb1, Itgb8, and Itga6, might be important players in network regulation. Furthermore, the lncRNA-mRNA network analysis showed dynamic interactions between the dysregulated lncRNAs and mRNAs. This is the first study to present an overview of lncRNA and mRNA expressions in DRG tissues from DPN rats. Our results indicate that these differentially expressed lncRNAs may have crucial roles in pathological processes of DPN by regulating their coexpressed mRNAs. The data may provide novel targets for future studies, which should focus on validating their roles in the progression of DPN.

Smart nanomaterials constitute a new approach toward safer and more effective combined anti-cancer immunotherapy. In this study, polydopamine-multiprotein conjugates (DmPCs) that can be used for targeted delivery of multiple proteins to cells, realize imaging and combine the advantages of multiple treatment methods (photothermal therapy, chemodynamic therapy, and immunotherapy) can be synthesized and characterized. Proteins, as biological agents, are frequently used in this context, given their low toxicity in vivo. To overcome protein instability and short half-life in vivo, the use of several proteins in combination with selected nanomaterials to treat patients with melanoma is proposed. In addition to the synthesis and characterization of protein-bound nanoparticles, it is further demonstrated that several proteins can be efficiently delivered to tumor sites. DmPCs have a wide range of potential adaptability, which provides new opportunities for proteins in the field of treatment and imaging.

BackgroundMesenchymal stem cells including adipose stem cells (ASCs) have a huge potential in the field of translational medicine. Unfortunately, multiple factors including older age, co-existing diabetes and obesity may impair cellular function, which hinders the overall effectiveness of autologous stem cell therapy. Noncoding RNAs including microRNAs (miRNA), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) have been demonstrated to play an important role in stem cell biology. However, the whole expression pattern and interaction of these RNAs in ASCs related to diabetes and aging remain unknown.MethodEdU, transwell and β-galactosidase staining assays were performed to assess the proliferation, migration and senescence of ASCs isolated from diabetic (D-ASCs), old (O-ASCs), and young (Y-ASCs) donators. The abilities of these ASCs modulating endothelial cells and fibroblasts functions were evaluated by tube formation and wound scratch assays. We conducted high-throughput RNA sequencing (RNA-seq) in these ASCs to uncover the differentially expressed (DE) RNAs. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interactions (PPI) analyses were performed to interpret the mRNAs with significant differences. The lncRNAs or circRNAs associated competing endogenous RNA (ceRNA) networks were constructed based on the bioinformatic analyses and real-time polymerase chain reaction (RT-PCR) results. The miR-145-5p mimics were transfected into old ASCs and verified by PCR.ResultsASCs from diabetic and old donators showed inferior migration ability and increased cellular senescence. Besides, old ASCs have decreased capacities for promoting endothelial cells angiogenesis and fibroblasts migration comparing to young ASCs. The DE miRNAs, mRNAs, lncRNAs and circRNAs were successfully identified by RNA-seq in O-ASCs vs Y-ASCs and D-ASCs vs O-ASCs. GO and KEGG analyses demonstrated DE mRNAs were significantly enriched in aging and cell senescence terms separately. PPI networks performed critical DE mRNAs in above groups. MiRNAs with high fold change and low p value were validated by PCR. The four ceRNA networks were conducted based on the bioinformatic analyses and validated miRNAs. The selected mRNAs, lncRNAs and circRNAs in PPI and ceRNA networks were further evaluated by PCR. Then, the ceRNA subnetworks were constructed based on above validated RNAs. In addition, the lncRNA RAET1E-AS1 - miR-145-5p - WNT11/BMPER axis was selected and validated by the PCR and correlation analyses. Finally, overexpression of miR-145-5p could rejuvenate old ASCs phenotype and augment their abilities for modulating endothelial cells and fibroblasts functions.ConclusionTaken together, our research may provide new clues to unveil the underlying mechanisms of ASCs dysfunction, and disclose novel targets for restoring their therapeutic properties.

Background Mesenchymal stem cells including adipose-derived stem cells (ASCs) have a considerable potential in the field of translational medicine. Unfortunately, multiple factors (e.g., older age, co-existing diabetes, and obesity) may impair cellular function, which hinders the overall effectiveness of autologous stem cell therapy. Noncoding RNAs—including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs)—have been shown to play important roles in stem cell biology. However, the overall diabetes-related and aging-related expression patterns and interactions of these RNAs in ASCs remain unknown. Method The phenotypes and functions of ASCs isolated from diabetic (D-ASCs), old (O-ASCs), and young (Y-ASCs) donors were evaluated by in vitro assays. We conducted high-throughput RNA sequencing (RNA-seq) in these ASCs to identify the differentially expressed (DE) RNAs. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analyses were performed to investigate mRNAs with significant differences among groups. The lncRNA- or circRNA-associated competing endogenous RNA (ceRNA) networks were constructed based on bioinformatics analyses and real-time polymerase chain reaction (RT-PCR) results. The miR-145-5p mimics were transfected into O-ASCs and verified by PCR. Results ASCs from diabetic and old donors showed inferior migration ability and increased cellular senescence. Furthermore, O-ASCs have decreased capacities for promoting endothelial cell angiogenesis and fibroblast migration, compared with Y-ASCs. The DE miRNAs, mRNAs, lncRNAs, and circRNAs were successfully identified by RNA-seq in O-ASCs vs. Y-ASCs and D-ASCs vs. O-ASCs. GO and KEGG analyses demonstrated that DE mRNAs were significantly enriched in aging and cell senescence terms separately. PPI networks revealed critical DE mRNAs in the above groups. RNAs with high fold changes and low p values were validated by PCR. ceRNA networks were constructed based on bioinformatics analyses and validated RNAs. Additionally, the lncRNA RAET1E-AS1–miR-145-5p–WNT11/BMPER axis was validated by PCR and correlation analyses. Finally, the overexpression of miR-145-5p was found to rejuvenate O-ASCs phenotype and augment the functionality of these cells. Conclusion Our research may provide insights regarding the underlying mechanisms of ASC dysfunction; it may also offer novel targets for restoring therapeutic properties in ASCs.

Background Epidemiological and clinical features of patients with COVID‐19 have been reported, but none of them focused on medical staff, and few predictors of the duration of viral shedding have been reported. It is urgent to help healthcare workers prevent and recover quickly from the coronavirus disease 2019 (COVID‐19). Methods We enrolled 140 medical workers with COVID‐19 in Wuhan. Epidemiological, demographic, clinical, laboratory, radiological, treatment and clinical outcome data were collected, and predictors of the duration of viral shedding were explored through multivariable linear regression analysis. Results The medical staff with COVID‐19 presented mild clinical symptoms and showed a low frequency of abnormal laboratory indicators. All the medical staff were cured and discharged, of whom 96 (68.6%) were female, 39 (27.9%) had underlying diseases, the median age was 36.0 years, and 104 (74.3%) were infected whilst working in hospital. The median duration of viral shedding was 25.0 days (IQR:20.0–30.0). Multivariable linear regression analysis showed reducing viral shedding duration was associated with receiving recombinant human interferon alpha (rIFN‐α) treatment, whilst the prolonged duration of viral shedding correlated with the use of glucocorticoid treatment, the durations from the first symptom to hospital admission and the improvement in chest computed tomography (CT) evidence. Moreover, infected healthcare workers with lymphocytes less than 1.1 × 109/L on admission had prolonged viral shedding. Conclusion Medical staff with timely medical interventions shows milder clinical features. Glucocorticoid treatment and lymphocytes less than 1.1 × 109/L are associated with prolonged viral shedding. Early admission and rIFN‐α treatment help shorten the duration of viral shedding.

Aim We aim to study the anti-apoptotic effect of microRNA-21-5p (miR-21-5p) in the oxidative stress-induced apoptosis of Schwann cells and the relevant mechanism in this research, laying a foundation for the treatment of peripheral neuropathy (PNP). Methods and materials The oxidative stress model was established by using hydrogen peroxide (H2O2). ROS level were detected by DCFH-DA (2,7-Dichlorodi-hydrofluorescein diacetate). Western blot and fluorescence staining were used to detect the apoptosis and autophagy level. The miR-21-5p overexpression model was established by transfection of miR-21-5p mimics into RSC96 cells. Five groups of control group, H2O2 group, H2O2 + chloroquine (CQ) group, H2O2 + miR-21-5p mimics group, and H2O2 + miR-21-5p mimics+rapamycin (RAPA) group were included in our experiment. Key findings Compared with control group, miR-21-5p was decreased in H2O2-treated RSC96 cells, while autophagy and apoptosis were both promoted. The result revealed that apoptosis was probably triggered by activation of autophagy in H2O2-treated group. In order to verify the relationship between autophagy and apoptosis more accurately, we used CQ to inhibit autophagy. Compared with H2O2-treated group, autophagy and apoptosis were both weakened in H2O2 + CQ group. Subsequently, we found the antiapoptotic effect of miR-21-5p in this model, overexpression of miR-21-5p prevented cells from being damaged by oxidative stress, it induced the decrease of PTEN and the level of autophagy, leading to decreased level of apoptosis. Significance The identified relationship between miR-21-5p, apoptosis, and autophagy promotes us to find a new mechanism to improve the treatment for PNP.

Background Diabetes mellitus is a worldwide disease with high incidence. Diabetic peripheral neuropathy (DPN) is one of the most common but often ignored complications of diabetes mellitus that cause numbness and pain, even paralysis. Recent studies demonstrate that Schwann cells (SCs) in the peripheral nervous system play an essential role in the pathogenesis of DPN. Furthermore, various transcriptome analyses constructed by RNA-seq or microarray have provided a comprehensive understanding of molecular mechanisms and regulatory interaction networks involved in many diseases. However, the detailed mechanisms and competing endogenous RNA (ceRNA) network of SCs in DPN remain largely unknown. Methods Whole-transcriptome sequencing technology was applied to systematically analyze the differentially expressed mRNAs, lncRNAs and miRNAs in SCs from DPN rats and control rats. Gene ontology (GO) and KEGG pathway enrichment analyses were used to investigate the potential functions of the differentially expressed genes. Following this, lncRNA-mRNA co-expression network and ceRNA regulatory network were constructed by bioinformatics analysis methods. Results The results showed that 2925 mRNAs, 164 lncRNAs and 49 miRNAs were significantly differently expressed in SCs from DPN rats compared with control rats. 13 mRNAs, 7 lncRNAs and 7 miRNAs were validated by qRT-PCR and consistent with the RNA-seq data. Functional and pathway analyses revealed that many enriched biological processes of GO terms and pathways were highly correlated with the function of SCs and the pathogenesis of DPN. Furthermore, a global lncRNA-miRNA-mRNA ceRNA regulatory network in DPN model was constructed and miR-212-5p and the significantly correlated lncRNAs with high degree were identified as key mediators in the pathophysiological processes of SCs in DPN. These RNAs would contribute to the diagnosis and treatment of DPN. Conclusion Our study has shown that differentially expressed RNAs have complex interactions among them. They also play critical roles in regulating functions of SCs involved in the pathogenesis of DPN. The novel competitive endogenous RNA network provides new insight for exploring the underlying molecular mechanism of DPN and further investigation may have clinical application value.

Schwannoma, which is also known as neurilemmoma, is a type of tumor that arises from the peripheral nerve sheaths. Cases of schwannomas located in different regions have been reported. Some schwannomas present as asymptomatic masses, while others cause discomfort, such as pain and numbness. Magnetic resonance imaging (MRI) is a valuable diagnostic tool. A 23-year-old woman presented to our hospital with a mass in the left axilla that was misdiagnosed as mammae erraticae. The patient also considered the condition to be mammae erraticae for approximately 14 months because of a lack of symptoms. MRI was recommended by a surgeon from the galactophore department. A giant schwannoma was found. The mass was surgically excised, while preserving the continuity of the long thoracic nerve. Routine histopathological analysis confirmed the presence of a benign schwannoma. Schwannomas located in the axilla are rare and may be easily misdiagnosed as mammae erraticae or enlarged lymph nodes. Early investigation is necessary to make the diagnosis, and surgical excision is usually curative.

Neuroactive steroids such as progesterone, testosterone, and their derivatives have been widely studied for their neuroprotective roles in the nervous system. Autologous nerve transplantation is considered as the gold standard repair technique when primary suture is impossible; nevertheless, this method is far from ideal. In this study, we aimed to explore the impact of dihydrotestosterone (DHT), a 5α-reduced derivative of testosterone, on the recovery of peripheral nerve injury treated with autologous nerve transplantation. Sprague-Dawley rats were subjected to a 10-mm right side sciatic nerve reversed autologous nerve transplantation and randomly divided into groups that received DHT or DHT + flutamide (an androgen receptor blocker) daily for 8 weeks after operation. Our results demonstrated that DHT could speed up the rate of axonal regeneration and increase the expression of myelin protein zero (P0) in autograft reversal sciatic nerves. Thus, our study provided new insights into improving the prognosis of patients with long gap peripheral nerve defects.

Rationale: Peripheral nerve injury is common in clinic, which leads to severe atrophy and dysfunction of the denervated muscles, but the underlying mechanism is not fully understood. Recent studies advanced the causative role of mitochondrial dysfunction in muscle atrophy, while the upstream triggers remained unclear. Methods: In the present study, Atrophy of gastrocnemius and tibialis anterior (TA) were evaluated in mice sciatic nerve transection model. Transmission electron microscopy (TEM) was then used to observe the microstructure of atrophic gastrocnemius and mitochondria. Subsequently, small RNA sequencing, luciferase reporter assay and Electrophoretic Mobility Shift (EMSA) were performed to explore the potential signaling pathway involved in skeletal muscle atrophy. The effects of the corresponding pathway on mitochondrial function, mitophagy, apoptosis and muscle atrophy were further determined in C2C12 cells and denervated gastrocnemius. Results: Gastrocnemius and TA atrophied rapidly after denervation. Obvious decrease of mitochondria number and activation of mitophagy was further observed in atrophic gastrocnemius. Further, miR-142a-5p/ mitofusin-1 (MFN1) axis was confirmed to be activated in denervated gastrocnemius, which disrupted the tubular mitochondrial network, and induced mitochondrial dysfunction, mitophagy and apoptosis. Furthermore, the atrophy of gastrocnemius induced by denervation was relieved through targeting miR-142a-5p/MFN1 axis. Conclusions: Collectively, our data revealed that miR-142a-5p was able to function as an important regulator of denervation-induced skeletal muscle atrophy by inducing mitochondrial dysfunction, mitophagy, and apoptosis via targeting MFN1. Our findings provide new insights into the mechanism of skeletal muscle atrophy following denervation and propose a viable target for therapeutic intervention in individuals suffering from muscle atrophy after peripheral nerve injury.

Human adipose-derived stem cells (ASCs) have a potential for the treatment of peripheral nerve injury. Recent studies demonstrated that stem cells can mediate therapeutic effect by secreting exosomes. We aimed to investigate the effect of human ASCs derived exosomes (ASC-Exos) on peripheral nerve regeneration in vitro and in vivo. Our results showed after being internalized by Schwann cells (SCs), ASC-Exos significantly promoted SC proliferation, migration, myelination, and secretion of neurotrophic factors by upregulating corresponding genes in vitro. We next evaluated the efficacy of ASC-Exo therapy in a rat sciatic nerve transection model with a 10-mm gap. Axon regeneration, myelination, and restoration of denervation muscle atrophy in ASC-Exos treated group was significantly improved compared to vehicle control. This study demonstrates that ASC-Exos effectively promote peripheral nerve regeneration via optimizing SC function and thereby represent a novel therapeutic strategy for regenerative medicine and nerve tissue engineering.

Background Human adipose stem cells (ASCs) have emerged as a promising treatment paradigm for skin wounds. Recent works demonstrate that the therapeutic effect of stem cells is partially mediated by extracellular vesicles, which comprise exosomes and microvesicles. In this study, we investigate the regenerative effects of isolated microvesicles from ASCs and evaluate the mechanisms how ASC microvesicles promote wound healing. Methods Adipose stem cell-derived microvesicles (ASC-MVs) were isolated by differential ultracentrifugation, stained by PKH26, and characterized by electron microscopy and dynamic light scattering (DLS). We examined ASC-MV effects on proliferation, migration, and angiogenesis of keratinocytes, fibroblasts, and endothelial cells both in vitro and in vivo. Next, we explored the underlying mechanisms by gene expression analysis and the activation levels of AKT and ERK signaling pathways in all three kinds of cells after ASC-MV stimulation. We then assessed the effect of ASC-MVs on collagen deposition, neovascularization, and re-epithelialization in an in vivo skin injury model. Results ASC-MVs could be readily internalized by human umbilical vein endothelial cells (HUVECs), HaCAT, and fibroblasts and significantly promoted the proliferation, migration, and angiogenesis of these cells both in vitro and in vivo. The gene expression of proliferative markers (cyclin D1, cyclin D2, cyclin A1, cyclin A2) and growth factors (VEGFA, PDGFA, EGF, FGF2) was significantly upregulated after ASC-MV treatment. Importantly, ASC-MVs stimulated the activation of AKT and ERK signaling pathways in those cells. The local injection of ASC-MVs at wound sites significantly increased the re-epithelialization, collagen deposition, and neovascularization and led to accelerated wound closure. Conclusions Our data suggest that ASC-MVs can stimulate HUVEC, HaCAT, and fibroblast functions. ASC-MV therapy significantly accelerates wound healing, and the benefits of ASC-MVs may due to the involvement of AKT and ERK signaling pathways. This illustrates the therapeutic potential of ASC-MVs which may become a novel treatment paradigm for cutaneous wound healing. Electronic supplementary material The online version of this article (10.1186/s13287-019-1152-x) contains supplementary material, which is available to authorized users.

Table S1. Primers used for real-time polymerase chain reaction. (DOCX 14 kb)

Background Transforming growth factor beta 1 (TGF-β1) is a classical modulator of skeletal muscle and regulates several processes, such as myogenesis, regeneration and muscle function in skeletal muscle diseases. Skeletal muscle atrophy, characterized by the loss of muscle strength and mass, is one of the pathological conditions regulated by TGF-β1, but the underlying mechanism involved in the atrophic effects of TGF-β1 is not fully understood. Methods Mice sciatic nerve transection model was created and gastrocnemius were analysed by western blot, immunofluorescence staining and fibre diameter quantification after 2 weeks. Exogenous TGF-β1 was administrated and high-mobility group box-1 (HMGB1), autophagy were blocked by siRNA and chloroquine (CQ) respectively to explore the mechanism of the atrophic effect of TGF-β1 in denervated muscle. Similar methods were performed in C2C12 cells. Results We found that TGF-β1 was induced in denervated muscle and it could promote atrophy of skeletal muscle both in vivo and in vitro, up-regulated HMGB1 and increased autophagy activity were also detected in denervated muscle and were further promoted by exogenous TGF-β1. The atrophic effect of TGF-β1 could be inhibited when HMGB1/autophagy pathway was blocked. Conclusions Thus, our data revealed that TGF-β1 is a vital regulatory factor in denervated skeletal muscle in which HMGB1/ autophagy pathway mediates the atrophic effect of TGF-β1. Our findings confirmed a new pathway in denervation-induced skeletal muscle atrophy and it may be a novel therapeutic target for patients with muscle atrophy after peripheral nerve injury. Electronic supplementary material The online version of this article (10.1186/s12964-018-0310-6) contains supplementary material, which is available to authorized users.