Advances in meniscus tissue engineering: Towards bridging the gaps from bench to bedside.

Meniscus is vital for maintaining the anatomical and functional integrity of knee. Injuries to meniscus, commonly caused by trauma or degenerative processes, can result in knee joint dysfunction and secondary osteoarthritis, while current conservative and surgical interventions for meniscus injuries bear suboptimal outcomes. In the past decade, there has been a significant focus on advancing meniscus tissue engineering, encompassing isolated scaffold strategies, biological augmentation, physical stimulus, and meniscus organoids, to improve the prognosis of meniscus injuries. Despite noteworthy promising preclinical results, translational gaps and inconsistencies in the therapeutic efficiency between preclinical and clinical studies exist. This review comprehensively outlines the developments in meniscus tissue engineering over the past decade (Scheme 1). Reasons for the discordant results between preclinical and clinical trials, as well as potential strategies to expedite the translation of bench-to-bedside approaches are analyzed and discussed.

Intelligent response micelles with high andrographolide loading for the effective treatment of atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease which associated with a maladaptive immune response driven by macrophages. In the development of AS, macrophages have gradually become new therapeutic targets due to their involvement in numerous inflammatory-related pathological processes in AS. However, despite significant breakthroughs in the development of macrophages targeting nanocarriers, unsatisfactory drug loading, and inexact drug release limited the development of nano-therapy. Therefore, developing a high drug-loading nanocarrier that can accurately release drugs at AS lesions is quite essential. Herein, we optimized double moieties coupled mPEG-PLA copolymer micelles via phenylboronic acid (PBA)-terminated on the hydrophobic chain and cRGD coupled in hydrophilic chain to enhance AS therapy. The micelles loaded with andrographolide (AND) exhibited advanced drug loading capacity, as PBA could form a reversible boronic ester with AND at physiological pH. The cRGD-modified AND-loaded micelles (RPPPA) could be efficaciously internalized by macrophages and efficiently prevent macrophages from differentiating to foam cells. After intravenous administration, RPPPA could accumulate in plaques and exert therapeutic effects. The optimistic therapeutic results of atherosclerosis were shown in RPPPA, included the fewer plaques, a smaller necrotic core, a more stabilized fibrous cap, and lower macrophages and MMP-9, compared with the control group. To sum up, the proposed encouraging therapy can contribute to high drug loading, exact target, and precise drug release as well as reduce inflammation for AS treatment.

CT imaging-based nomogram for predicting early-stage glottic cancer recurrence following transoral laser microsurgery.

OBJECTIVE: To explore the differences between clinical features and computed tomography (CT) findings of early-stage glottic cancer (EGC) with or without recurrence after transoral laser microsurgery (TLM) and to establish a preoperative nomogram to predict postoperative recurrence. METHODS: The clinical and CT features of 168 consecutive patients with EGC with or without recurrence were analyzed retrospectively. Multivariate logistic regression analysis was used to determine the independent predictors of recurrence. A nomogram was constructed to preoperatively predict recurrence. To assess the nomogram's performance, the C-index and calibration plot were used. RESULTS: EGCs with and without recurrence differed significantly in T-stage, depth, and normalized CT values in the arterial phase (NCTAP) and venous phase (NCTVP) (all P < 0.05). T-stage, depth, and NCTVP were independent predictors of recurrence in EGCs (all P < 0.05). The C-index (0.765, 95% confidence interval: 0.703-0.827) and calibration plot showed that the nomogram has good prediction accuracy. Nomograms based on T-stage and CT variables provided numerically predicted recurrence rates and were better than those based on only T-stage (C-index of 0.765 vs. 0.608). CONCLUSIONS: Using clinical and CT variables, we developed a novel nomogram to predict the recurrence of EGC before TLM, which may be a potential noninvasive tool for guiding personalized treatment.

Interfacial Study of Steel Joints Prepared with a Catechol-Modified Epoxy Adhesive with Enhanced Bonding Performance and Durability.

Bonding is widely used in aircraft and vehicles due to its light weight and simple process, but its strength decreases sharply in hot and humid environments. Anodization treatment, used for enhancing aging performance, is environmentally harmful and unsuitable for steel. In this study, a catechol-modified epoxy adhesive (CMEA) was prepared on a hectogram scale. Comparative analysis with phenol-modified epoxy adhesive (PMEA) and pristine epoxy adhesive (EA) revealed that the underwater bonding of CMEA (13.0 MPa) on stainless steel (SS) significantly outperformed the two control groups. Moreover, after 32 days of hydrothermal aging at 50 °C, CMEA preserved 73.9% of its initial bonding strength, while PMEA and EA retained 59.8 and 11.4%, respectively. Furthermore, X-ray photoelectron spectroscopy (XPS) etching at different times to analyze the interface between adhesives and the SS substrate indicated a marked increase in the O-H/O2- value at the interface between CMEA and the SS substrate compared to the two control groups. The above results demonstrated that the catechol-modified adhesive enhanced the bonding and aging properties of the adhesive, possibly due to the formation of a higher density of hydroxyl groups at the interface between the adhesive and the SS substrate. These findings contribute to the understanding of the enhancement mechanism of catechol in improving the bonding and aging properties of adhesives and suggest a feasible direction for designing adhesives with high bonding strength and high durability.

Unveiling the regulatory mechanism of nimotuzumab on PD-L1 expression in head and neck squamous cell carcinoma patients: Implications for enhanced anticancer treatment strategies.

The overexpression of programmed death ligand 1 (PD-L1) is associated with resistance to anticancer therapies and poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Nimotuzumab, a humanized anti-epidermal growth factor receptor (EGFR) mAb, has been widely used clinically for treating several solid tumors. However, whether its anticancer effect involves a reduction in PD-L1 expression remains unclear. The current study aimed to investigate the regulatory effects and underlying mechanism of nimotuzumab on PD-L1 expression in HNSCC both in vitro and in vivo. In vitro, nimotuzumab inhibited IFN-γ-induced PD-L1 upregulation at both the transcriptional and protein levels in the HNSCC cell lines. Subsequent mechanism research revealed that nimotuzumab suppressed IFN-γ-stimulated PD-L1 upregulation mainly by inhibiting phosphorylation of EGFR/MEK/ERK pathway, which was further validated by MEK and ERK inhibitors. In a HNSCC tumor-bearing model, nimotuzumab significantly decreased PD-L1 expression during tumor progression or chemotherapy, and this reduction was accompanied by increased sensitivity of the tumor to docetaxel and atezolizumab. Additionally, nimotuzumab reversed PD-L1 upregulation when combined with Taxol + Cisplatin (TP) induction chemotherapy regimens and improved the CD4+ and CD8+ T cells infiltration in HNSCC patients. These findings provide new insights into the anticancer mechanisms of nimotuzumab in HNSCC.

Genetic etiology study in a large cohort with congenital insensitivity to pain with anhidrosis.

ABSTRACT: Pathogenic variations in the NTRK1 can cause congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive inherited neuropathy. The precise diagnosis of CIPA relies on the identification of pathogenic genotypes. Therefore, it is essential to expand the NTRK1 variation spectrum and improve molecular diagnosis methods. In this study, 74 probands with typical manifestations of CIPA but unknown genotypes were recruited. A comprehensive molecular genetic analysis was performed to identify variations in the NTRK1 , using techniques including Sanger and next-generation sequencing, bioinformatic analysis, quantitative polymerase chain reaction (qPCR), gap-PCR, short tandem repeat (STR) genotyping, and reverse-transcription PCR. In addition, functional assays were conducted to determine the pathogenicity of variants of uncertain significance (VUS) and further characterized changes in glycosylation and phosphorylation of 14 overexpressed mutant vectors with variants at different domains in the TrkA protein, which is encoded by NTRK1 . A total of 48 variations in the NTRK1 were identified, including 22 novel ones. When combined with data from another 53 CIPA patients examined in our previous work, this study establishes the largest genotypic and phenotypic spectra of CIPA worldwide, including 127 CIPA families. Moreover, functional studies indicated that the pathogenicity of VUS mainly affected insufficient glycosylation in the extracellular domain and abnormal phosphorylation in the intracellular domain. This study not only provides important evidence for precise diagnosis of CIPA but also further enriches our understanding of the pathogenesis of this disease.

Multiscale Synergistic Gecko-Inspired Adhesive for Stable Adhesion under Varying Preload and Surface Roughness.

Inspired by geckos, fibrillar microstructures hold great promise as controllable and reversible adhesives in the engineering field. However, enhancing the adhesion strength and stability of gecko-inspired adhesives (GIAs) under complex real-world contact conditions, such as rough surfaces and varying force fields, is crucial for its commercialization, yet further research is lacking. Here, we propose a hierarchically designed GIA, which features a silicone foam (SF) backing layer and a film-terminated fibrillar microstructure under a subtle multiscale design. This structure has been proven to have a "multiscale synergistic effect", allowing the material to maintain strong and stable adhesion to surfaces with changing normal pressures and roughness. Specifically, under a high load, the adhesive strength is 2 times more than that of conventional GIA, and it is 1.5 times stronger on rough surfaces compared to conventional GIA. Under high pressure and high surface roughness simultaneously, the adhesive strength is 3.3 times higher compared to conventional GIA. Our research demonstrates that the synergistic effect of multiscale biomimetic adhesion structures is highly effective in enhancing the adhesive strength of GIA under some harsh contact conditions.

First-in-human study on pharmacokinetics, safety, and tolerability of single and multiple escalating doses of PA9159 nasal spray, a highly potent glucocorticoid in healthy Chinese volunteers.

OBJECTIVE: PA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated. METHODS: This was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10-80 µg and 20-40 µg, respectively. PA9159 was administered bilaterally via nasal spray once only or once daily for seven days. Pharmacokinetic, safety, and tolerability profiles were evaluated. RESULTS: A total of 60 participants completed the study. PA9159 doses of up to 80 µg in the SAD and up to 40 µg in the MAD were shown to be safe and tolerable. The most common treatment-related AEs were mild and transient local nasal AEs. Morning serum cortisol levels approximately remained unchanged in both the single-dose and multiple-dose groups. PA9159 was quantified in 41.8 % (368/880) of the samples in all treatment groups, including 25.2 % (105/416) of the SAD and 56.7 % (263/464) of the MAD. The majority (>80.0 %) of PA9159 plasma concentrations ranged from 0.5 to 2 pg/mL in determined samples. The mean AUC0-t of PA9159 in the SAD was 0.91, 1.39±0.68, 11.40±9.91, and 46.30±25.80 h*pg/mL in the 10 to 80 ug single group. The mean terminal half-life time (t1/2) was 8.43 h and 8.97±2.28 h in 40 ug and 80 ug single group, respectively. The mean AUCss of PA9159 in the MAD was 31.70±7.04, 44.20±20.60 h*pg /mL, and the t1/2 was 16.00±4.18 h, 21.20±10.20 h in the 20 ug and 40 ug multiple groups, respectively. The median Tmax was approximately 6 h in both the SAD and MAD cohorts. CONCLUSIONS: The PA9159 nasal spray was generally safe and well tolerated, and the effects of PA9159 on serum cortisol levels were limited. The plasma concentration and systemic exposure to PA9159 were very low. These findings support the necessity for further clinical studies on PA9159 nasal spray in patients suffering from allergic rhinitis.

[Genetic analysis of a fetus with cryptophthalmos due to variants of FREM2 gene].

OBJECTIVE: To explore the genetic etiology of a fetus with cryptophthalmos detected by prenatal ultrasonography. METHODS: A fetus undergoing induced labor at 32nd gestational week due to absence of bilateral eye fissures detected by prenatal ultrasonography in January 2017 was selected as the study subject. Umbilical cord blood sample from the fetus and peripheral blood samples from its parents were collected for the extraction of genomic DNA. Pathogenic variants were screened through whole exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity of candidate variants was verified by bioinformatic analysis and protein structure simulation. Based on the results of genetic testing, prenatal diagnosis was provided to the couple upon their subsequent pregnancy. RESULTS: The couple had four adverse pregnancies previously. The aborted fetus was the fifth, with fused bilateral upper and lower eyelids, poorly developed eyeballs, adhesion of the cornea with the upper eyelid, low-set ears, and abnormal plantar creases, and was diagnosed with cryptophthalmos. WES and Sanger sequencing revealed that the fetus has harbored compound heterozygous variants of the FREM2 gene, namely c.4537G>A (p.D1513N) and c.7292C>T (p.T2431M). Both variants were unreported associated with cryptophthalmos previously. Protein structure simulation showed that they may lead to loss of hydrogen bonds in the protein product. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1_Supporting+PM2_Supporting+PM5+PP3+PP4; PM2_Supporting+PM3+PP3+PP4). The mother was performed prenatal diagnosis in her sixth pregnancy based on the variants detected in this family, and delivered a daughter with normal phenotype. CONCLUSION: The FREM2: c.4537G>A and c.7292C>T compound heterozygous variants probably underlay the pathogenesis of cryptophthalmos in this fetus. Above finding has enriched the mutational spectrum of the FREM2 gene.

Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial.

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).

The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice.

Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifth metacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) of HOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlying pathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed to generate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly and partial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes. Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limb development, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud at E10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibited notable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involved in various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopic expression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both the anterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascade ultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations in homozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may be responsible for the manifestation of human SDTY5.

A Method of Reducing Salt Content in Fermented Soy Sauce Improves Its Flavor and Quality.

Most commercially available soy sauce is fermented by high-salt liquid-state (HS) fermentation, which has an excessive salt content and a long fermentation period. In this study, a new salt-reduced fermentation (SR) soy sauce technology involving multiple strains of bacteria was developed to reduce consumers' salt intake. The SR soy sauce was found to have an amino acid nitrogen content of 8.40 g/L and over 80 kinds of flavor substances, which were significantly higher than those of low-salt solid-state fermented soy sauce and approximately equal to HS soy sauce. Compared with HS soy sauce, the salt content of the SR soy sauce was reduced by 59.2%, achieving the salt reduction goal. The proportion of umami amino acids in SR soy sauce reached 32.0% of the total level, enhancing SR soy sauce's quality. Hence, the new fermentation process can decrease salt content and shorten fermentation time.

A novel extraction-free dual HiFi-LAMP assay for detection of methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

Staphylococcus aureus (S. aureus) is a leading cause of bacteremia and blood stream infections. Methicillin-resistant S. aureus (MRSA) that first appeared in 1961 often caused hospital-acquired infections (HAIs) and community-acquired infections (CAIs) and was associated with high mortality rate. Accurate and rapid point-of-care testing (POCT) of MRSA is crucial for clinical management and treatment of MRSA infections, as well as the prevention and control of HAIs and CAIs. Here, we reported a novel extraction-free dual HiFi-LAMP assay for discriminative detection of methicillin-susceptible S. aureus and MRSA. The dual HiFi-LAMP assay can detect 30 copies/reaction of nuc and mecA genes with detection limits of 147 and 158 copies per 25 µL reaction, respectively. A retrospective clinical evaluation with 107 clinical S. aureus isolates showed both sensitivity and specificity of 100%. A prospective clinical evaluation with 35 clinical samples revealed a specificity of 100% and a sensitivity of 92.3%. The dual HiFi-LAMP assay can detect almost all S. aureus samples (141/142; 99.3%) within 20 min, implying that the entire HiFi-LAMP assay (including sample process) can be completed within 40 min, extremely significantly shorter than 3-5 days by the traditional clinical microbial culture and antibiotic susceptibility testing. The novel extraction-free dual HiFi-LAMP assay can be used as a robust POCT tool to promote precise diagnosis and treatment of MRSA infections in hospitals and to facilitate surveillance of MRSA at hospital and community settings.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA) was associated with high mortality rate and listed as a "priority pathogen" by the World Health Organization. Accurate and rapid point-of-care testing (POCT) of MRSA is critically required for clinical management and treatment of MRSA infections. Some previous LAMP-based POCT assays for MRSA might be questionable due to their low specificity and the lack of appropriate evaluation directly using clinical samples. Furthermore, they are relatively tedious and time-consuming because they require DNA extraction and lack multiplex detection capacity. Here, we reported a novel extraction-free dual HiFi-LAMP assay for discriminative detection of MRSA and methicillin-susceptible S. aureus. The assay has high specificity and sensitivity and can be completed within 40 min. Clinical evaluation with real clinical samples and clinical isolates showed excellent performance with 100% specificity and 92.3%-100% sensitivity. The novel extraction-free assay may be a robust POCT tool to promote precise diagnosis of MRSA infections and facilitate surveillance of MRSA at hospital and community settings.

[Generation of skin-derived iPSCs from an Osteogenesis imperfecta patient carrying WNT1c.677C>T mutation].

OBJECTIVE: To obtain skin-derived induced pluripotent stem cells (iPSCs) from an Osteogenesis imperfecta (OI) patient carrying WNT1c.677C>T mutation in order to provide a new cell model for investigating the underlying molecular mechanism and stem cell therapy for OI. METHODS: The pathogenic variant of the patient was identified by Sanger sequencing. With informed consent from the patient, skin tissue was biopsied, and primary skin fibroblasts were cultured. Skin fibroblasts were induced into iPSCs using Sendai virus-mediated non-genomic integration reprogramming method. The iPSC cell lines were characterized for pluripotency, differentiation capacity, and karyotyping assay. RESULTS: The patient was found to carry homozygous missense c.677C>T (p.Ser226Leu) mutation of the WNT1 gene. The established iPSC lines possessed self-renewal and capacity for in vitro differentiation. It also has a diploid karyotype (46,XX). CONCLUSION: A patient-specific WNT1 gene mutation (WNT1c.677C>T) iPSC line was established, which can provide a cell model for the study of OI caused by the mutation.

Celastrol-loaded bovine serum albumin nanoparticles target inflamed neutrophils for improved rheumatoid arthritis therapy.

Inflammatory neutrophils (INEs), motivated by cytokines, continue to migrate into the inflamed joints, driving the development of RA. Hence, inducing apoptosis of INEs to reduce recruitment at inflamed joints is an effective strategy for the treatment of RA. However, simply apoptotic INEs may trigger the release of neutrophil extracellular traps (NETs) and accelerate the inflammatory process. To overcome these drawbacks, an RGD-modified bovine serum albumin (BSA) nanoparticles (CBR NPs) was fabricated to selectively target INEs in situ for intracellular delivery of CLT. Studies have demonstrated that CBR NPs can selectively target circulating INEs and induce INEs apoptosis. Meanwhile, CBR NPs inhibited the activation of NETs via NF-κB pathway and the release of Cit-H3 thereby blocking the release process of NETs. In collagen-induced arthritis (CIA) mouse model, CBR NPs suppressed the inflammatory response, and reduced the toxic effects of CLT. In summary, this study shed light on an innovative approach to treat RA by inducing apoptosis of circulating INEs and inhibiting NETs. STATEMENT OF SIGNIFICANCE: RGD-modified bovine serum albumin (BSA) nanoparticles for delivering celastrol, abbreviated as CBR NPs, were constructed to inhibit the infiltration of circulating inflammatory neutrophils (INEs) into inflamed joints while inhibiting the release of NETs to alleviate tissue damage. CBR NPs were prepared for the first time to induce apoptosis of INEs; CBR NPs could inhibit the release of NETs while inducing apoptosis of INEs in vivo and vitro cellular experiments; CBR NPs had favorable anti-inflammatory effects and low toxicity side-effects in collagen-induced arthritis (CIA) mouse models. The application of nanotechnology to induce apoptosis of INEs while inhibiting the release of NETs was a promising approach for the treatment of RA.

Cognitive flexibility and entrepreneurial creativity: the chain mediating effect of entrepreneurial alertness and entrepreneurial self-efficacy.

Entrepreneurial creativity is an important part of entrepreneurs' competency structure, and studies have been conducted to explore its impact on outcome variables like entrepreneurial performance, etc., but there are fewer studies on its antecedent variables at the individual level. In the relational model of entrepreneurial creativity, cognitive flexibility, entrepreneurial alertness, and entrepreneurial self-efficacy are included to construct a mediated use spss26.0 model, and data are collected from a research sample of 325 entrepreneurs for empirical analysis. The results indicate that: cognitive flexibility has a positive effect on entrepreneurial creativity; entrepreneurial alertness plays an independent mediating role between cognitive flexibility and entrepreneurial creativity, which is similar to how entrepreneurial self-efficacy plays the role between cognitive flexibility and creativity; entrepreneurial alertness and entrepreneurial self-efficacy then play a chain mediating role between cognitive flexibility and creativity. These findings reveal that three variables jointly influence entrepreneurial creativity, providing new theoretical and practical insights for understanding and enhancing entrepreneurial creativity. In addition, the study provides valuable guidance for entrepreneurship education and training, which can help entrepreneurs to better utilize their creativity and thus promote innovation and success in entrepreneurial activities.

Coffee Leaf Tea Extracts Improve Hyperuricemia Nephropathy and Its Associated Negative Effect in Gut Microbiota and Amino Acid Metabolism in Rats.

Hyperuricemia nephropathy (HN) is a metabolic disease characterized by tubular damage, tubulointerstitial fibrosis, and uric acid kidney stones and has been demonstrated to be associated with hyperuricemia. Coffee leaf tea is drunk as a functional beverage. However, its prevention effects on HN remain to be explored. This study showed that coffee leaf tea extracts (TE) contain 19 polyphenols, with a total content of 550.15 ± 27.58 mg GAE/g. TE decreased serum uric acid levels via inhibiting XOD activities and modulating the expression of urate transporters (GLUT9, OAT3, and ABCG2) in HN rats. TE prevented HN-induced liver and kidney damage and attenuated renal fibrosis. Moreover, it upregulated the abundance of SCFA-producing bacteria (Phascolarctobacterium, Alloprevotella, and Butyricicoccus) in the gut and reversed the amino acid-related metabolism disorder caused by HN. TE also decreased the circulating LPS and d-lactate levels and increased the fecal SCFA levels. This study supported the preliminary and indicative effect of coffee leaf tea in the prevention of hyperuricemia and HN.

Enhanced soy sauce stability and reduced precipitation by improving critical steps in the fermentation process.

Conventional high-salt dilute-state soy sauce is vulnerable to precipitation after processing, which will reduce the systemic stability and nutrition of soy sauce. This work aims to optimize key steps of the soy sauce fermentation process to improve its stability and reduce precipitation. The amino acid nitrogen (AAN) and the total nitrogen (TN) contents of the new soy sauce were 8.3 g/L and 18.7 g/L, which were significantly enhanced by 33.9% and 14.0%, respectively, compared to the control group. More flavor substances were detected in the new soy sauce, including furans and pyrazines, which contribute to the special flavor of soy sauce. The particle size distribution curve was significantly shifted to the left, and the absolute value of zeta-potential increased. The new fermentation process soy sauce had a higher raw material utilization rate, smaller average particle size of 15.56 µm, and significantly higher stability when combined with the rheological examination. Consequently, the quality and flavor of soy sauce can be improved by using the new fermentation process.

pH-Responsive Injectable Multifunctional Pluronic F127/Gelatin-Based Hydrogels with Hydrogen Production for Treating Diabetic Wounds.

Diabetic chronic wounds remain a major clinical challenge with long-term inflammatory responses and extreme oxidative damage. Hence, a pH-responsive injectable multifunctional hydrogel [Gel/CUR-FCHO/Mg (GCM) micromotors] via a Schiff base reaction between gelatin and benzaldehyde-grafted Pluronic F127 drug-loaded micelles (FCHO) was fabricated for the first time. Dynamic Schiff base linkage endowed the GCM hydrogel with the ability to be self-healing, injectable, and pH-responsive for on-demand drug delivery at the wound site. Curcumin (CUR), a hydrophobic drug with antioxidative, anti-inflammatory, and antibacterial activities, was encapsulated into the hydrogel matrix by micellization (CUR-FCHO micelles). Simultaneously, magnesium-based micromotors (Mg micromotors) were physically entrapped into the system for providing active hydrogen (H2) to scavenge reactive oxygen species and alleviate inflammatory responses. As a result, the GCM micromotor hydrogel displayed an inherent antibacterial property, extraordinary antioxidative performance, and remarkable biocompatibility. In the diabetic mouse with a full-thickness cutaneous defect wound, the GCM hydrogel could remodel the inflammatory microenvironment and stimulate vascularization and collagen deposition, thereby facilitating wound closure and enhancing tissue regeneration, which offered a promising therapeutic option for diabetic chronic wound management.

An SS31-rapamycin conjugate via RBC hitchhiking for reversing acute kidney injury.

Mitochondrial dysfunction plays a major role in driving acute kidney injury (AKI) via alteration in energy and oxygen supply, which creates further ROS and inflammatory responses. However, mitochondrial targeting medicine in recovering AKI is challenging. Herein, we conjugated SS31, a mitochondria-targeted antioxidant tetrapeptide connecting a cleavable linker to rapamycin (Rapa), which provided specific interaction with FK506-binding protein (FKBP) in the RBCs. Once entering the bloodstream, SS31-Rapa could be directed to the intracellular space of RBCs, allowing the slow diffusion of the conjugate to tissues via the concentration gradient. The new RBC hitchhiking strategy enables the encapsulation of conjugate into RBC via a less traumatic and more natural and permissive manner, resulting in prolonging the t1/2 of SS31 by 6.9 folds. SS31-Rapa underwent the direct cellular uptake, instead of the lysosomal pathway, released SS31 in response to activated caspase-3 stimulation in apoptotic cells, favoring the mitochondrial accumulation of SS31. Combined with autophagy induction associated with Rapa, a single dose of SS31-Rapa can effectively reverse cisplatin and ischemia reperfusion-induced AKI. This work thus highlights a simple and effective RBC hitchhiking strategy and a clinically translatable platform technology to improve the outcome of other mitochondrial dysfunctional related diseases.