Abnormal metabolism in melanocytes participates in the activation of dendritic cell in halo nevus.

A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.

[Acupuncture combined with tuina therapy for stiff neck with levator scapula injury type: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of acupuncture combined with tuina therapy for stiff neck with levator scapula injury type. METHODS: A total of 162 patients with stiff neck of levator scapula injury type were randomly divided into an acupuncture combined with tuina group (combined group, 52 patients), a tuina group (55 patients), and an acupuncture group (55 patients). The patients in the acupuncture group received acupuncture on the affected side's Houxi (SI 3), inserting the needle 10 to 20 mm towards Laogong (PC 8) with strong or moderate stimulation, and patients were instructed to move their neck, shoulders, and upper limbs during the process, with the needle retained for 2 to 3 min. The patients in the tuina group received strong stimulation pressing on tender points to release the starting and ending points of the trapezius muscle with modified techniques. The combined group first received tuina therapy, followed immediately by acupuncture treatment at the Houxi (SI 3). Treatments were administered every other day for a total of three sessions. Before treatment and on 1, 3, and 7 days after treatment, the simple McGill pain questionnaire (SF-MPQ) scores [including the pain rating index (PRI), visual analogue scale (VAS), and present pain intensity (PPI) scores] of the head, neck and shoulder, cervical spine mobility scores were observed, and the clinical efficacy and safety of each group were evaluated. RESULTS: On the 1, 3, and 7 days after treatment, the SF-MPQ, PRI, VAS, and PPI scores of the head, neck, and shoulder in all groups were significantly reduced (P<0.01). On the 1 and 3 days after treatment, the above scores in the combined group were lower than those in the tuina group and the acupuncture group (P<0.05, P<0.01). On the 7 days after treatment, the above scores in the combined group were lower than those in the acupuncture group (P<0.01). On the 3 days after treatment, the SF-MPQ, PRI, and VAS scores in the tuina group were lower than those in the acupuncture group (P<0.01). On the 7 days after treatment, the SF-MPQ, PRI, VAS, and PPI scores in the tuina group were lower than those in the acupuncture group (P<0.01, P<0.05). On the 1, 3, and 7 days after treatment, the cervical spine mobility scores in each group were decreased compared to those before treatment (P<0.01). On the 3 days after treatment, the cervical spine mobility score in the combined group was lower than that in the acupuncture group and the tuina group (P<0.01). On the 1, 3, and 7 days after treatment, the cured rate in the combined group was higher than that in the tuina group and the acupuncture group (P<0.01). During the treatment period, no serious adverse reactions occurred in any group. CONCLUSION: Acupuncture combined with tuina therapy could effectively improve stiff neck with levator scapula injury type, alleviate patient pain, restore cervical spine mobility, and clinically outperform both tuina and acupuncture therapy alone.

Stem cell-derived extracellular vesicles in the therapeutic intervention of Alzheimer's Disease, Parkinson's Disease, and stroke.

With the increase in the aging population, the occurrence of neurological disorders is rising. Recently, stem cell therapy has garnered attention due to its convenient sourcing, minimal invasiveness, and capacity for directed differentiation. However, there are some disadvantages, such as poor quality control, safety assessments, and ethical and logistical issues. Consequently, scientists have started to shift their attention from stem cells to extracellular vesicles due to their similar structures and properties. Beyond these parallels, extracellular vesicles can enhance biocompatibility, facilitate easy traversal of barriers, and minimize side effects. Furthermore, stem cell-derived extracellular vesicles can be engineered to load drugs and modify surfaces to enhance treatment outcomes. In this review, we summarize the functions of native stem cell-derived extracellular vesicles, subsequently review the strategies for the engineering of stem cell-derived extracellular vesicles and their applications in Alzheimer's disease, Parkinson's disease, and stroke, and discuss the challenges and solutions associated with the clinical translation of stem cell-derived extracellular vesicles.

[Live biotherapeutic products: the forefront of innovative drug development driven by biotechnology].

As human microbiome research advances, a large body of evidence shows that microorganisms are closely related to human health. Probiotics were discovered and used as foods or dietary supplements with health benefits in the last century. Microorganisms have shown broader application prospects in human health since the turn of the century, owing to the rapid development of technologies such as microbiome analysis, DNA synthesis and sequencing, and gene editing. In recent years, the concept of "next-generation probiotics" has been proposed as new drugs, and microorganisms are considered as "live biotherapeutic products (LBP)". In a nutshell, LBP is a living bacterial drug that can be used to prevent or treat certain human diseases and indications. Because of its distinct advantages, LBP has risen to the forefront of drug development research and has very broad development prospects. This review introduces the varieties and research advances on LBP from a biotechnology standpoint, followed by summarizing the challenges and opportunities for LBP clinical implementations, with the aim to facilitate LBP development.

LncRNA UCA1 promotes keratinocyte-driven inflammation via suppressing METTL14 and activating the HIF-1α/NF-κB axis in psoriasis.

Keratinocytes are closely associated with innate immunity and inflammatory responses, and are dysregulated during the development of psoriasis, but the underlying mechanisms are not yet fully understood. This work aims to reveal the effects of long non-coding RNA (lncRNA) UCA1 in psoriatic keratinocytes. UCA1 was identified as a psoriasis-related lncRNA that highly expressed in psoriatic lesions. The transcriptome and proteome data of keratinocyte cell line HaCaT showed that UCA1 could positively regulate inflammatory functions, such as response to cytokine. Furthermore, UCA1 silencing decreased inflammatory cytokine secretion and innate immunity gene expression in HaCaT, its culture supernatant also decreased the migration and tube formation ability of vascular endothelial cells (HUVECs). Mechanistically, UCA1 activated the NF-κB signaling pathway, which is regulated by HIF-1α and STAT3. We also observed a direct interaction between UCA1 and N6-methyladenosine (m6A) methyltransferase METTL14. Knocking down METTL14 counteracted the effects of UCA1 silencing, indicating that it can suppress inflammation. In addition, the levels of m6A-modified HIF-1α were decreased in psoriatic lesions, indicating that HIF-1α is a potential target of METTL14. Taken together, this work indicates that UCA1 positively regulates keratinocyte-driven inflammation and psoriasis development by binding to METTL14, and activating HIF-1α and NF-κB signaling pathway. Our findings provide new insights into the molecular mechanisms of keratinocyte-driven inflammation in psoriasis.

Crosstalk between G-quadruplex and ROS.

The excessive production of reactive oxygen species (ROS) can lead to single nucleic acid base damage, DNA strand breakage, inter- and intra-strand cross-linking of nucleic acids, and protein-DNA cross-linking involved in the pathogenesis of cancer, neurodegenerative diseases, and aging. G-quadruplex (G4) is a stacked nucleic acid structure that is ubiquitous across regulatory regions of multiple genes. Abnormal formation and destruction of G4s due to multiple factors, including cations, helicases, transcription factors (TFs), G4-binding proteins, and epigenetic modifications, affect gene replication, transcription, translation, and epigenetic regulation. Due to the lower redox potential of G-rich sequences and unique structural characteristics, G4s are highly susceptible to oxidative damage. Additionally, the formation, stability, and biological regulatory role of G4s are affected by ROS. G4s are involved in regulating gene transcription, translation, and telomere length maintenance, and are therefore key players in age-related degeneration. Furthermore, G4s also mediate the antioxidant process by forming stress granules and activating Nrf2, which is suggestive of their involvement in developing ROS-related diseases. In this review, we have summarized the crosstalk between ROS and G4s, and the possible regulatory mechanisms through which G4s play roles in aging and age-related diseases.

Opportunities and challenges for synthetic biology in the therapy of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a complex, chronic intestinal inflammatory disorder that primarily includes Crohn's disease (CD) and ulcerative colitis (UC). Although traditional antibiotics and immunosuppressants are known as the most effective and commonly used treatments, some limitations may be expected, such as limited efficacy in a small number of patients and gut flora disruption. A great many research studies have been done with respect to the etiology of IBD, while the composition of the gut microbiota is suggested as one of the most influential factors. Along with the development of synthetic biology and the continuing clarification of IBD etiology, broader prospects for novel approaches to IBD therapy could be obtained. This study presents an overview of the currently existing treatment options and possible therapeutic targets at the preclinical stage with respect to microbial synthesis technology in biological therapy. This study is highly correlated to the following topics: microbiota-derived metabolites, microRNAs, cell therapy, calreticulin, live biotherapeutic products (LBP), fecal microbiota transplantation (FMT), bacteriophages, engineered bacteria, and their functional secreted synthetic products for IBD medical implementation. Considering microorganisms as the main therapeutic component, as a result, the related clinical trial stability, effectiveness, and safety analysis may be the major challenges for upcoming research. This article strives to provide pharmaceutical researchers and developers with the most up-to-date information for adjuvant medicinal therapies based on synthetic biology.

In vitro-in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans.

New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro-in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose-response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.

The Current Status of Antioxidants in the Treatment of Vitiligo in China.

Little is known about the use of antioxidants in the clinical treatment of vitiligo. To investigate the specific use of antioxidants in the treatment of vitiligo and the possible reasons behind its use in China, we conducted a prospective questionnaire-based study using an online questionnaire comprising 26 questions in 5 areas. A total of 323 clinical frontline dermatologists participated in this study. Differences among groups were compared using Pearson's chi-square test. Ordinal logistic regression was used to develop knowledge-use multiple regression models. Among the 323 dermatologists, 293 (90.7%) approved the oxidative stress theory of vitiligo, and 182 (56.3%) encouraged the use of antioxidants for treating vitiligo; nonetheless, only 11.8% frequently treated vitiligo with antioxidants. Insufficient knowledge of antioxidants was a significant predictor of lower frequency of antioxidant usage (adjusted odds ratio, 0.401 [95% confidence interval, 0.256-0.629]; P < .001). The predictors associated with higher antioxidant efficacy included advanced or rapid progression, moderate or moderate-to-severe vitiligo, age of 0-2 years or 13-18 years, segmental vitiligo, oral and topical combination therapy, and course duration of <1 month. The use of antioxidants for treating vitiligo is highly encouraged; however, the rates of their clinical use are considerably low. Insufficient knowledge of antioxidants is associated with a lower frequency of antioxidant usage. The synergistic curative efficacy of antioxidants could be affected by the stage, type, severity, age of patients with vitiligo, and method of using antioxidants.