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Abstract Non-coding RNAs (ncRNAs), including circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), are unique RNA molecules widely identified in the eukaryotic genome. Their dysregulation has been discovered and played key roles in the pathogenesis of numerous diseases, including various cancers. Previously considered devoid of protein-coding ability, recent research has revealed that a small number of open reading frames (ORFs) within these ncRNAs endow them with the potential for protein coding. These ncRNAs-derived peptides or proteins have been proven to regulate various physiological and pathological processes through diverse mechanisms. Their emerging roles in disease diagnosis and targeted therapy underscore their potential utility in clinical settings. This comprehensive review aims to provide a systematic overview of proteins or peptides encoded by lncRNAs and circRNAs, elucidate their production and functional mechanisms, and explore their promising applications in cancer diagnosis, disease prediction, and targeted therapy.

Fractures and bone nonunion commonly require surgical intervention. Serious outcomes of non‐healing in the late stages of fracture place a significant financial burden on society and families. Bone nonunion occurs when a fracture stops healing, for many reasons, and leads to a variety of bad outcomes. Numerous factors, including biomechanics and immunology, are involved in the complicated mechanisms of bone nonunion. The immune‐inflammatory response plays a significant part in the emergence of bone nonunion, and the occurrence, control, and remission of inflammation in the bone healing process have a significant influence on the ultimate success of bone tissue repair. In the bone microenvironment, immune cells and associated cytokines control bone repair, which is significantly influenced by macrophages, T cells, and fibroblast growth factor. To limit acute inflammation and balance osteogenesis and osteoblastogenesis for tissue repair and regeneration, immune cells and various cytokines in the local microenvironment must be precisely regulated. As a bad complication of late‐stage fractures, bone nonunion has a significant effect on patients’ quality of life and socioeconomic development. Therefore, in‐depth research on its pathogenesis and treatment methods has important clinical value. To provide more precise, focused therapeutic options for the treatment of bone nonunion, we discuss the regulatory roles of the key immune cells engaged in bone healing within the microenvironment during bone healing and their effect on osteogenesis.

Abstract Intervertebral disc degeneration (IVDD) stands as a prevalent chronic orthopedic ailment, profoundly impacting patients' well‐being due to incapacitating low back pain. Studies have highlighted a close correlation between IVDD and the programmed cell death of nucleus pulposus (NP) cells orchestrated by interleukin‐1 beta (IL‐1β), tumor necrosis factor‐alpha (TNF‐α), and caspase‐3 (CASP3). Puerarin, renowned for its anti‐inflammatory attributes and its influence on IL‐1β and TNF‐α, emerges as a promising candidate for IVDD treatment. However, the precise mechanism by which it regulates apoptosis via these pathways remains ambiguous. This investigation utilizes bioinformatics to unveil the molecular intricacies of puerarin‐mediated apoptosis regulation in IVDD, substantiated by preliminary in vitro experiments. Analysis exposes aberrant expression of pivotal apoptosis‐associated proteins (IL‐1β, TNF‐α, CASP3, CASP8, and BCL2) in IVDD patients, with network pharmacology indicating puerarin's potential efficacy in IVDD treatment by modulating apoptosis and cellular senescence pathways. Further experiments elucidate puerarin's capacity to stimulate NP cell proliferation while inhibiting apoptosis, potentially contributing to IVDD mitigation. Western blot and PCR outcomes reveal escalated expression of apoptosis‐related proteins (IL‐1β, TNF‐α, and CASP3) in lipopolysaccharide‐treated NPCs, ameliorated by puerarin intervention. Molecular docking simulations demonstrate favorable binding properties of puerarin with apoptotic proteins, while flow cytometry analysis indicates its ability to diminish NPC apoptosis. These discoveries imply that puerarin might alleviate NPC apoptosis by modulating key targets, thereby potentially ameliorating IVDD. In summary, this study unveils the intrinsic mechanism of puerarin in regulating NPC apoptosis to alleviate IVDD, underscoring its therapeutic promise.

Abstract Introduction Neck pain constitutes a prevalent and burdensome health issue, substantially impairing patients’ quality of life and functional capabilities. Kinesio taping (KT), a commonly employed intervention within physical therapy, holds promise for mitigating such symptoms; however, a comprehensive evaluation of its efficacy and evidence base is lacking. Therefore, this study endeavors to systematically investigate the therapeutic effects of KT on both subjective neck pain intensity and objective measures of physical activity limitations through a rigorous meta-analytic approach. By synthesizing existing literature and scrutinizing methodological nuances, we aim to furnish healthcare practitioners with evidence-informed insights, facilitating more judicious clinical decision-making and optimizing patient outcomes. Methods According to the PRISMA guidelines, we conducted searches on PubMed, Cochrane Library, Embase, and Web of Science for randomized controlled trials (RCTs) investigating the efficacy of KT in treating neck pain. Screening was performed based on predefined inclusion and exclusion criteria. Characteristics of the included RCTs were extracted. Trial heterogeneity was assessed using the I 2 statistic. Meta-analysis was conducted using Stata 17 software. Risk of bias and methodological quality were evaluated using the Cochrane Risk of Bias 2 tool and the PEDro scale, respectively. Results In our analysis of 10 RCTs involving 620 patients meeting our inclusion criteria, KT demonstrated significant beneficial effects on neck pain, notably surpassing conventional treatment (weighted mean difference = −0.897, 95% CI −1.30 to −0.49, P

Objective The talus is an important component in the ankle, and its treatment after injury is crucial. However, complications and adverse events due to incomplete traditional classifications may still occur, and these classifications fail to analyze the patterns and distribution of fractures from a three‐dimensional perspective. Therefore, in this study, we aimed to analyze the location and distribution of fracture lines in different types of talus fractures using three‐dimensional (3D) and heat mapping techniques. Additionally, we aimed to determine the surface area of the talus that can be utilized for different approaches of internal fixation, aiding in the planning of surgical procedures. Methods We retrospectively analyzed data from CT scans from 126 patients diagnosed with talus fractures at our two hospitals. We extracted the CT data of a healthy adult and created a standard talus model. We performed 3D reconstruction using patients' CT images and superimposed the fracture model onto the standard model for drawing fracture lines. Subsequently, we converted the fracture lines into a heat map for visualization. Additionally, we measured 20 specimens to determine the boundary for various ligaments attached to the talus. We determined the surface area of the talus available for different surgical approaches by integrating the boundary data with previously reported data on area of exposure. Results Without considering the displacement distance of the fracture, fracture types were classified as follows, by combining Hawkins and Sneppen classifications: talar neck, 41.3%; posterior talar tubercle, 22.2%; body for the talus and comminuted, 17.5%; lateral talar tubercle, 11.9%; and talar head, 7.1%. We established fracture line and heat maps using this classification. Additionally, we demonstrated the available area for anteromedial, anterolateral, posteromedial, posterolateral, and medial malleolus osteotomy and Chaput osteotomy approaches. Conclusion Fracture line and heat map analyses can aid surgeons in planning a single or combined surgical approach for the reduction and internal fixation of talus fractures. Demonstrating the different surgical approaches can help surgeons choose the most effective technique for individual cases.

Abstract AMP-activated protein kinase (AMPK) is a ubiquitous sensor of energy and nutritional status in eukaryotic cells. It plays a key role in regulating cellular energy homeostasis and multiple aspects of cell metabolism. During macrophage polarisation, AMPK not only guides the metabolic programming of macrophages, but also counter-regulates the inflammatory function of macrophages and promotes their polarisation toward the anti-inflammatory phenotype. AMPK is located at the intersection of macrophage metabolism and inflammation. The metabolic characteristics of macrophages are closely related to immune-related diseases, infectious diseases, cancer progression and immunotherapy. This review discusses the structure of AMPK and its role in the metabolism, function and polarisation of macrophages. In addition, it summarises the important role of the AMPK pathway and AMPK activators in the development of macrophage-related diseases.

Objectives The role of the distal tibiofibular ligament in the occurrence of high ankle sprain (HAS) has been widely studied. But previous studies have overlooked the physiological and anatomical differences between males and females and have not further refined gender. Therefore, the impact of the anatomical morphology of fibular notch (FN) on HAS in different genders is still unclear. This study aimed to explore the impact of different types of FN on the severity of HAS and to estimate the prognosis of patients with HAS while excluding anatomical differences caused by gender. Methods One hundred and eighty patients with HAS were included in this study as the experimental group (i.e., HAS group). They were further divided into four groups according to gender and FN depth, with deep concave FN ≥ 4 mm and shallow flat FN

Abstract Background Syndesmosis injury is proposed to contribute to ankle stability and osteoarthritis (OA). However, whether distal tibiofibular syndesmosis structure is closely related to ankle OA is unclear. We hypothesized that different DTS morphology classifications would affect the biomechanics properties in ankle OA. The study aimed to determine the association between the distal tibiofibular syndesmosis (DTS) morphological classification and ankle OA. Methods This is a retrospective study examining imaging data of 147 patients (87 males and 60 females) with ankle OA. Magnetic resonance imaging was used to access the DTS morphological classification, according to measuring various parameters. Joint space narrowing and osteophytes were measured using ankle weight-bearing radiography. The classification and parameters were analyzed to determine the relationship between the syndesmosis classification and the abnormality of ankle OA. Results Five morphological classifications of the DTS, including Chevron (19.6%), Widow’s peak (16.2%), Flat (22.3%), Trapezoid (32.0%), and Crescent (19.6%), were shown. There were statistical differences between DTS classification and tibial angle surface angle (TAS) (P = .009) and talar tilt angle (TTA) (P = .014). The TAS (degree) of the Crescent (86.47 ± 3.21) was less than Chevron (88.75 ± 2.72) (P = .006), Widow’s peak (89.26 ± 3.15) (P = .001), Flat (88.83 ± 3.62) (P = .003) and Trapezoid (88.11 ± 2.62) (P = .041), respectively. The TTA (degree) of Crescent (86.83 ± 5.30) was less than Chevron (89.28 ± 2.46) and Widow’s peak (89.82 ± 3.41). The men were greater than women for TAS (P = .008) and angle (P = .003), which are consistent with osteophyte (P = .019) and the modified Kellgren–Lawrence grades (P = .041) between gender. Conclusions DTS morphological classification might affect the biomechanics properties in TAS and TTA in ankle OA. In clinical practice, surgeons should pay attention to the effects of DTS on ankle OA. Level of Evidence: Level III, retrospective study.

Background: The transfer of the anterior tibiofibular ligament distal fascicle (ATiFL-DF) for the augmentation repair of the anterior talofibular ligament (ATFL) shows potential as a surgical technique. However, evidences on the benefits and disadvantages of this method in relation to ankle joint function are lacking.Purpose: This study aimed to provide comprehensive experimental data to validate the feasibility of ATiFL-DF transfer augmentation repair of the ATFL.Methods: This study included 50 embalmed ankle specimens to measure various morphological features, such as length, width, thickness, and angle, for evaluating similarities between the ATiFL-DF and ATFL. Furthermore, 24 fresh-frozen ankle specimens were examined for biomechanical testing of the ATiFL-DF transfer augmented repair of the ATFL. Finally, 12 pairs of ATiFL-DF and ATFL tissues from fresh-frozen ankle specimens were treated with gold chloride staining to analyze mechanoreceptor densities.Results: Anatomical studies found that the lengths and thicknesses of the ATFL and ATiFL-DF are similar. Biomechanical outcomes showed that performing ATiFL-DF transfer for ATFL repair can improve the stability of the talus and ankle joints. This is evident from the results of the anterior drawer, axial load, and ultimate failure load tests. However, performing ATiFL-DF transfer may compromise the stability of the distal tibiofibular joint, based on the Cotton and axial load tests at an external rotation of 5°. Analysis of the histological findings revealed that mechanoreceptor densities for four types of mechanoreceptors were comparable between the ATiFL-DF and ATFL groups.Conclusion: ATiFL-DF transfer is a viable method for augmenting ATFL repair. This technique helps to improve the stability of the talus and ankle joints while compensating for proprioception loss. Although ATiFL-DF transfer augmented repair of the ATFL may negatively affect the stability of the distal tibiofibular joint, this procedure can enhance the stability of the talus and ankle joints.

Abstract Circular RNA (circRNA) is a type of non-coding RNA that forms a covalently closed, uninterrupted loop. The expression of circRNA differs among cell types and tissues, and various circRNAs are aberrantly expressed in a variety of diseases, including cancer. Aberrantly expressed circRNAs contribute to disease progression by acting as microRNA sponges, functional protein sponges, or novel templates for protein translation. Recent studies have shown that circRNAs are enriched in exosomes. Exosomes are spherical bilayer vesicles released by cells into extracellular spaces that mediate intercellular communication by delivering cargoes. These cargoes include metabolites, proteins, lipids, and RNA molecules. Exosome-mediated cell-cell or cell-microenvironment communications influence the progression of carcinogenesis by regulating cell proliferation, angiogenesis, metastasis as well as immune escape. In this review, we summarize the current knowledge about exosomal circRNAs in cancers and discuss their specific functions in tumorigenesis. Additionally, we discuss the potential value of exosomal circRNAs as diagnostic biomarkers and the potential applications of exosomal circRNA-based cancer therapy.

Etomidate is a general anesthetic that has shown good hemodynamic stability without significant cardiovascular or respiratory depression. Despite several kinds of dosage forms having been reported for this drug, formulation types are very limited in clinical practice, and brain-targeted formulations for this central nervous system (CNS) drug have been rarely reported. Moreover, studies on the biocompatibility, toxicity, and anesthetic effects of the etomidate preparations in vivo were inadequate. The present study was to develop lactoferrin-modified liposomal etomidate (Eto-lip-LF) for enhanced drug distribution in the brain and improved anesthetic effects. Eto-lip-LF had good stability for storage and hemocompatibility for intravenous injection. Compared with the non-lactoferrin-containing liposomes, the lactoferrin-modified liposomes had notably enhanced brain-targeting ability in vivo, which was probably realized by the binding of transferrin with the transferrin and lactoferrin receptors highly distributed in the brain. Eto-lip-LF had a therapeutic index of about 25.3, higher than that of many other general anesthetics. Moreover, compared with the commercial etomidate emulsion, Eto-lip-LF could better achieve rapid onset of general anesthesia and rapid recovery from anesthesia, probably due to the enhanced drug delivery to the brain. The above results demonstrated the potential of this lactoferrin-modified liposomal etomidate to become an alternative preparation for clinical general anesthesia.

Osteoarthritis (OA) is a prevalent chronic degenerative joint disease worldwide. Obesity has been linked to OA, and increased free fatty acid levels (e.g., palmitate) contribute to inflammatory responses and cartilage degradation. Xanthohumol (Xn), a bioactive prenylated chalcone, was shown to exhibit antioxidative, anti-inflammatory, and anti-obesity capacities in multiple diseases. However, a clear description of the preventive effects of Xn on obesity-associated OA is unavailable. This study aimed to assess the chondroprotective function of Xn on obesity-related OA. The in vitro levels of inflammatory and ECM matrix markers in human chondrocytes were assessed after the chondrocytes were treated with PA and Xn. Additionally, in vivo cartilage degeneration was assessed following oral administration of HFD and Xn. This study found that Xn treatment completely reduces the inflammation and extracellular matrix degradation caused by PA. The proposed mechanism involves AMPK signaling pathway activation by Xn, which increases mitochondrial biogenesis, attenuates mitochondrial dysfunction, and inhibits NLRP3 inflammasome and the NF-κB signaling pathway induced by PA. In summary, this study highlights that Xn could decrease inflammation reactions and the degradation of the cartilage matrix induced by PA by inhibiting the NLRP3 inflammasome and attenuating mitochondria dysfunction in human chondrocytes.

Dihydromyricetin (DHM) is an important natural flavonoid that has attracted much attention because of its various functions such as protecting the cardiovascular system and liver, treating cancer and neurodegenerative diseases, and anti-inflammation effect, etc. Despite its great development potential in pharmacy, DHM has some problems in pharmaceutical applications such as low solubility, permeability, and stability. To settle these issues, extensive research has been carried out on its physicochemical properties and dosage forms to produce all kinds of DHM preparations in the past ten years. In addition, the combined use of DHM with other drugs is a promising strategy to expand the application of DHM. However, although invention patents for DHM preparations have been issued in several countries, the current transformation of DHM research results into market products is insufficient. To date, there is still a lack of deep research into the pharmacokinetics, pharmacodynamics, toxicology, and action mechanism of DHM preparations. Besides, preparations for combined therapy of DHM with other drugs are scarcely reported, which necessitates the development of dosage forms for this application. Apart from medicine, the development of DHM in the food industry is also of great potential. Due to its multiple effects and excellent safety, DHM preparations can be developed for functional drinks and foods. Through this review, we hope to draw more attention to the development potential of DHM and the above challenges and provide valuable references for the research and development of other natural products with a similar structure-activity relationship to this drug.

Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP) and disability in the elderly, imposing significant public health and economic burden worldwide. Meanwhile, the pathological mechanisms of IDD remain complicated, and treatment strategy to reverse IDD is primarily due to the unclear specific mechanisms of IDD and the lack of particular effective targets. Interleukin-1β (IL-1β), one of the most important members of the IL-1 family, can induce solid pro-inflammatory activity by stimulating the secretion of various pro-inflammatory mediators and is considered the key to IDD mediator. However, in recent years, IL-1β is considered to be able to regulate IVD cell death in many ways, such as apoptosis, pyroptosis, ferroptosis, and so on. At the same time, numerous studies on IL-1β inhibitors suggest that inhibition of IL-1β may be a promising biological therapy for IDD. Many IL-1β inhibitors have been investigated through various pathogenic biological mechanisms, including inhibiting inflammatory processes, regulating ECM degradation, and more. Therefore, anti-IL-1β therapy may have the effect of alleviating disc degeneration. This article mainly reviews the mechanisms and functions of IL-1β in IDD and investigates advances in IL-1β inhibition as a promising biotherapeutic approach for disc degeneration.

Low back pain (LBP) is one of the most common health problems in people's lives, which brings a massive burden to clinicians, and the leading cause of LBP is intervertebral disc degeneration (IDD). IDD is mainly caused by factors such as aging, mechanical stress, and lack of nutrition. The pathological mechanism of IDD is very complex, involving inflammatory response, cell metabolism disorder, and so on. Unfortunately, in the current treatment of IDD, only relieving symptoms as the primary means of relieving a patient's pain cannot effectively inhibit or reverse the progression of IDD. Tumor necrosis factor-α (TNF-α) is a multifunctional pro-inflammatory factor involved in many diseases' pathological processes. With the in-depth study of the pathological mechanism of IDD, more and more evidence has shown that TNF-α is an essential activator of IDD, which is related to the metabolic disorder, inflammatory responses, apoptosis, and other pathological processes of extracellular dissociation in the intervertebral disc. Therefore, anti-TNF-α therapy is an effective therapeutic target for alleviating IDD, especially in inhibiting extracellular matrix degradation and reducing inflammatory responses. This article reviews the pathological role of TNF-α in IDD and the latest research progress of TNF-α inhibitors in treating IDD.

Tendon injury is one of the prevalent disorders of the musculoskeletal system in orthopedics and is characterized by pain and limitation of joint function. Due to the difficulty of spontaneous tendon healing, and the scar tissue and low mechanical properties that usually develops after healing. Therefore, the healing of tendon injury remains a clinical challenge. Although there are a multitude of approaches to treating tendon injury, the therapeutic effects have not been satisfactory to date. Recent studies have shown that stem cell therapy has a facilitative effect on tendon healing. In particular, tendon stem/progenitor cells (TSPCs), a type of stem cell from tendon tissue, play an important role not only in tendon development and tendon homeostasis, but also in tendon healing. Compared to other stem cells, TSPCs have the potential to spontaneously differentiate into tenocytes and express higher levels of tendon-related genes. TSPCs promote tendon healing by three mechanisms: modulating the inflammatory response, promoting tenocyte proliferation, and accelerating collagen production and balancing extracellular matrix remodeling. However, current investigations have shown that TSPCs also have a negative effect on tendon healing. For example, misdifferentiation of TSPCs leads to a “failed healing response,” which in turn leads to the development of chronic tendon injury (tendinopathy). The focus of this paper is to describe the characteristics of TSPCs and tenocytes, to demonstrate the roles of TSPCs in tendon healing, while discussing the approaches used to culture and differentiate TSPCs. In addition, the limitations of TSPCs in clinical application and their potential therapeutic strategies are elucidated.

Dihydromyricetin (DHM) is a natural dihydroflavonol compound with quite a number of important pharmacological properties. However, its low solubility in water and poor stability in aqueous environment, have compromised drug efficacy of DHM, thus hindering its clinical use. The present study was to develop DHM-loaded gastric floating sustained-release tablet (DHM-GFT) to improve the bioavailability of DHM. DHM-GFT was prepared via powder direct compression. The formulation of tablet was optimized in terms of the floating ability and drug release rate. The optimized DHM-GFT exhibited short floating lag time of less than 10 s and long floating duration of over 12 h in acidic medium. It had a 12-hour sustained release of DHM, which proved its potential to develop as a twice-a-day dosing preparation. The physicochemical properties of DHM-GFT well satisfied the pharmacopoeial requirements. In addition, the results from pharmacokinetic studies demonstrated that, DHM-GFT could considerably prolong the in vivo residence time of drug and improve the bioavailability via good gastric floating ability and sustained drug release when compared to DHM powder. Therefore, DHM-GFT is promising to promote the application of DHM and merits studies for further development. Keywords: Gastric floating tablet, Sustained release, Dihydromyricetin, Stability, Pharmacokinetics, Bioavailability