Hyaluronan and Glucose Dual-targeting Probe: Synthesis and Application.

In this work, we developed a dual-targeting probe consisted of well-defined hyaluronan (HA) oligosaccharide and glucose (Glc) labeled with Rhodamine B (HGR). The probe was designed to enhance tumor targeting both in vitro and in vivo, by simultaneously targeting CD44 and Glc transporter 1 (GLUT1). The HA oligosaccharide component was crucial for accurately assessing the impact of sugar chain structure on targeting efficacy, while its unoccupied carboxyl groups could minimize interference with HA's binding affinity to CD44. In vitro studies demonstrated that HGR possessed remarkable cytocompatibility and superior targeting abilities compared to single-targeting probes. It displayed a marked preference for CD44high/GLUT1high cells rather than CD44low/GLUT1low cells. In vivo studies using murine models further confirmed the significantly enhanced targeting efficacy and excellent biocompatibility of HGR. Therefore, this designed dual-targeting probe holds potential for clinical tumor detection.

Indications and adverse events of teriparatide: based on FDA adverse event reporting system (FAERS).

Background: Teriparatide is approved for osteoporosis. Post-marketing surveillance is critical given its widespread use. Objective: To investigate adverse events (AEs) associated with teriparatide using the FAERS database, compare association strengths for key AEs, and explore potential applications to provide clinical reference. Methods: FAERS data from 2004 to 2023 were analyzed. Reports where teriparatide was the primary suspect drug were included. Adverse events were mapped to System Organ Classes and Preferred Terms. Disproportionality analysis using ROR, PRR, BCPNN and EBGM algorithms was conducted to detect safety signals. Results: Out of 107,123 reports with teriparatide as the primary suspect, key AEs identified included pain in extremity (PRR: 4.54), muscle spasms (PRR: 5.11), fractures (PRR range: 17.67-552.95), and increased calcium levels (PRR: 50.73). Teriparatide exhibited a stronger association with increased calcium levels (PRR: 50.73) compared to fractures (PRR range: 17.67-552.95). Notably, only 10.86% of AE reports were submitted by physicians and another 10% by other health professionals. Subset analyses showed a higher consistency of reported AEs from health professionals compared to the general dataset. Off-label uses were noted in conditions such as arthritis (0.57%) and cancer (0.12%). For osteoporosis, main AEs were pain (18.2%), fractures (12.4%), muscle spasms (7.7%), and nausea (6.5%), while glucocorticoid-induced osteoporosis AEs included fractures (24.1%), pain (13.2%), decreased bone density (9.8%), and nausea (5.1%). Conclusion: Our findings provide real-world safety data on teriparatide, revealing key AEs and their association strengths. The low proportion of reports by healthcare professionals suggests the need for cautious interpretation. Continuous vigilance and further research are imperative to guide teriparatide's clinical use.

Methotrexate-Loaded Chitosan Oligosaccharide-ES2 for Targeted Cancer Therapy.

Cancer presents a significant health threat, necessitating the development of more precise, efficient, and less damaging treatment approaches. To address this challenge, we employed the 1-ethyl-(3-dimethyl aminopropyl) carbodiimide/N-hydroxy succinimide (EDC/NHS) catalytic system and utilized quaternized chitosan oligosaccharide (HTCOSC) as a drug carrier to construct a nanoparticle delivery system termed HTCOSC-cRGD-ES2-MTX (CREM). This system specifically targets integrin αvß3 on tumor cell surfaces and enables simultaneous loading of the antiangiogenic agent ES2 (IVRRADRAAVP) and the chemotherapy drug methotrexate (MTX). Due to its amphiphilic properties, CREM self-assembles into nanoparticles in aqueous solution, exhibiting an average diameter of 179.47 nm. Comparative studies demonstrated that CREM, in contrast to free ES2 and MTX-free nanoparticles (CRE), significantly suppressed the proliferation of EAhy926 endothelial cells and B16 melanoma cells in vitro, resulting in inhibition rates of 71.18 and 82.25%, respectively. Furthermore, CREM exhibited a hemolysis rate below 2%, indicating excellent in vitro antiangiogenic and antitumor activity as well as favorable blood compatibility. Additionally, both CRE and CREM demonstrated favorable tumor targeting capabilities through the specific binding action of cyclic RGD (cRGD) to integrin αvß3. Further in vivo investigations revealed that CREM induced apoptosis in tumor cells via the mitochondrial apoptotic pathway and reduced the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), thereby inhibiting tumor angiogenesis. This potent antitumor effect was evident through a tumor suppression rate of 80.19%. Importantly, histopathological staining (HE staining) demonstrated the absence of significant toxic side effects of CREM on various organs compared to MTX. In conclusion, the CREM nano drug delivery system synergistically enhances the therapeutic efficacy of antiangiogenic drugs and chemotherapeutic agents, thus offering a novel targeted approach for cancer treatment.

In situ visualization of the cellular uptake and sub-cellular distribution of mussel oligosaccharides.

Unlike chemosynthetic drugs designed for specific molecular and disease targets, active small-molecule natural products typically have a wide range of bioactivities and multiple targets, necessitating extensive screening and development. To address this issue, we propose a strategy for the direct in situ microdynamic examination of potential drug candidates to rapidly identify their effects and mechanisms of action. As a proof-of-concept, we investigated the behavior of mussel oligosaccharide (MOS-1) by tracking the subcellular dynamics of fluorescently labeled MOS-1 in cultured cells. We recorded the entire dynamic process of the localization of fluorescein isothiocyanate (FITC)-MOS-1 to the lysosomes and visualized the distribution of the drug within the cell. Remarkably, lysosomes containing FITC-MOS-1 actively recruited lipid droplets, leading to fusion events and increased cellular lipid consumption. These drug behaviors confirmed MOS-1 is a candidate for the treatment of lipid-related diseases. Furthermore, in a high-fat HepG2 cell model and in high-fat diet-fed apolipoprotein E (ApoE) -/- mice, MOS-1 significantly promoted triglyceride degradation, reduced lipid droplet accumulation, lowered serum triglyceride levels, and mitigated liver damage and steatosis. Overall, our work supports the prioritization of in situ visual monitoring of drug location and distribution in subcellular compartments during the drug development phase, as this methodology contributes to the rapid identification of drug indications. Collectively, this methodology is significant for the screening and development of selective small-molecule drugs, and is expected to expedite the identification of candidate molecules with medicinal effects.

Comparing musculoskeletal and connective tissue disorder risks of teriparatide and abaloparatide in osteoporosis: an analysis based on FDA adverse event reporting system (FAERS).

BACKGROUND: Osteoporosis (OP), characterized by low bone mass and increased fracture risk, is a prevalent skeletal disorder. Teriparatide (TP) and abaloparatide (ABL) are anabolic agents that may reduce fracture incidence, but their impact on musculoskeletal and connective tissue disorders (MCTD) risk is uncertain. RESEARCH DESIGN AND METHODS: A retrospective, observational disproportionality analysis was conducted utilizing FAERS data from Q1 2004 to Q3 2023, where TP or ABL was identified as the primary suspect drug. Multiple data mining algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to detect MCTD safety signals. RESULTS: A total of 366,747 TP-related and 422,377 ABL-related cases were identified, predominantly among female patients aged ≥45 years. The top specific AEs involved musculoskeletal, connective tissue, and administration site disorders. Comparative analysis revealed a higher frequency of AEs related to the nervous, cardiovascular, and gastrointestinal systems for ABL compared to TP. Both drugs exhibited strong signals for arthralgia, limb pain, back pain, muscle spasms, bone pain, muscle pain, and muscle weakness. CONCLUSION: The analysis suggests a potential MCTD risk with TP and ABL treatment in OP patients, highlighting the need for AE monitoring and management in clinical practice. This contributes to a better understanding of the safety profiles of these anabolic medications.

Enhanced optical imaging and fluorescent labeling for visualizing drug molecules within living organisms.

The visualization of drugs in living systems has become key techniques in modern therapeutics. Recent advancements in optical imaging technologies and molecular design strategies have revolutionized drug visualization. At the subcellular level, super-resolution microscopy has allowed exploration of the molecular landscape within individual cells and the cellular response to drugs. Moving beyond subcellular imaging, researchers have integrated multiple modes, like optical near-infrared II imaging, to study the complex spatiotemporal interactions between drugs and their surroundings. By combining these visualization approaches, researchers gain supplementary information on physiological parameters, metabolic activity, and tissue composition, leading to a comprehensive understanding of drug behavior. This review focuses on cutting-edge technologies in drug visualization, particularly fluorescence imaging, and the main types of fluorescent molecules used. Additionally, we discuss current challenges and prospects in targeted drug research, emphasizing the importance of multidisciplinary cooperation in advancing drug visualization. With the integration of advanced imaging technology and molecular design, drug visualization has the potential to redefine our understanding of pharmacology, enabling the analysis of drug micro-dynamics in subcellular environments from new perspectives and deepening pharmacological research to the levels of the cell and organelles.

Chondroitin sulfate-based universal nanoparticle delivers angiogenic inhibitor and paclitaxel to exhibit a combination of chemotherapy and anti-angiogenic therapy.

Blocking the tumor nutrient supply through angiogenic inhibitors is an effective treatment approach for malignant tumors. However, using angiogenic inhibitors alone may not be enough to achieve a significant tumor response. Therefore, we recently designed a universal drug delivery system combining chemotherapy and anti-angiogenic therapy to target tumor cells while minimizing drug-related side effects. This system (termed as PCCE) is composed of biomaterial chondroitin sulfate (CS), the anti-angiogenic peptide ES2, and paclitaxel (PTX), which collectively enhance antitumor properties. Interestingly, the PCCE system is conferred exceptional cell membrane permeability due to inherent characteristics of CS, including CD44 receptor-mediated endocytosis. The PCCE could respond to the acidic and high glutathione conditions, thereby releasing PTX and ES2. PCCE could effectively inhibit the proliferation, migration, and invasion of tumor cells and cause apoptosis, while PCCE can affect the endothelial cells tube formation and exert anti-angiogenic function. Consistently, more potent in vivo antitumor efficacy and non-toxic sides were demonstrated in B16F10 xenograft mouse models. PCCE can achieve excellent antitumor activity via modulating angiogenic and apoptosis-related factors. In summary, we have successfully developed an intelligent and responsive CS-based nanocarrier known as PCCE for delivering various antitumor drugs, offering a promising strategy for treating malignant tumors.

Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy.

Frequently, subcellular-targeted drugs tend to accumulate in lysosomes after cellular absorption, a process termed the lysosomal trap. This accumulation often interferes with the drug's ability to bind to its target, resulting in decreased efficiency. Existing methods for addressing lysosome-induced drug resistance mainly involve improving the structures of small molecules or enveloping drugs in nanomaterials. Nonetheless, these approaches can lead to changes in the drug structure or potentially trigger unexpected reactions within organisms. To address these issues, we introduced a strategy that involves inactivating the lysosome with the use of Ag nanoparticles (Cy3.5@Ag NPs). In this method, the Cy3.5@Ag NPs gradually accumulate inside lysosomes, leading to permeation of the lysosomal membrane and subsequent lysosomal inactivation. In addition, Cy3.5@Ag NPs also significantly affected the motility of lysosomes and induced the occurrence of lysosome passivation. Importantly, coincubating Cy3.5@Ag NPs with various subcellular-targeted drugs was found to significantly increase the efficiency of these treatments. Our strategy illustrates the potential of using lysosomal inactivation to enhance drug efficacy, providing a promising therapeutic strategy for cancer.

Enzymatic modular synthesis of asymmetrically branched human milk oligosaccharides.

Human milk oligosaccharides (HMOs) are intricate glycans that promote healthy growth of infants and have been incorporated into infant formula as food additives. Despite their importance, the limited availability of asymmetrically branched HMOs hinders the exploration of their structure and function relationships. Herein, we report an enzymatic modular strategy for the efficient synthesis of these HMOs. The key branching enzyme for the assembly of branched HMOs, human ß1,6-N-acetylglucosaminyltransferase 2 (GCNT2), was successfully expressed in Pichia pastoris for the first time. Then, it was integrated with six other bacterial glycosyltransferases to establish seven glycosylation modules. Each module comprises a one-pot multi-enzyme (OPME) system for in-situ generation of costly sugar nucleotide donors, combined with a glycosyltransferase for specific glycosylation. This approach enabled the synthesis of 31 branched HMOs and 13 linear HMOs in a stepwise manner with well-programmed synthetic routes. The binding details of these HMOs with related glycan-binding proteins were subsequently elucidated using glycan microarray assays to provide insights into their biological functions. This comprehensive collection of synthetic HMOs not only serves as standards for HMOs structure identification in complex biological samples but also significantly enhances the fields of HMOs glycomics, opening new avenues for biomedical applications.

Anti-neuroinflammatory effect of hydroxytyrosol: a potential strategy for anti-depressant development.

Introduction: Depression is a complex psychiatric disorder with substantial societal impact. While current antidepressants offer moderate efficacy, their adverse effects and limited understanding of depression's pathophysiology hinder the development of more effective treatments. Amidst this complexity, the role of neuroinflammation, a recognized but poorly understood associate of depression, has gained increasing attention. This study investigates hydroxytyrosol (HT), an olive-derived phenolic antioxidant, for its antidepressant and anti-neuroinflammatory properties based on mitochondrial protection. Methods: In vitro studies on neuronal injury models, the protective effect of HT on mitochondrial ultrastructure from inflammatory damage was investigated in combination with high-resolution imaging of mitochondrial substructures. In animal models, depressive-like behaviors of chronic restraint stress (CRS) mice and chronic unpredictable mild stress (CUMS) rats were examined to investigate the alleviating effects of HT. Targeted metabolomics and RNA-Seq in CUMS rats were used to analyze the potential antidepressant pathways of HT. Results: HT protected mitochondrial ultrastructure from inflammatory damage, thus exerting neuroprotective effects in neuronal injury models. Moreover, HT reduced depressive-like behaviors in mice and rats exposed to CRS and CUMS, respectively. HT's influence in the CRS model included alleviating hippocampal neuronal damage and modulating cytokine production, mitochondrial dysfunction, and brain-derived neurotrophic factor (BDNF) signaling. Targeted metabolomics in CUMS rats revealed HT's effect on neurotransmitter levels and tryptophan-kynurenine metabolism. RNA-Seq data underscored HT's antidepressant mechanism through the BDNF/TrkB signaling pathways, key in nerve fiber functions, myelin formation, microglial differentiation, and neural regeneration. Discussion: The findings underscore HT's potential as an anti-neuroinflammatory treatment for depression, shedding light on its antidepressant effects and its relevance in nutritional psychiatry. Further investigations are warranted to comprehensively delineate its mechanisms and optimize its clinical application in depression treatment.

Connexin 43 in the function and homeostasis of osteocytes: a narrative review.

Background and Objective: Connexin 43 (Cx43) is the main gap junction (GJ) protein and hemichannel protein in bone tissue. It is involved in the formation of hemichannels and GJs and establishes channels that can communicate directly to exchange substances and signals, affecting the structure and function of osteocytes. CX43 is very important for the normal development of bone tissue and the establishment and balance of bone reconstruction. However, the molecular mechanisms by which CX43 regulates osteoblast function and homeostasis have been less well studied, and this article provides a review of research in this area. Methods: We searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases for studies published up to June 2023 using the keywords Connexin 43/Cx43 and Osteocytes. Screening of literatures according to inclusion and exclusion guidelines and summarized the results. Key Content and Findings: Osteocytes, osteoblasts, and osteoclasts all express Cx43 and form an overall network through the interaction between GJs. Cx43 is not only involved in the mechanical response of bone tissue but also in the regulation of signal transduction, which could provide new molecular markers and novel targets for the treatment of certain bone diseases. Conclusions: Cx43 is expressed in osteoblasts, osteoclasts, and osteoclasts and plays an important role in regulating the function, signal transduction, and mechanotransduction of osteocytes. This review offers a new contribution to the literature by summarizing the relationship between Cx43, a key protein of bone tissue, and osteoblasts.

Design and construction of poly (L-lactic-acid) nanofibrous yarns and threads with controllable structure and performances.

The design and development of electrospun nanofibrous yarns (ENYs) have attracted intensive attentions in the fields of biomedical textiles and tissue engineering, but the inferior fiber arrangement structure, low yarn eveness, and poor tensile properties of currently-obtained ENYs has been troubled for a long time. In this study, a series of innovative strategies which combined a modified electrospinning method with some traditional textile processes like hot stretching, twisting, and plying, were designed and implemented to generate poly (L-lactic-acid) (PLLA) ENYs with adjustable morphology, structure, and tensile properties. PLLA ENYs made from bead-free and uniform PLLA nanofibers were fabricated by our modified electrospinning method, but the as-spun PLLA ENYs exhibited relatively lower fiber alignment degree and tensile properties. A hot stretching technique was explored to process the primary PLLA ENYs to improve the fiber alignment and crystallinity, resulting in a 779.7% increasement for ultimate stress and a 470.4% enhancement for Young's modulus, respectively. Then, the twisting post-treatment was applied to process as-stretched PLLA ENYs, and the tensile performances of as-twisted ENYs was found to present a trend of first increasing and then decreasing with the increasing of twisting degree. Finally, the PLLA threads made from different numbers of as-stretched PLLA ENYs were also manufactured with a traditional plying process, demonstrating the feasibility of further improving the yarn diameter and tensile properties. In all, this study reported a simple and cost-effective technique roadmap which could generate high performance PLLA nanofiber-constructed yarns or threads with controllable structures like highly aligned fiber orientation, twisted structure, and plied structure.

CD44 targeting nanodrug based on chondroitin sulfate for melanoma therapy by inducing mitochondrial apoptosis pathways.

Neovascularization is crucial to the occurrence and progression of tumors, and the development of antiangiogenic drugs has essential theoretical value and clinical significance. However, antiangiogenesis therapy alone cannot meet the needs of tumor therapy. Meanwhile, polysaccharides are ideal drug carriers with promising applications in drug modification and delivery. In this research, we developed a novel redox and acid sensitive nanodrug (CDDP-CS-Cys-EA, CCEA) composed of chondroitin sulfate (CS), antiangiogenic peptide (endostatin2-alft1, EA) and chemotherapeutic drug (cisplatin, CDDP). CCEA exhibited redox and acid responsiveness, better blood hemocompatibility (hemolysis rate < 5 %), the ability to target tumors (CD44-mediated endocytosis), and strong antiangiogenesis and antitumor characteristics in vitro. Moreover, CCEA showed excellent antitumor activity and low toxicity in B16 xenograft mice. It also has been confirmed that CCEA induced tumor cell apoptosis through promoting the expression of Bax, suppressing the expression of Bcl-2, decreasing mitochondrial membrane potential, releasing cytochrome C (Cyto C), and enhancing the activities of Caspase 9 and Caspase 3. The results of this paper provided a theoretical basis and insight for the development of antitumor drugs.

Advances, challenges, and prospects for surgical suture materials.

As one of the long-established and necessary medical devices, surgical sutures play an essentially important role in the closing and healing of damaged tissues and organs postoperatively. The recent advances in multiple disciplines, like materials science, engineering technology, and biomedicine, have facilitated the generation of various innovative surgical sutures with humanization and multi-functionalization. For instance, the application of numerous absorbable materials is assuredly a marvelous progression in terms of surgical sutures. Moreover, some fantastic results from recent laboratory research cannot be ignored either, ranging from the fiber generation to the suture structure, as well as the suture modification, functionalization, and even intellectualization. In this review, the suture materials, including natural or synthetic polymers, absorbable or non-absorbable polymers, and metal materials, were first introduced, and then their advantages and disadvantages were summarized. Then we introduced and discussed various fiber fabrication strategies for the production of surgical sutures. Noticeably, advanced nanofiber generation strategies were highlighted. This review further summarized a wide and diverse variety of suture structures and further discussed their different features. After that, we covered the advanced design and development of surgical sutures with multiple functionalizations, which mainly included surface coating technologies and direct drug-loading technologies. Meanwhile, the review highlighted some smart and intelligent sutures that can monitor the wound status in a real-time manner and provide on-demand therapies accordingly. Furthermore, some representative commercial sutures were also introduced and summarized. At the end of this review, we discussed the challenges and future prospects in the field of surgical sutures in depth. This review aims to provide a meaningful reference and guidance for the future design and fabrication of innovative surgical sutures. STATEMENT OF SIGNIFICANCE: This review article introduces the recent advances of surgical sutures, including material selection, fiber morphology, suture structure and construction, as well as suture modification, functionalization, and even intellectualization. Importantly, some innovative strategies for the construction of multifunctional sutures with predetermined biological properties are highlighted. Moreover, some important commercial suture products are systematically summarized and compared. This review also discusses the challenges and future prospects of advanced sutures in a deep manner. In all, this review is expected to arouse great interest from a broad group of readers in the fields of multifunctional biomaterials and regenerative medicine.

Review: Application of chitosan and its derivatives in medical materials.

Chitin is a natural polymeric polysaccharide extracted from marine crustaceans, and chitosan is obtained by removing part of the acetyl group (usually more than 60 %) in chitin's structure. Chitosan has attracted wide attention from researchers worldwide due to its good biodegradability, biocompatibility, hypoallergenic and biological activities (antibacterial, immune and antitumor activities). However, research has shown that chitosan does not melt or dissolve in water, alkaline solutions and general organic solvents, which greatly limits its application range. Therefore, researchers have carried out extensive and in-depth chemical modification of chitosan and prepared a variety of chitosan derivatives, which have expanded the application field of chitosan. Among them, the most extensive research has been conducted in the pharmaceutical field. This paper summarizes the application of chitosan and chitosan derivatives in medical materials over the past five years.

Preparation, function, and safety evaluation of a novel degradable dermal filler, the cross-linked poly-γ-glutamic acid hydrogel particles.

Poly-γ-glutamic acid (PGA) is a naturally degradable hydrophilic linear microbial polymer with moisturizing, immunogenic, cross-linking, and hydrogel water absorption properties similar to hyaluronic acid, a biomaterial that is commonly used as a dermal filler. To explore the development feasibility of cross-linked PGA as a novel dermal filler, we studied the local skin response to PGA fillers and the effect of various cross-linking preparations on the average longevity of dermal injection. Injection site inflammation and the formation of collagen and elastin were also determined. PGA hydrogel particles prepared using 28% PGA and 10% 1,4-butanediol diglycidyl ether showed optimal filler properties, resistance to moist heat sterilization, and an average filling longevity of 94.7 ± 61.6 days in the dermis of rabbit ears. Local redness and swelling due to filler injection recovered within 14.2 ± 3.6 days. Local tissue necrosis or systemic allergic reactions were not observed, and local collagen formation was promoted. Preliminary results suggested that dermal injection of cross-linked PGA particles appeared safe and effective, suggesting that cross-linked PGA particles could be developed as a new hydrogel dermal filler.

Glycol-Split Heparin-Linked Prodrug Nanoparticles Target the Mitochondrion Apparatus for Cancer Metastasis Treatment.

The progression and metastasis of solid tumors rely strongly on neovascularization. However, angiogenesis inhibitors alone cannot meet the needs of tumor therapy. This study prepared a new drug conjugate (PTX-GSHP-CYS-ES2, PGCE) by combining polysaccharides (heparin without anticoagulant activity, GSHP), chemotherapeutic drugs (paclitaxel, PTX), and antiangiogenic drugs (ES2). Furthermore, a tumor-targeted prodrug nanoparticle delivery system is established. The nanoparticles appear to accumulate in the mitochondrial of tumor cells and achieve ES2 and PTX release under high glutathione and acidic environment. It has been confirmed that PGCE inhibited the expression of multiple metastasis-related proteins by targeting the tumor cell mitochondrial apparatus and disrupting their structure. Furthermore, PGCE nanoparticles inhibit migration, invasion, and angiogenesis in B16F10 tumor-bearing mice and suppress tumor growth and metastasis in vitro. Further in vitro and in vivo experiments show that PGCE has strong antitumor growth and metastatic effects and exhibits efficient anti-angiogenesis properties. This multi-targeted nanoparticle system potentially enhances the antitumor and anti-metastatic effects of combination chemotherapy and antiangiogenic drugs.

Single Image Capture of Bioactive Ion Crosstalk within Inter-Organelle Membrane Contacts at Nanometer Resolution.

Rapid bioactive ion exchange is a form of communication that regulates a wide range of biological processes. Despite advances in super-resolution optical microscopy, visualizing ion exchange remains challenging due to the extremely fast nature of these events. Here, a "converting a dynamic event into a static image construction" (CDtSC) strategy is developed that uses the color transformation of a single dichromatic molecular probe to visualize bioactive ion inter-organelle exchange in live cells. As a proof of concept, a reactive sulfur species (RSS) is analyzed at the mitochondria-lysosome contact sites (MLCs). A non-toxic and sensitive probe based on coumarin-hemicyanine structure is designed that responds to RSS localized in both mitochondria and lysosomes while fluorescing different colors. Using this probe, RSS give-and-take at MLCs is visualized, thus providing the first evidence that RSS is involved in inter-organelle contacts and communication. Taken together, the CDtSC provides a strategy to visualize and analyze rapid inter-organelle ion exchange events in live cells at nanometer resolution.

Injectable and Self-Healing Probiotics-Loaded Hydrogel for Promoting Superbacteria-Infected Wound Healing.

Superbacteria-induced skin wound infections are huge health challenges, resulting in significant financial and medical costs due to notable morbidity and mortality worldwide. Probiotics are found in the skin and are effective in treating bacterial infection, moderating the microbial dysbiosis and inflammation induced by pathogens, regulating the immune system, as well as even promoting tissue repair. However, improving their colonization efficiency and viability remains a large obstacle for proper applications. Inspired by probiotic therapy and the natural extracellular matrix structure, hyaluronate-adipic dihydrazide/aldehyde-terminated Pluronic F127/fucoidan hydrogels loaded with Lactobacillus rhamnosus (HPF@L.rha) with unique (bio)physicochemical characteristics were developed through the dynamic Schiff-base reaction for superbacteria-infected trauma management. The developed HPF@L.rha exhibit a shortened gelation time, enhanced mechanical strength, and excellent self-healing and liquid-absorption abilities. Importantly, their anti-superbacteria (Pseudomonas aeruginosa) effect was greatly increased in a dose-dependent fashion. Additionally, in vitro evaluation shows that the prepared HPF@L.rha containing appropriate probiotic concentrations (less than 1 × 107 CFU/mL) possess satisfactory cytocompatibility and blood compatibility. Further, compared to the HPF hydrogel, in vivo the hydrogel combined with probiotics significantly inhibits P. aeruginosa infection and inflammation, promotes the formation of re-epithelialization and collagen, and thus accelerates full-thickness superbacteria-infected wound repair, which is comparable to commercial Prontosan gel formulation. This work suggests that the combination of biomimicking hydrogels and probiotic therapy displays the great potential to manage superbug-infected trauma.

miR-590-5p affects chondrocyte proliferation, apoptosis, and inflammation by targeting FGF18 in osteoarthritis.

OBJECTIVE: To investigate the potential miRNA targeting FGF18, and its role in regulating the proliferation, apoptosis and inflammation in human primary chondrocytes. METHODS: The normal human chondrocytes were induced by IL-1ß to mimic OA in vitro. qPCR and Western blotting were performed to evaluate the expression of FGF18. Target Scan analysis was performed to predict the miRNA targeting FGF18. Then, the expression of miR-590-5p was quantified by qPCR in IL-1ß-induced chondrocytes. After transfection of miR-590-5p mimics or inhibitors, CCK-8 assay was conducted to determine the cell viability and apoptosis-related proteins, and cartilage degeneration related biomarkers were assayed by qPCR and Western blotting. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 were determined by ELISA. The targeting relationship between miR-590-5p and FGF18 was assayed by luciferase reporter assay in IL-1ß-induced chondrocytes. RESULTS: Target Scan analysis predicted that FGF18 is directly targeted by miR-590-5p. miR-590-5p was up-regulated, whereas FGF18 expression was inhibited in IL-1ß-induced chondrocytes. miR-590-5p mimics reduced the expression of FGF18 protein, inhibited the cell viability of chondrocytes, and promoted secretion of inflammatory factors in chondrocytes, while miR-590-5p inhibitors increased FGF18 levels in IL-1ß-treated chondrocytes. Furthermore, expression of inflammatory factors in chondrocytes was reduced by miR-590-5p inhibitors. The luciferase reporter assay showed that miR-590-5p could target FGF18. CONCLUSIONS: miR-590-5p promotes OA progression by targeting FGF18, which serves as a potential therapeutic target for OA.