An injectable cartilage-coating composite with long-term protection, effective lubrication and chondrocyte nourishment for osteoarthritis treatment.

The osteoarthritic (OA) environment within articular cartilage poses significant challenges, resulting in chondrocyte dysfunction and cartilage matrix degradation. While intra-articular injections of anti-inflammatory drugs, biomaterials, or bioactive agents have demonstrated some effectiveness, they primarily provide temporary relief from OA pain without arresting OA progression. This study presents an injectable cartilage-coating composite, comprising hyaluronic acid and decellularized cartilage matrix integrated with specific linker polymers. It enhances the material retention, protection, and lubrication on the cartilage surface, thereby providing an effective physical barrier against inflammatory factors and reducing the friction and shear force associated with OA joint movement. Moreover, the composite gradually releases nutrients, nourishing OA chondrocytes, aiding in the recovery of cellular function, promoting cartilage-specific matrix production, and mitigating OA progression in a rat model. Overall, this injectable cartilage-coating composite offers promising potential as an effective cell-free treatment for OA. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) in the articular cartilage leads to chondrocyte dysfunction and cartilage matrix degradation. This study introduces an intra-articular injectable composite material (HDC), composed of decellularized cartilage matrix (dECMs), hyaluronan (HA), and specially designed linker polymers to provide an effective cell-free OA treatment. The linker polymers bind HA and dECMs to form an integrated HDC structure with an enhanced degradation rate, potentially reducing the need for frequent injections and associated trauma. They also enable HDC to specifically coat the cartilage surface, forming a protective and lubricating layer that enhances long-term retention, acts as a barrier against inflammatory factors, and reduces joint movement friction. Furthermore, HDC nourishes OA chondrocytes through gradual nutrient release, aiding cellular function recovery, promoting cartilage-specific matrix production, and mitigating OA progression.

Optimization of exosome-based cell-free strategies to enhance endogenous cell functions in tissue regeneration.

Exosomes, nanoscale extracellular vesicles, play a crucial role in intercellular communication, owing to their biologically active cargoes such as RNAs and proteins. In recent years, they have emerged as a promising tool in the field of tissue regeneration, with the potential to initiate a new trend in cell-free therapy. However, it's worth noting that not all types of exosomes derived from cells are appropriate for tissue repair. Thus, selecting suitable cell sources is critical to ensure their efficacy in specific tissue regeneration processes. Current therapeutic applications of exosomes also encounter several limitations, including low-specific content for targeted diseases, non-tissue-specific targeting, and short retention time due to rapid clearance in vivo. Consequently, this review paper focuses on exosomes from diverse cell sources with functions specific to tissue regeneration. It also highlights the latest engineering strategies developed to overcome the functional limitations of natural exosomes. These strategies encompass the loading of specific therapeutic contents into exosomes, the endowment of tissue-specific targeting capability on the exosome surface, and the incorporation of biomaterials to extend the in vivo retention time of exosomes in a controlled-release manner. Collectively, these innovative approaches aim to synergistically enhance the therapeutic effects of natural exosomes, optimizing exosome-based cell-free strategies to boost endogenous cell functions in tissue regeneration. STATEMENT OF SIGNIFICANCE: Exosome-based cell-free therapy has recently emerged as a promising tool for tissue regeneration. This review highlights the characteristics and functions of exosomes from different sources that can facilitate tissue repair and their contributions to the regeneration process. To address the functional limitations of natural exosomes in therapeutic applications, this review provides an in-depth understanding of the latest engineering strategies. These strategies include optimizing exosomal contents, endowing tissue-specific targeting capability on the exosome surface, and incorporating biomaterials to extend the in vivo retention time of exosomes in a controlled-release manner. This review aims to explore and discuss innovative approaches that can synergistically improve endogenous cell functions in advanced exosome-based cell-free therapies for a broad range of tissue regeneration.

Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes.

As chondrocytes from osteoarthritic cartilage usually exhibit aging and senescent characteristics, targeting aging chondrocytes could be a potential therapeutic strategy. In this study, exosomes derived from umbilical cord-derived mesenchymal stem cells (UCMSC-EXOs) combined with the chondrocyte-targeting capacity and controlled-release system were proposed for osteoarthritis (OA) treatment via rejuvenating aging chondrocytes. The essential functional miRNAs within UCMSC-EXOs were investigated, with the p53 signaling pathway identified as the key factor. To improve the therapeutic efficiency and retention time of UCMSC-EXOs in vivo, the exosomes (EXOs) were engineered on membranes with a designed chondrocyte-targeting polymers, and encapsulated within thiolated hyaluronic acid microgels to form a "two-phase" releasing system, which synergistically facilitated the repair of OA cartilage in a rat model. Together, this study highlighted the rejuvenating effects of UCMSC-EXOs on OA chondrocytes and the potential to combine with chondrocyte-targeting and sustained-release strategies toward a future cell-free OA treatment.

Depression increased risk of coronary heart disease: A meta-analysis of prospective cohort studies.

Background: Depression, as an independent risk factor, can lead to a substantially increased risk of coronary heart disease (CHD). The overall body of evidence involving depression and CHD is not consistent. Therefore, we performed an update meta-analysis to evaluate the association between depression and the risk of patients with CHD. Methods: Studies were identified through a comprehensive literature search of the PubMed, Embase, and the Cochrane Library database from its inception to 28 September 2021 for titles/abstracts with restricted to English language articles. The literature was screened according to the inclusion and exclusion criteria. Along with data extraction, we evaluated the quality of eligible studies using the Newcastle-Ottawa Scale (NOS). The primary outcome was fatal or non-fatal CHD. We calculated relative risk (RR) with 95% confidence intervals (CIs) using a random-effects models. The protocol was registered in the PROSPERO registration (registration number CRD42021271259). Results: From 9,151 records, we included 26 prospective cohort studies published from 1998 to 2018, consisting of 402,597 patients. Either in depression-exposured group or non-depression-exposured group, the mean age of all participants ranged from 18 to 99 years. Moreover, the NOS scores of these studies are eventually indicated that the quality of these eligible studies was reliable. In general, the pooled results showed that patients with depression had a higher risk of CHD compared to patients without depression (RR = 1.21, 95% CI: 1.14-1.29). Additionally, the funnel plot appeared to be asymmetry, indicating there existing publication bias for the pooled results between depression and CHD. A sensitivity analysis was used to assess the stability of the relationship between depression and CHD that indicating the results robust (RR = 1.15, 95% CI: 1.09-1.21). Conclusion: Depression may increase risk of CHD. Future studies on the share pathogenic mechanisms of both depression and CHD may develop novel therapies.

Childhood Cartilage ECM Enhances the Chondrogenesis of Endogenous Cells and Subchondral Bone Repair of the Unidirectional Collagen-dECM Scaffolds in Combination with Microfracture.

Despite the formation of mechanically inferior fibrocartilage, microfracture (MF) still remains the gold standard to repair the articular cartilage defects in clinical settings. To date, although many tissue-engineering scaffolds have been developed to enhance the MF outcome, the clinical outcomes remain inconsistent. Decellularized extracellular matrix (dECM) is among the most promising scaffold for cartilage repair due to its inheritance of the natural cartilage components. However, the impact of dECM from different developmental stages on cellular chondrogenesis and therapeutic effect remains elusive, as the development of native cartilage involves the distinct temporal dependency of the ECM components and various growth factors. Herein, we hypothesized that the immature cartilage dECM at various developmental stages was inherently different, and would consequently impact the chondrogenic potential BMSCs. In this study, we fabricated three different unidirectional collagen-dECM scaffolds sourced from neonatal, childhood, and adolescent rabbit cartilage tissues, and identified the age-dependent biological variations, including DNA, cartilage-specific proteins, and growth factors; along with the mechanical and degradation differences. Consequently, the different local cellular microenvironments provided by these scaffolds led to the distinctive cell morphology, circularity, proliferation, chondrogenic genes expression, and chondrogenesis of BMSCs in vitro, and the different gross morphology, cartilage-specific protein production, and subchondral bone repair when in combination with microfracture in vivo. Together, this work highlights the immature cartilage dECM at different developmental stages that would result in the diversified effects to BMSCs, and childhood cartilage would be considered the optimal dECM source for the further development of dECM-based tissue engineering scaffolds in articular cartilage repair.

[Role of Stem Cells and Their Biomimetic Matrix Microenvironment in Regenerative Repair of Articular Cartilage: A Review].

It is difficult for the articular cartilage to self-heal any damage it may incur due to its lack of nerves and blood vessels. Development in stem cell technology provides new prospects for articular cartilage regeneration. Currently, stem cells from different sources and their diverse applications have demonstrated different degrees of therapeutic effect and potential in articular cartilage repair. However, stem cells are highly sensitive to their microenvironment. Therefore, more and more researchers are focusing their attention on regulating stem cells and thus accelerating cartilage regeneration through the biomimetic microenvironment constructed by biologically functional scaffolds. We reviewed in this paper the sources of the stem cells used for cartilage repair, the application method of these stem cells, as well as the therapeutic effect, mechanism and limitations in the application of stem cells synergizing with the biomimetic microenvironment in promoting articular cartilage repair and regeneration. We hoped to provide suggestions for practical clinical research in the design and improvement of biofunctional cartilage repair scaffolds that synergize with stem cells.

Bioinspired polysaccharide hybrid hydrogel promoted recruitment and chondrogenic differentiation of bone marrow mesenchymal stem cells.

Cartilage regeneration by biomimetic cartilage matrix with synchronously recruited stem cells was one of ideal strategies. Inspired by catechol for proteins adhesion, dopamine modified polysaccharide hybrid hydrogel (HD-C) was prepared by integrating collagen I (Col I) and hyaluronic acid derivatives (HA-DN) with sulfhydryl modified polysaccharide hybrid hydrogel (HS-C) as control. Because of double-crosslinking architecture, HD-C hydrogel was endowed with a more compact pore structure, higher mechanical properties and water retention ability in comparison with those of HS-C hydrogel. Meanwhile, it significantly promoted the proliferation and spread of rabbit bone marrow stem cells (rBMSCs), and accelerated cartilaginous matrix secretion. RT-PCR results also verified higher related gene expression of chondrogenesis (Sox 9, Agg and Col II). Moreover, HD-C hydrogel could enhance the enrichment and migration of rBMSCs in vitro by potential functional protein adsorption mechanisms, and this phenomenon was further confirmed by more rBMSCs migration in short-term joint implantation experiments in vivo.

Different Doses of Pharmacological Treatments for Mild to Moderate Alzheimer's Disease: A Bayesian Network Meta-Analysis.

BACKGROUND: Pharmacological treatments play a significant role in treating mild to moderate Alzheimer's disease (AD), but the optimal doses of various drugs used for these treatments are unknown. Our study compared the efficacy, acceptability, and safety of different doses of pharmacological treatments for mild to moderate AD. METHODS: Randomized controlled trials (RCTs) were identified by searching the PubMed, EMBASE, and Cochrane Library databases (all RCTs published from the date of inception of the databases until September 19, 2019). Trials comparing the efficacy, acceptability, and safety of pharmacological interventions involving donepezil, galantamine, rivastigmine, memantine, huperzine A, and Ginkgo biloba extract EGb761, alone or in combination, were identified. The primary outcomes were efficacy, acceptability, and safety. RESULTS: Our meta-analysis included 37 studies involving 14,705 participants. In terms of improving cognitive function, galantamine 32 mg, galantamine 24 mg, donepezil 5 mg, and donepezil 10 mg were more effective than other interventions, with the surface under the cumulative ranking curve (SUCRA) values of 93.2, 75.5, 73.3, and 65.6%, respectively. According to the SUCRA values, EGb761 240 mg was considered to be the optimal intervention in terms of both acceptability and safety. With regard to clinical global impression, rivastigmine 12 mg had the highest probability of being ranked first (83.7%). The rivastigmine 15 cm2 patch (SUCRA = 93.7%) may be the best choice for daily living. However, there were no interventions that could significantly improve neuropsychiatric symptoms, compared with the placebo. CONCLUSIONS: Different doses of the tested pharmacological interventions yielded benefits with regard to cognition, acceptability, safety, function, and clinical global impressions, but not effective behaviors.

Ginsenoside Rg3 for Chemotherapy-Induced Myelosuppression: A Meta-Analysis and Systematic Review.

Patients with advanced cancer often undergo myelosuppression after receiving chemotherapy. However, severe myelosuppression results in treatment delay, and some can even be life-threatening. At present, cancer patients undergoing chemotherapy urgently need effective intervention strategies to prevent myelosuppression. Fortunately, ginsenoside Rg3 has shown promise as an anti-myelosuppression agent. Therefore, this study was conducted to evaluate the effectiveness of ginsenoside Rg3 in preventing chemotherapy-induced myelosuppression in cancer patients. The PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Weipu (VIP), and Wanfang databases were searched in this study. A total of 18 trials which reported on 2,222 subjects were identified. All trials concerning the use of ginsenoside Rg3 for the prevention of chemotherapy-induced myelosuppression (the decline of leukocyte, hemoglobin, platelet, and neutrophil counts) were randomized-controlled trials. Dichotomous data were expressed as odds ratio (OR) with their respective 95% confidence intervals (CI). The Cochrane evidence-based medicine systematic evaluation was used to evaluate the methodological quality of the included trials. The Review Manager 5.3 and Stata 12.0 software were used to perform the statistical analyses. The trial sequential analysis (TSA) was used to evaluate information size and prevention benefits. The results revealed obvious ginsenoside Rg3-induced improvement in the leukocyte (OR, 0.46; 95% CI, 0.37-0.55), hemoglobin (OR, 0.64; 95% CI, 0.53-0.77), platelet (OR, 0.60; 95% CI, 0.48-0.75) and neutrophil (OR, 0.62; 95% CI, 0.43-0.90) counts at toxic grades I-IV, and leukocyte (OR, 0.39; 95% CI, 0.28-0.54) counts at toxic grades III-IV. The sensitivity analysis revealed that the results were robust. The Egger's test indicated that there was no publication bias in the results. Overall, this study suggested that ginsenoside Rg3 is beneficial for alleviating the chemotherapy-induced decrease in leukocyte, hemoglobin, platelet, and neutrophil counts. However, the confirmation of the ginsenoside Rg3 can be recommended for myelosuppression patients was limited due to poor methodological quality. Thus, more rigorously designed randomized-controlled trials (RCTs) are required to assess the efficacy of ginsenoside Rg3 for myelosuppression.

Efficient manufacturing of tissue engineered cartilage in vitro by a multiplexed 3D cultured method.

Cell culture has become an indispensable tool to uncover fundamental biophysical and biomolecular mechanisms of cells assembling into tissues. An important advancement in cell culture techniques was the introduction of three-dimensional (3D) culture systems. In this study, the mutual fusion of chondrocyte pellets was promoted in order to produce large-sized tissue-engineered cartilage by a multiplexed 3D hanging drop culture and agarose mold method to optimize the means of cultivation. Cell proliferation, aggregation, cell morphology maintenance as well as cartilage related gene expression and matrix secretion in vitro and subcutaneous implantation models were evaluated. These results indicated that the multiplexed 3D hanging drop culture involving the fusion of small pellets into a large structure enabled the efficient production of 3D tissue engineered cartilage that was closer to physiological cartilage tissue in comparison to that of the agarose mold method.

Novel liquid fermentation medium of Cordyceps militaris and optimization of hydrothermal reflux extraction of cordycepin.

In this study, we developed a novel liquid fermentation medium of Cordyceps militaris using pupa powder and wheat bran as nitrogen resources instead of the traditionally used peptone. This process not only reduced the cost by approximately 50%, but increased production by over 30%. Then, we explored a method to extract and purify cordycepin by combining hydrothermal reflux extraction with macroporous resin adsorption, which is inexpensive and suitable for the industrial production. The optimum conditions for hydrothermal reflux were extracting three times at 95 °C with 1:10 sample-to-water ratio, and the cordycepin purity with macroporous resin HPD-100 reached 95.23%.[Formula: see text].

Optimizing the Extraction and Encapsulation of Mucilage from Brasenia Schreberi.

The mucilage from Brasenia schreberi (BS) exhibits various biological activities, including antialgal, antibacterial, soluble-fiber properties, and excellent lubricating behavior. Thus, the extraction and wide use of mucilage in the food industry are crucial. In this study, the high-speed shear-assisted extraction of mucilage from BS was optimized by using response surface methodology (RSM). The optimal extraction conditions were as follows: Extraction temperature of 82 °C, extraction time of 113 min, liquid-solid ratio of 47 mL/g, and shear speed of 10,000 rpm. Under these conditions, the actual yield of BS mucilage was 71.67%, which highly matched the yield (73.44%) predicted by the regression model. Then, the BS mucilage extract was powdered to prepare the capsule, and the excipients of the capsule were screened using a single-factor test to improve the disintegration property and flowability. The final capsule formulation, which consisted of: 39% BS mucilage powder (60 meshes); 50% microcrystalline cellulose (60 meshes) as the filler; both 10% sodium starch glycolate and PVPP XL-10 (3:1, 60 meshes) as the disintegrant; both 1% colloidal silicon dioxide and sodium stearyl fumarate (1:1, 100 meshes) as the glidant by weight; were used for preparing the weights of a 320 mg/grain of capsule with 154.7 ± 0.95 mg/g polysaccharide content. Overall, the optimized extraction process had a high extraction rate for BS mucilage and the capsule formulation was designed reasonably.

Screening and identification of Lactic acid bacteria from Ya'an pickle water to effectively remove Pb2.

Heavy metal lead, which enters the human body through food intake, endangers human health. Microbe has the ability of adsorbing heavy metal, among which lactic acid bacteria are promising microbes to adsorb and remove Pb2+. The purpose of this study was to screen lactic acid bacteria from Ya'an pickle water to effectively remove Pb2+. The 7 strains having strong ability to effectively remove Pb2+ were detected. These strains were identified by microscopic examination and 16S rDNA sequencing, 4 strains of Lactobacillus plantarum and 3 strains of Lactobacillus brevis were obtained. Then the bacteria had a blind adsorption effect on Pb2+. After microwave digestion, the Pb2+ concentration was measured by flame atomic absorption spectrometry. The highest removal reached 82.25%. The adsorption mechanism of lactic acid bacteria was mainly divided into biosorption and bioaccumulation. The 7 strains of lactic acid bacteria could provide potential for detoxification of contaminated foods and reduction of the Pb2+ accumulation in the human diet and animal feed. At the same time, this study was helpful to further understand the mechanism of Pb2+ being adsorbed by lactic acid bacteria.