Engineering injectable hyaluronic acid-based adhesive hydrogels with anchored PRP to pattern the micro-environment to accelerate diabetic wound healing.

Diabetic wounds remain a global challenge due to disordered wound healing led by inflammation, infection, oxidative stress, and delayed proliferation. Therefore, an ideal wound dressing for diabetic wounds not only needs tissue adhesiveness, injectability, and self-healing properties but also needs a full regulation of the microenvironment. In this work, adhesive wound dressings (HA-DA/PRP) with injectability were fabricated by combining platelet rich plasma (PRP) and dopamine-modified-hyaluronic acid (HA-DA). The engineered wound dressings exhibited tissue adhesiveness, rapid self-healing, and shape adaptability, thereby enhancing stability and adaptability to irregular wounds. The in vitro experiments demonstrated that HA-DA/PRP adhesives significantly promoted fibroblast proliferation and migration, attributed to the loaded PRP. The adhesives showed antibacterial properties against both gram-positive and negative bacteria. Moreover, in vitro experiments confirmed that HA-DA/PRP adhesives effectively mitigated oxidative stress and inflammation. Finally, HA-DA/PRP accelerated the healing of diabetic wounds by inhibiting bacterial growth, promoting granulation tissue regeneration, accelerating neovascularization, facilitating collagen deposition, and modulating inflammation through inducing M1 to M2 polarization, in an in vivo model of infected diabetic wounds. Overall, HA-DA/PRP adhesives with the ability to comprehensively regulate the microenvironment in diabetic wounds may provide a novel approach to expedite the diabetic wounds healing in clinic.

α-ketoglutarate preconditioning extends the survival of engrafted adipose-derived mesenchymal stem cells to accelerate healing of burn wounds.

The application of adipose-derived stem cells (ADSCs) in treating hard-to-heal wounds has been widely accepted, while the short-term survival rate remains an obstacle in stem cell therapy. The aim of this study is to investigate the effect of preconditioning ADSCs with α-ketoglutarate (α-KG) on the healing of acid burn wounds and cell survival within wounds. Preconditioning of ADSCs was performed by treating cells at passage 3 with 3.5 mM DM-αKG for 24 h. Proliferation and migration of ADSCs was examined. An acid burn wound was created on the dorsal skin of mice. Cell suspension of ADSCs (2 × 106 cells/ml), either pre-treated with α-KG or not, was injected subcutaneously around the margin of wound. At 1,4,7,10,14 days after injection, the percentage of wound closure was evaluated. Expression of pro-angiogenic factors, matrix molecules and HIF1-α in pretreated ADSCs or in wounds was evaluated by qRT-PCR and immunohistochemistry staining, respectively. The survival rate of DiO-labelled ADSCs was determined with the in vivo bioluminescent imaging system. Treating with α-KG induced an enhancement in migration of ADSCs, while their proliferation was not affected. Expression of Vegf and Fgf-2 was significantly increased. With injection of pretreated ADSCs, healing of wounds was remarkably accelerated, along with increased ECM deposition and microvessel density. Moreover, pretreatment with α-KG resulted a prolonged survival of engrafted ADSCs was observed. Expression of HIF-1α was significantly increased in ADSCs treated with α-KG and in wounds injected with preconditioned ADSCs. Our results revealed that healing of acid burn wound was accelerated with administration of ADSCs pretreated with α-KG, which induced elevated expression of HIF-1α and prolonged survival of engrafted stem cells.

Silk Fibroin-Laponite Porous Microspheres as Cell Microcarriers for Osteogenic Differentiation.

Silk fibroin (SF) has garnered significant attention as a natural polymer for fabricating porous scaffolds in various engineering applications. However, the limited osteoinductive property of SF has hindered its efficacy in bone repair applications. In this study, we constructed an SF-based injectable porous microcarrier that is doped with laponite (LAP), containing magnesium ions (Mg2+). The influence of freezing temperatures and concentrations of SF and LAP on the structural parameters of SF-LAP microcarriers was investigated. The SF-LAP microcarrier exhibited a porosity of 76.7 ± 1.2% and a controlled pore size of 24.6 ± 4.0 µm. At the 6 weeks of in vitro degradation test, a mild alkaline level in culture medium containing SF-LAP microcarriers was detected. The release of Mg2+ from the SF-LAP microcarrier was maintained at a concentration within the range of 1.2-2.3 mM during the 6 weeks. The seeded human adipose-derived stem cells in the SF-LAP microcarrier demonstrated a significant enhancement in osteogenic differentiation compared with cells seeded in the pure SF microcarrier, as evidenced by quantitative alkaline phosphatase activity and the expression of osteogenic marker genes. These findings underscore the potential of the SF-LAP microcarrier as an ideal cell carrier in the treatment of bone defects.

Effects of stand ages on soil enzyme activities in Chinese fir plantations and natural secondary forests.

Forest type and stand age are important biological factors affecting soil enzyme activities. However, the changes in soil enzyme activities across stand ages and underlying mechanisms under the two forest restoration strate-gies of plantations and natural secondary forests remain elusive. In this study, we investigated the variations of four soil enzyme activities including cello-biohydrolase (CBH), ß-1,4-glucosidase (ßG), acid phosphatase (AP) and ß-1,4-N-acetylglucosaminidase (NAG), which were closely associated with soil carbon, nitrogen, and phosphorus cycling, across Cunninghamia lanceolata plantations and natural secondary forests (5, 8, 21, 27 and 40 years old). The results showed that soil enzyme activities showed different patterns across different forest types. The acti-vities of AP, ßG and CBH in the C. lanceolata plantations were significantly higher than those in the natural secon-dary forests, and there was no significant difference in the NAG activity. In the plantations, AP activity showed a decreasing tendency with the increasing stand ages, with the AP activity in the 5-year-old plantations significantly higher than other stand ages by more than 62.3%. The activities of NAG and CBH decreased first and then increased, and ßG enzyme activity fluctuated with the increasing stand age. In the natural secondary forests, NAG enzyme activity fluctuated with the increasing stand age, with that in the 8-year-old and 27-year-old stand ages being significantly higher than the other stand ages by more than 14.9%. ßG and CBH enzyme activities increased first and then decreased, and no significant difference was observed in the AP activity. Results of the stepwise regression analyses showed that soil predictors explained more than 34% of the variation in the best-fitting models predicting soil enzyme activities in the C. lanceolata plantations and natural secondary forests. In conclusion, there would be a risk of soil fertility degradation C. lanceolata plantations with the increasing stand age, while natural secondary forests were more conducive to maintaining soil fertility.

"On/off"-switchable crosslinked PTX-nanoformulation with improved precise delivery for NSCLC brain metastases and restrained adverse reaction over nab-PTX.

Non-small cell lung cancer (NSCLC) brain metastases present a significant treatment challenge due to limited drug delivery efficiency and severe adverse reactions. In this study, we address these challenges by designing a "on/off" switchable crosslinked paclitaxel (PTX) nanocarrier, BPM-PD, with novel ultra-pH-sensitive linkages (pH 6.8 to 6.5). BPM-PD demonstrates a distinct "on/off" switchable release of the anti-cancer drug paclitaxel (PTX) in response to the acidic extratumoral microenvironment. The "off" state of BPM-PD@PTX effectively prevents premature drug release in the blood circulation, blood-brain barrier (BBB)/blood-tumor barrier (BTB), and normal brain tissue, surpassing the clinical PTX-nanoformulation (nab-PTX). Meanwhile, the "on" state facilitates precise delivery to NSCLC brain metastases cells. Compared to nab-PTX, BPM-PD@PTX demonstrates improved therapeutic efficacy with a reduced tumor area (only 14.6%) and extended survival duration, while mitigating adverse reactions (over 83.7%) in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), offering a promising approach for the treatment of NSCLC brain metastases. The precise molecular switch also helped to increase the PTX maximum tolerated dose from 25 mg/kg to 45 mg/kg This research contributes to the field of cancer therapeutics and has significant implications for improving the clinical outcomes of NSCLC patients.

Augmented drug resistance of osteosarcoma cells within decalcified bone matrix scaffold: The role of glutamine metabolism.

Due to the lack of a precise in vitro model that can mimic the nature microenvironment in osteosarcoma, the understanding of its resistance to chemical drugs remains limited. Here, we report a novel three-dimensional model of osteosarcoma constructed by seeding tumor cells (MG-63 and MNNG/HOS Cl no. 5) within demineralized bone matrix scaffolds. Demineralized bone matrix scaffolds retain the original components of the natural bone matrix (hydroxyapatite and collagen type I), and possess good biocompatibility allowing osteosarcoma cells to proliferate and aggregate into clusters within the pores. Growing within the scaffold conferred elevated resistance to doxorubicin on MG-63 and MNNG/HOS Cl no. 5 cell lines as compared to two-dimensional cultures. Transcriptomic analysis showed an increased enrichment for drug resistance genes along with enhanced glutamine metabolism in osteosarcoma cells in demineralized bone matrix scaffolds. Inhibition of glutamine metabolism resulted in a decrease in drug resistance of osteosarcoma, which could be restored by α-ketoglutarate supplementation. Overall, our study suggests that microenvironmental cues in demineralized bone matrix scaffolds can enhance osteosarcoma drug responses and that targeting glutamine metabolism may be a strategy for treating osteosarcoma drug resistance.

A nomogram for predicting death for infants born at a gestational age of <28 weeks: a population-based analysis in 18 neonatal intensive care units in northern China.

Background: In China, the number of preterm infants is the second largest globally. Compared with those in developed countries, the mortality rate and proportion of treatment abandonment for extremely preterm infants (EPIs) are higher in China. It would be valuable to conduct a multicenter study and develop predictive models for the mortality risk. This study aimed to identify a predictive model among EPIs who received complete care in northern China in recent years. Methods: This study included EPIs admitted to eighteen neonatal intensive care units (NICUs) within 72 hours of birth for receiving complete care in northern China between January 1, 2015, and December 31, 2018. Infants were randomly assigned into a training dataset and validation dataset with a ratio of 7:3. Univariate Cox regression analysis and multiple regression analysis were used to select the predictive factors and to construct the best-fitting model for predicting in-hospital mortality. A nomogram was plotted and the discrimination ability was tested by an area under the receiver operating characteristic curve (AUROC). The calibration ability was tested by a calibration curve along with the Hosmer-Lemeshow (HL) test. In addition, the clinical effectiveness was examined by decision curve analysis (DCA). Results: A total of 568 EPIs were included and divided into the training dataset and validation dataset. Seven variables [birth weight (BW), being inborn, chest compression in the delivery room (DR), severe respiratory distress syndrome, pulmonary hemorrhage, invasive mechanical ventilation, and shock] were selected to establish a predictive nomogram. The AUROC values for the training and validation datasets were 0.863 [95% confidence interval (CI): 0.813-0.914] and 0.886 (95% CI: 0.827-0.945), respectively. The calibration plots and HL test indicated satisfactory accuracy. The DCA demonstrated that positive net benefits were shown when the threshold was >0.6. Conclusions: A nomogram based on seven risk factors is developed in this study and might help clinicians identify EPIs with risk of poor prognoses early.

Litter decomposition and nutrient release are faster under secondary forests than under Chinese fir plantations with forest development.

In terrestrial ecosystems, leaf litter is the main source of nutrients returning to the soil. Understanding how litter decomposition responds to stand age is critical for improving predictions of the effects of forest age structure on nutrient availability and cycling in ecosystems. However, the changes in this critical process with stand age remain poorly understood due to the complexity and diversity of litter decomposition patterns and drivers among different stand ages. In this study, we examined the effects of stand age on litter decomposition with two well-replicated age sequences of naturally occurring secondary forests and Chinese fir (Cunninghamia lanceolata) plantations in southern China. Our results showed that the litter decomposition rates in the secondary forests were significantly higher than those in the Chinese fir plantations of the same age, except for 40-year-old forests. The litter decomposition rate of the Chinese fir initially increased and then decreased with stand age, while that of secondary forests gradually decreased. The results of a structural equation model indicated that stand age, litter quality and microbial community were the primary factors driving nutrient litter loss. Overall, these findings are helpful for understanding the effects of stand age on the litter decomposition process and nutrient cycling in plantation and secondary forest ecosystems.

Effects of Mud Content on the Setting Time and Mechanical Properties of Alkali-Activated Slag Mortar.

High mud content in the sand has a negative impact on cement mortar but there is little research on Alkali-activated slag (AAS) mortar. In order to explore the impacts of mud content in the sand on the performance of AAS mortar, this paper used sand that contains silt, clay, and a mixture of silt and clay; tested the setting time of AAS with different mud contents of 0%, 2%, 4%, 6%, 8%, and 10%; and measured the unconfined compressive strength and beam flexural strength of 3 d, 7 d, and 28 d AAS mortar specimens. The microstructure of AAS mortar with different kinds of mud was observed by scanning electron microscope (SEM), the elemental composition of the hydration product was tested by energy dispersive spectroscopy (EDS), and the AAS interaction mechanism with different kinds of mud was analyzed. The main conclusions are: the higher the mud content in the sand, the shorter the initial setting time and the longer the final setting time of AAS, mainly because the mud in the sand affects the hydration process; mud content above 4% causes a rapid decrease in the compressive and flexural strengths of AAS mortar, mainly because the mud affects the hydration process and hinders the bonding of the hydration product with the sand. When there is no mud in the sand, the main hydration product of AAS is dense calcium-alumina-silicate-hydrate (C-A-S-H) gel. When the sand contains silt, the hydration product of AAS is loose C-A-S-H gel. When the sand contains clay, the hydration products of AAS contain C-A-S-H gel and a small amount of sodium-aluminum-silicate-hydrate (N-A-S-H), and needle-like crystals. Loose gel and crystals have a negative effect on the AAS mortar strength.

PET117 assembly factor stabilizes translation activator TACO1 thereby upregulates mitochondria-encoded cytochrome C oxidase 1 synthesis.

Cytochrome c oxidase, also known as complex IV, facilitates the transfer of electrons from cytochrome c to molecular oxygen, resulting in the production of ATP. The assembly of complex IV is a tightly regulated and intricate process that entails the coordinated synthesis and integration of subunits encoded by the mitochondria and nucleus into a functional complex. Accurate regulation of translation is crucial for maintaining proper mitochondrial function, and defects in this process can lead to a wide range of mitochondrial disorders and diseases. However, the mechanisms governing mRNA translation by mitoribosomes in mammals remain largely unknown. In this study, we elucidate the critical role of PET117, a chaperone protein involved in complex IV assembly, in the regulation of mitochondria-encoded cytochrome c oxidase 1 (COX1) protein synthesis in human cells. Depletion of PET117 reduced mitochondrial oxygen consumption rate and impaired mitochondrial function. PET117 was found to interact with and stabilize translational activator of COX1 (TACO1) and prevent its ubiquitination. TACO1 overexpression rescued the inhibitory effects on mitochondria caused by PET117 deficiency. These findings provide evidence for a novel PET117-TACO1 axis in the regulation of mitochondrial protein expression, and revealed a previously unknown role of PET117 in human cells.

Effects of Borax, Sucrose, and Citric Acid on the Setting Time and Mechanical Properties of Alkali-Activated Slag.

The setting time of alkali-activated slag (AAS) binders is extremely short, while traditional retarders of Portland cement may be invalid for AAS. To find an effective retarder with a less negative impact on strength, borax (B), sucrose (S), and citric acid (CA) were selected as potential retarders. The setting time of AAS with different admixtures dosages of 0%, 2%, 4%, 6%, and 8%, and the unconfined compressive strength and beam flexural strength of 3 d, 7 d, and 28 d AAS mortar specimens were tested. The microstructure of AAS with different additives was observed by scanning using an electron microscope (SEM), and the hydration products were analyzed by energy dispersive spectroscopy (EDS), X-ray diffraction analysis (XRD), and thermogravimetric analysis (DT-TGA) to explain the retarding mechanism of AAS with different additives. The results showed that the incorporation of borax and citric acid could effectively prolong the setting time of AAS more than that of sucrose, and the retarding effect is more and more obvious with the increase in borax and citric acid dosages. However, sucrose and citric acid negatively influence AAS's unconfined compressive strength and flexural stress. The negative effect becomes more evident with the increase in sucrose and citric acid dosages. Borax is the most suitable retarder for AAS among the three selected additives. SEM-EDS analysis showed that the incorporation of borax does three things: produces gels, covers the surface of the slag, and slows down the hydration reaction rate.

Programmed-response cross-linked nanocarrier for multidrug-resistant ovarian cancer treatment.

The application of numerous chemotherapeutic drugs has been limited due to poor solubility, adverse side effects, and even multidrug resistance in patients. Polymeric micelles with reversibly cross-linked structures provide a promising solution to these issues. Herein, we optimized and synthesized programable-released disulfide cross-linked micelle (PDCM) based on our previous well-defined dendrimers to deliver the antitumor drug betulinic acid (BA) and paclitaxel (PDCM@PTX) and evaluated the therapeutic efficacy of multidrug-resistant (MDR) simulative orthotopic intraperitoneal ovarian cancer mice models. Comprehensive results demonstrated that PDCM@PTX formed stable nanoparticles able to improve the pharmacokinetic profile and circulation time of PTX, allowing for increased tumor penetration. Furthermore, in the tumor microenvironment, the programable-switches (ester bonds and disulfide cross-linking) of PDCM@PTX were cleaved by the high concentration of glutathione (tumor microenvironment) and esterase (intracellular) present in the tumor, allowing for in situ release of PTX and BA, resulting in intensive therapeutic efficacy in MDR ovarian cancer.

Low-density lipoprotein: a versatile nanoscale platform for targeted delivery.

Low-density lipoprotein (LDL) is a small lipoprotein that plays a vital role in controlling lipid metabolism. LDL has a delicate nanostructure with unique physicochemical properties: superior payload capacity, long residence time in circulation, excellent biocompatibility, smaller size, and natural targeting. In recent decades, the superiority and feasibility of LDL particles as targeted delivery carriers have attracted much attention. In this review, we introduce the structure, composition, advantages, defects, and reconstruction of LDL delivery systems, summarize their research status and progress in targeted diagnosis and therapy, and finally look forward to the clinical application of LDL as an effective delivery vehicle.

On-demand targeting nanotheranostics with stimuli-responsive releasing property to improve delivery efficiency to cancer.

Nanocarriers have great potential to enhance drug delivery efficiency and therapeutic effect for various cancers. However, premature drug leakage and non-specific targeting still limit the delivery efficiency. Here, we present a smart on-demand targeting nanotheranostic system (PO-PB@SPIOs) with stimuli-responsive releasing property to improve the delivery efficiency for ovarian cancer. This delivery system prevents premature drug leakage via boronate ester linkages and shields the targeting moieties (phenylboronic acid) from non-specific binding when circulating in the blood. The PO-PB@SPIOs would release the tumor-targeting payload (PB) in response to the tumor microenvironment. Then, PB was able to target the overexpressed sialic acids on tumor cells. The significant improvement of delivery efficiency was demonstrated in vivo by a significantly enhanced signal in near-infrared-fluorescence (NIRF)/magnetic-resonance (MR) imaging (5-fold higher) and a remarkable photo-thermal therapeutic effect (complete cure rate (CCR) up to 80%). Furthermore, due to the on-demand targeting and stimuli-responsive releasing strategy, this nanotheranostic system shows a greater delivery efficiency even than the active-targeting small molecules or control nanoformulations. We believe this delicate design has great potential to develop novel drug nanoformulation.

A Simulation Methodology for Analyzing the Energy-Absorption Capabilities of Nanofluidic-System-Filled Tube under Split Hopkinson Pressure Bar Experiment.

The energy-absorption mechanism of nanofluidic systems is being investigated under dynamic cases, represented by the split Hopkinson pressure bar experiment. However, the cost of this cannot be ignored. Therefore, numerical simulation is playing an increasingly important role in optimizing the split Hopkinson pressure bar experimental technology and analyzing its accuracy. In this paper, a three-dimensional finite element simulation model of the split Hopkinson pressure bar experimental devices was proposed to analyze the energy-absorption capabilities of nanofluidic-system-filled tubes. The reliability of this methodology was discussed in terms of model construction, model validation and potential application, indicating the simulation methodology is applicable to further investigation and can provide a reference for engineering practice. The simulation results showed that the infiltration pressure and the mass ratio of solid to liquid determine the post-buckling compression stress and the effective compression stroke, respectively.

Flexoelectric enhanced film for an ultrahigh tunable piezoelectric-like effect.

Recent advancements in electromechanical coupling effects enable electromechanical materials in soft and stretchable formats, offering unique opportunities for biomimetic applications. However, high electromechanical performance and mechanical elasticity hardly coexist in soft materials. Flexoelectricity, an electromechanical coupling between strain gradient and electric polarization, possesses great potential of strain gradient engineering and material design in soft elastomeric materials. In this work, we report a flexoelectric enhanced elastomer-based film (FEEF) with both high electromechanical capability and stretchability. The integrated strategies with biaxial pre-stretch, crosslinking density of the elastomer along with nanoparticle size, particle filling ratio and electric field charging lead to an enhanced flexoelectricity by two orders of magnitude. Furthermore, this FEEF reveals an ultrahigh electromechanical performance by flexoelectric enhancement with its mechanical design. As a representative demonstration, an ultrahigh piezoelectric-like sensing array is fabricated for multifunctional sensing applications in strain, force and vibration, verifying an equivalent piezoelectric coefficient d33 value as high as 1.42 × 104 pC N-1, and an average d33 value of 4.23 × 103 pC N-1 at a large-scale deformation range. This proposed ultra-high piezoelectric-like effect with its approach is anticipated to provide a possibility for highly tunable piezoelectric-like effect by enhanced flexoelectricity and mechanical design in elastomeric materials.

Quantitative Proteomics and Functional Characterization Reveal That Glutathione Peroxidases Act as Important Antioxidant Regulators in Mulberry Response to Drought Stress.

Mulberry (Morus alba L.) has been an economically important food crop for the domesticated silkworm, Bombyx mori, in China for more than 5000 years. However, little is known about the mechanism underlying mulberry response to environmental stress. In this study, quantitative proteomics was applied to elucidate the molecular mechanism of drought response in mulberry. A total of 604 differentially expressed proteins (DEPs) were identified via LC-MS/MS. The proteomic profiles associated with antioxidant enzymes, especially five glutathione peroxidase (GPX) isoforms, as a scavenger of reactive oxygen species (ROS), were systematically increased in the drought-stressed mulberry. This was further confirmed by gene expression and enzymatic activity. Furthermore, overexpression of the GPX isoforms led to enhancements in both antioxidant system and ROS-scavenging capacity, and greater tolerance to drought stress in transgenic plants. Taken together, these results indicated that GPX-based antioxidant enzymes play an important role in modulating mulberry response to drought stress, and higher levels of GPX can improve drought tolerance through enhancing the capacity of the antioxidant system for ROS scavenging.

Lensless light intensity model for quasi-spherical cell size measurement.

Quasi-spherical cell size measurement plays an important role in medical test. Traditional methods such as a microscope and a flow cytometer are either it depends on professionals and cannot be automated, or it is expensive and bulky, which are not suitable for point-of-care test. Lab-on-a-chip technology using the lensless imaging system gives a good solution for obtaining the quasi-spherical cell size. The diffraction effects and the low resolution are the two main problems faced by the lensless imaging system. In this paper, a lensless light intensity model for the quasi-spherical cell size measurement is given. First, the diffraction characteristics of a quasi-spherical cell edge are given. Then, a diffraction model at an arc edge is constructed based on the Fresnel diffraction at a straight edge. Using the diffraction model at an arc edge, we explained the mechanism of the formation of the quasi-spherical cell diffraction fringes. Finally, the light intensity of the first bright ring of the quasi-spherical cell diffraction pattern is used to achieve quasi-spherical cell size measurement. The required equipment and the measurement methods are extremely simple, very suitable for point-of-care test. The experimental results show that the proposed model can realize the statistical measurement of the quasi-spherical cells and the classification of the quasi-spherical cells with a difference of 1 [Formula: see text].

Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis.

Damaged hyaline cartilage has no capacity for self-healing, making osteoarthritis (OA) "difficult-to-treat". Cartilage destruction is central to OA patho-etiology and is mediated by matrix degrading enzymes. Here we report decreased expression of miR-17 in osteoarthritic chondrocytes and its deficiency contributes to OA progression. Supplementation of exogenous miR-17 or its endogenous induction by growth differentiation factor 5, effectively prevented OA by simultaneously targeting pathological catabolic factors including matrix metallopeptidase-3/13 (MMP3/13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2). Single-cell RNA sequencing of hyaline cartilage revealed two distinct superficial chondrocyte populations (C1/C2). C1 expressed physiological catabolic factors including MMP2, and C2 carries synovial features, together with C3 in the middle zone. MiR-17 is highly expressed in both superficial and middle chondrocytes under physiological conditions, and maintains the physiological catabolic and anabolic balance potentially by restricting HIF-1α signaling. Together, this study identified dual functions of miR-17 in maintaining cartilage homeostasis and prevention of OA.

Fermentation supernatant of Staphylococcus aureus drives catabolism in chondrocytes via NF-κB signaling mediated increase of cholesterol metabolism.

Septic arthritis induced by Staphylococcus aureus (S. aureus) causes irreversible cartilage degradation and subsequent permanent joint dysfunction. Recently, cartilage degradation in osteoarthritis is recognized to be associated with metabolic disorders. However, whether cholesterol metabolism is linked to septic arthritis pathology remains largely unknown. Here, we found that exposure to fermentation supernatant (FS) of S. aureus in chondrocytes resulted in a significant increase in expression of key modulators involved in cholesterol metabolism, including lectin-type oxidized low density lipoprotein receptor 1 (LOX1), cholesterol 25-hydroxylase (CH25H), 25- hydroxycholesterol 7α-hydroxylase (CYP7B1) as well as retinoic acid-related orphan receptor alpha (RORα), a binding receptor for cholesterol metabolites. We further demonstrated that enhancement of CH25H/CYP7B1/RORα axis resulted from FS exposure was mediated by activation of NF-κB signaling, along with upregulation in catabolic factors including matrix metallopeptidases (MMP3 and MMP13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2) in chondrocytes. Exogenous cholesterol acts synergistically with FS in activating NF-κB pathway and increases cholesterol metabolism. While, the addition of tauroursodeoxycholic acid (TUDCA) which promotes cholesterol efflux, resulted in remarkable reduction of intracellular cholesterol level and restoration of balance between anabolism and catabolism in FS treated chondrocytes. Collectively, our data indicated that, in response to FS of S. aureus, NF-κB signaling activation coupled with increased cholesterol metabolism to stimulate catabolic factors in chondrocytes, highlighting cholesterol metabolism as a potential therapeutic target for treating septic arthritis.