Upregulation of FABP4 induced inflammation in the pathogenesis of chronic tendinopathy.

Objectives: Excessive inflammation contributes to the pathogenesis of tendinopathy. Fatty acid binding protein 4 (FABP4) is a pro-inflammatory adipokine mediating various metabolic and inflammatory diseases. This study aimed to examine the expression of FABP4 and its association with the expressions of inflammatory cytokines in tendinopathy. The effects of a single injection of FABP4 on tendon pathology and inflammation were examined. The effect of FABP4 on the expressions of inflammatory cytokines and the effect of IL-1ß on the expression of FABP4 in tendon-derived stem/progenitor cells (TDSCs) were also investigated. Methods: 1) Clinical patellar tendinopathy samples, healthy hamstring tendon samples, and healthy patellar tendon samples, 2) rotator cuff tendinopathy samples and healthy hamstring tendon samples; and 3) Achilles tendons of mice after saline or collagenase injection (CI) were stained for FABP4, IL-1ß, IL-6, TNF-α and IL-10 by immunohistochemistry (IHC). For the rotator cuff tendinopathy samples, co-localization of FABP4 with IL-1ß and TNF-α was done by immunofluorescent staining (IF). Mouse Achilles tendons injected with FABP4 or saline were collected for histology and IHC as well as microCT imaging post-injection. TDSCs were isolated from human and mouse tendons. The mRNA expressions of inflammatory cytokines in human and mouse TDSCs after the addition of FABP4 was quantified by qRT-PCR. The expression of FABP4 in TDSCs isolated from rotator cuff tendinopathy samples and healthy hamstring tendon samples was examined by IF. Mouse Achilles TDSCs were treated with IL-1ß. The mRNA and protein expressions of FABP4 were examined by qRT-PCR and IF, respectively. Results: There was significant upregulation of FABP4 in the patellar tendinopathy samples and rotator cuff tendinopathy samples compared to their corresponding controls. FABP4 was mainly expressed in the pathological areas including blood vessels, hypercellular and calcified regions. The expressions of IL-1ß and TNF-α increased in human rotator cuff tendinopathy samples and co-localized with the expression of FABP4. Collagenase induced tendinopathic-like histopathological changes and ectopic calcification in the mouse Achilles tendinopathy model. The expressions of inflammatory cytokines (IL-1ß, IL-6, TNF-α, IL-10) and FABP4 increased in hypercellular region, round cells chondrocyte-like cells and calcified regions in the mouse Achilles tendons post-collagenase injection. A single injection of FABP4 in mouse Achilles tendons induced histopathological changes resembling tendinopathy, with increased cell rounding, loss of collagen fiber alignment, and additionally presence of chondrocyte-like cells and calcification post-injection. The expressions of IL1-ß, IL-6, TNF-α and IL-10 increased in mouse Achilles tendons post-FABP4 injection. FABP4 increased the expressions of IL10, IL6, and TNFa in human TDSCs as well as the expressions of Il1b, Il6, and Il10 in mouse TDSCs. Human tendinopathy TDSCs expressed higher level of FABP4 compared to healthy hamstring TDSCs. Besides, IL-1ß increased the expression of FABP4 in mouse TDSCs. Conclusion: In conclusion, an upregulation of FABP4 is involved in excessive inflammation and pathogenesis of tendinopathy. TDSCs is a potential source of FABP4 during tendon inflammation. Translation potential of this article: FABP4 can be a potential treatment target of tendinopathy.

Empirical assessment of carbon emissions in Guangdong Province within the framework of carbon peaking and carbon neutrality: a lasso-TPE-BP neural network approach.

The escalating global greenhouse gas emission crisis necessitates a robust scientific carbon accounting framework and innovative development approaches. Achieving emission peaks remains the primary goal for emission reduction. Guangdong Province, a pivotal region in China, faces pressure to reduce carbon emissions. In this study, data was leveraged from the China Carbon Accounting Database (CEADS) and panel data from the "Guangdong Statistical Yearbook" spanning 1997 to 2022. Factors impacting carbon emissions were selected based on Guangdong Province's carbon reduction goals, macroeconomic development strategies, and economic-population dynamics. To address multicollinearity, lasso regression identified key factors, including population size, economic development level, energy intensity, and technology factors. A novel STIRPAT extended model, combined with the BP neural network optimized using the TPE algorithm, enhanced carbon emission predictions for Guangdong Province. Employing scenario analysis, five scenarios were generated in alignment with the planning policies of Guangdong Province, to forecast carbon emissions from 2020 to 2050. The results suggest that to achieve a win-win situation for both economic development and environmental protection, Guangdong Province should prioritize the energy-saving scenario (S2), which aligns with the "13th Five-Year Plan's" ecological and green development directives, to reach a projected carbon peak of 637.05Mt by 2030. In conclusion, recommendations for carbon reduction are proposed in the areas of low-carbon transformation for the population, sustainable economic development, and the development of low-carbon technologies.

Folic acid enhances the cardiovascular protective effect of amlodipine in renal hypertensive rats with elevated homocysteine.

OBJECTIVES: To investigate the actions of amlodipine-folic acid (amlodipine-FA) preparation on hypertension and cardiovascular in renal hypertensive rats with hyperhomocysteinemia (HHcy), so as to provide experimental basis for clinical research of amlodipine folic acid tablets. METHODS: Rats model of renal hypertension with HHcy were established. The rats were randomly divided into groups of model, amlodipine, folic acid (FA) and amlodipine-FA of various dosages. Normal rats were used as normal control group. Blood pressure, Hcy as well as plasma NO, ET-1 and hemodynamics were assayed. Histological alterations of heart and abdominal aorta were also examined. RESULTS: Compared with the normal group, blood pressure, plasma Hcy, and NO of the rats in model group were significantly increased, while the plasma ET-1 was decreased. Compared with the normal group, the animals in the model group had reduced cardiac function, thickened wall of the aorta and narrowed lumen. In FA group and amlodipine group, the rat plasma NO was increased while ET-1 was decreased, the protective effect of amlodipine-FA group on endothelial cells was further enhanced. In amlodipine group, the rat hemodynamics (LVSP, LVEDP and ±dp/dtmax, et al.) and vascular damage were significantly reduced, while in amlodipine-FA group, the heart function were further improved, and myocardial and vascular hypertrophy were significantly reduced. CONCLUSIONS: As compared to amlodipine alone, amlodipine -FA can lower both blood pressure and plasma Hcy, significantly enhancing vascular endothelial function to protect the heart and blood vessel in renal hypertensive rats with HHcy.

Stromal cell-derived factor-1 may play pivotal role in distraction-stimulated neovascularization of diabetic foot ulcer.

Diabetic foot ulcer (DFU) has become a major medical, social and economic concern worldwide. It is highly desirable to develop promising new solutions to effectively and appropriately treat DFU. In recent years, investigators have used an innovative technology called proximal tibial cortex transverse distraction (PTCTD) to treat DFU and have achieved satisfactory results in terms of improved wound healing and circumvention of amputation as a consequence of enhanced neovascularization and perfusion of the ulcerated feet after the operation, but the underlying mechanism has not been explored. Previous studies have suggested that in addition to stimulating osteogenesis, bone distraction also facilitates neovascularization, which may be associated with the chemokine stromal cell-derived factor-1 (SDF-1). As an important member of the chemokine family, SDF-1 is primarily responsible for the homing and migration of endothelial progenitor cells (EPCs) or bone marrow-derived mesenchymal stem cells (BMSCs), and plays a central role in the process of neovascularization. In vivo or in vitro experiments show that bone distraction can induce the expression of SDF-1 and increase its plasma concentration. Moreover, some researchers have found that an insufficient level of SDF-1 in the circulation and wounds of patients with DFU can lead to impaired neovascularization. Therefore, we believe that SDF-1 plays an important role in promoting neovascularization of DFU as a result of bone distraction. We summarize the currently relevant literature to put forward an undisclosed but meaningful mechanism of bone distraction in the treatment of DFU.

High-resolution bimodal imaging and potent antibiotic/photodynamic synergistic therapy for osteomyelitis with a bacterial inflammation-specific versatile agent.

Unsatisfactory diagnosis and therapy of osteomyelitis are still common but challenging issues for clinicians. To overcome these problems, a bacterial inflammation-specific multifunctional agent, denoted bovine serum albumin-manganese dioxide-ubiquicidin29-41-indocyanine green (ICG) -gentamicin (BMUIG), was synthesized for combined high-resolution bimodal imaging and antibiotic/photodynamic therapy for osteomyelitis. BMUIG binding affinity and antibacterial ability were assessed by using Staphylococcus aureus (S. aureus). Photoacoustic/magnetic resonance imaging was performed on a mouse model of acute osteomyelitis after intravenous injection of BMUIG. Then, myelitis-bearing mice were treated with antibiotic/photodynamic combination therapy. BMUIG specifically targeted S. aureus in comparison with non-targeted agents. In the osteomyelitis model, the infection area was identified accurately and quickly through ICG-based photoacoustic imaging and Mn2+-based T1 magnetic resonance imaging after injection of BMUIG. Furthermore, the manganese dioxide in BMUIG reacted with the locally produced hydrogen peroxide under acidic inflammatory conditions, continuously generating oxygen for enhanced photodynamic therapy. In combination with low-dose gentamicin, a synergistic antibacterial effect was observed and bone infection was resolved. In summary, a non-invasive accurate diagnosis and effective synergistic therapy for osteomyelitis was successfully developed using a bacterial inflammation-specific versatile agent, which would provide a sound theranostic strategy for common infectious diseases. STATEMENT OF SIGNIFICANCE: Osteomyelitis is one of the most serious consequences in orthopedics. However, its inaccurate diagnosis and low-effective antibiotic treatment are still common but challenging issues for clinicians. To overcome these problems, we uniquely designed a bacterial inflammation-specific multifunctional nanoagent, bovine serum albumin-manganese dioxide-ubiquicidin29-41-indocyanine green-gentamicin (BMUIG), for high-resolution bimodal imaging and antibiotic/photodynamic combined therapy of osteomyelitis. Herein, high-resolution imaging technologies refer to classic magnetic resonance imaging and emerging photoacoustic imaging. Photodynamic therapy is subtly introduced because of its safe and effective killing mechanism, which can synergize the bactericidal effect of antibiotics. As a result, we successfully realize non-invasive accurate diagnosis and effective synergistic therapy for osteomyelitis by virtue of the bacterial inflammation-specific versatile agent, which will serve as a promising candidate for sound theranostics in common infectious diseases.

LncRNA ZEB2-AS1 promotes pancreatic cancer cell growth and invasion through regulating the miR-204/HMGB1 axis.

Recently, lncRNA ZEB2-AS1 was identified as a lncRNA that promoted cancer progression. However, the biological function and the underlying mechanism of ZEB2-AS1 in pancreatic cancer had not been reported. In the current study, we revealed that the expression level of ZEB2-AS1 was elevated in pancreatic cancer cell lines and tissues. ZEB2-AS1 inhibition decreased cell growth and invasion in pancreatic cancer. Mechanismly, ZEB2-AS1 exerted as a ceRNA and negatively regulated miR-204 expression. In addition, HMGB1 was identified as a down-stream target of miR-204. The miR-204/HMGB1 axis mediated ZEB2-AS1's effect on pancreatic cancer. Our findings revealed that lncRNA ZEB2-AS1 may be a candidate prognostic biomarker and a target for new therapies in pancreatic cancer patients.

An Innovative Approach for Enhancing Bone Defect Healing Using PLGA Scaffolds Seeded with Extracorporeal-shock-wave-treated Bone Marrow Mesenchymal Stem Cells (BMSCs).

Although great efforts are being made using growth factors and gene therapy, the repair of bone defects remains a major challenge in modern medicine that has resulted in an increased burden on both healthcare and the economy. Emerging tissue engineering techniques that use of combination of biodegradable poly-lactic-co-glycolic acid (PLGA) and mesenchymal stem cells have shed light on improving bone defect healing; however, additional growth factors are also required with these methods. Therefore, the development of novel and cost-effective approaches is of great importance. Our in vitro results demonstrated that ESW treatment (10 kV, 500 pulses) has a stimulatory effect on the proliferation and osteogenic differentiation of bone marrow-derived MSCs (BMSCs). Histological and micro-CT results showed that PLGA scaffolds seeded with ESW-treated BMSCs produced more bone-like tissue with commitment to the osteogenic lineage when subcutaneously implanted in vivo, as compared to control group. Significantly greater bone formation with a faster mineral apposition rate inside the defect site was observed in the ESW group compared to control group. Biomechanical parameters, including ultimate load and stress at failure, improved over time and were superior to those of the control group. Taken together, this innovative approach shows significant potential in bone tissue regeneration.

Phage display-derived oligopeptide-functionalized probes for in vivo specific photoacoustic imaging of osteosarcoma.

Specific detection of various tumor types remains crucial for designing effective treatment strategies. We demonstrate photoacoustic imaging (PAI) using high-affinity and high-specificity peptide-based probes for accurate and specific diagnosis of osteosarcoma. Herein, two new tumor-specific oligopeptides, termed PT6 and PT7, were identified using phage display-based screening on an osteosarcoma cell line (UMR-106). The identified oligopeptides were able to detect clinical osteosarcoma samples on tissue microarrays. Oligopeptide-conjugated PEGylated gold nanorods (PGNR) were designed to specifically target UMR-106 cells. More importantly, PAI revealed that both PGNR-PT6 and PGNR-PT7 could bind selectively to subcutaneous UMR-106 xenografts after systemic administration and enhance the contrast of osteosarcoma images by 170% and 230%, respectively, compared to tumor-bearing mice injected with PGNRs conjugated to scrambled oligopeptides. PAI employing PGNRs conjugated to specifically designed nanoprobes may provide a new method for tumor type-specific diagnosis of osteosarcoma.

Prostaglandin E2 and Connexin 43 crosstalk in the osteogenesis induced by extracorporeal shockwave.

As a type of mechanical stimulation, extracorporeal shockwave (ESW) has been widely used in the clinic to treat bone fracture delayed union and non-unions. A large number of studies have shown beneficial effects of ESW in promoting fracture healing by inducing bone regeneration; however, the underlying mechanisms remain unclear. ESW has been shown to induce the production of prostaglandin E2 (PGE2), which is essential for gap junction intercellular communication in response to mechanical stress. Among the 19 known gap junction subunits, connexin43 (Cx43) is the most prevalent for mediating the response of mechanical stress. However, to our knowledge, the effect of ESW on Cx43 expression has not been reported before. Herein, we propose that a crosstalk between PGE2 and Cx43 is involved in the enhancement of osteogenesis induced by ESW. We review the currently available data to propose an unrevealed, but important mechanism via which ESW treatment affects osteogenic differentiation of bone marrow stromal cells.

Focal Adhesion Kinase Signaling Mediated the Enhancement of Osteogenesis of Human Mesenchymal Stem Cells Induced by Extracorporeal Shockwave.

Extracorporeal shockwave (ESW) has been shown of great potential in promoting the osteogenesis of bone marrow mesenchymal stem cells (BMSCs), but it is unknown whether this osteogenic promotion effect can also be achieved in other MSCs (i.e., tendon-derived stem cells (TDSCs) and adipose-derived stem cells (ADSCs)). In the current study, we aimed not only to compare the osteogenic effects of BMSCs induced by ESW to those of TDSCs and ADSCs; but also to investigate the underlying mechanisms. We show here that ESW (0.16 mj/mm(2)) significantly promoted the osteogenic differentiation in all the tested types of MSCs, accompanied with the downregulation of miR-138, but the activation of FAK, ERK1/2, and RUNX2. The enhancement of osteogenesis in these MSCs was consistently abolished when the cells were pretreated with one of the following conditions: overexpression of miR-138, FAK knockdown using specific siRNA, and U0126, implying that all of these elements are indispensable for mediating the effect of ESW. Moreover, our study provides converging genetic and molecular evidence that the miR-138-FAK-ERK1/2-RUNX2 machinery can be generally activated in ESW-preconditioned MSCs, suggesting that ESW may be a promising therapeutic strategy for the enhancement of osteogenesis of MSCs, regardless of their origins.