Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age‐related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) ...regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y‐box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis‐splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age‐related osteoporosis.
Synopsis
Alternative splicing has been shown to regulate cellular senescence and differentiation. This study links the reduced expression of the splicing regulator YBX1 in aging bone marrow stromal cells to senescence and aging‐related bone loss.
The expression level of YBX1 in BMSCs decreases during aging.
Ybx1 overexpression in BMSCs stimulates bone formation, while its deletion accelerates bone loss.
YBX1 suppresses BMSC senescence and modulates BMSC differentiation by controlling RNA splicing.
The small compound sciadopitysin attenuates YBX1 degradation and bone loss in old mice.
Reduced expression of YBX1 in aging bone marrow stromal cells induces their senescence and bone loss due to mRNA mis‐splicing.
Plantar fasciitis (PF) is the most common cause of heel pain. Among conservative treatments, extracorporeal shock wave therapy (ESWT) is considered effective for refractory PF. Studies have shown ...that applying ESWT to the trigger points (TrPs) in the triceps surae may play an important role in pain treatment in patients with PF. Therefore, the purpose of this study was to combine the concept of trigger points and ESWT to explore the effect of this combination on plantar temperature and pressure in patients with PF.
After applying inclusion and exclusion criteria, 86 patients with PF were recruited from the pain clinic of Huadong Hospital, Fudan University and randomly divided into experimental (n = 43) and control groups (n = 43). The experimental group was treated with extracorporeal shock waves to treat the medial heel pain point and the gastrocnemius and soleus TrPs. The control group was only treated with extracorporeal shock waves at the medial heel pain point. The two groups were treated twice with an interval of 1 week. Primary measurements included a numerical rating scale (NRS) score (overall, first step, heel pain during daily activities), and secondary measurements included heel temperature, Roles-Maudsley score (RMS), and plantar pressure. All assessments were performed before treatment (i.e., baseline) and 6 and 12 weeks after treatment.
During the trial, 3 patients in the experimental group withdrew from the study, 2 due to interruption of the course of treatment by the COVID-19 epidemic and 1 due to personal reasons. In the control group, 3 patients fell and were removed due to swelling of the heel. Therefore, only 80 patients with PF were finally included. After treatment, the two groups showed good results in NRS score (overall, first step, heel pain during daily activities), RMS, and plantar temperature, especially in the experimental group, who showed a significantly better effect than the control group.
ESWT of the heel combined with the triceps trigger point of the calf can more effectively improve the pain, function and quality of life of refractory PF than ESWT of the heel alone. In addition, ESWT of the heel combined with the triceps trigger point of the calf can effectively reduce the skin temperature of the heel on the symptomatic side, indicating that the heel temperature as measured by infrared thermal imaging may be used as an independent tool to evaluate the therapeutic effect for patients with chronic PF. Although extracorporeal shock waves combined with TrPs treatment can cause changes in the patients' gait structure, plantar pressure is still difficult to use as an independent tool to evaluate the therapeutic effect for PF.
Registered in the Chinese Clinical Trial Registry ( www.chictr.org.cn ) on 12/17/2021 with the following code: ChiCTR-INR-2,100,054,439.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Altered Krüppel‐like factor 9 (KLF9) expression can regulate the progression of several cancers, including renal cell carcinoma (RCC). This study was conducted to investigate the role of KLF9 in the ...proliferation, invasion, and migration of RCC cells via regulation of stromal cell‐derived factor‐1 (SDF‐1)/CXC chemokine receptor 4 (CXCR4). The expression patterns of KLF9, SDF‐1, and CXCR4 in the experimental cell lines were determined by real‐time quantitative polymerase chain reaction and Western blotting. After transfection of the KLF9 siRNA and KLF9 pcDNA, cell proliferation, invasion, and migration were evaluated by experiments including cell counting kit‐8, colony formation, and Transwell assays. The binding of KLF9 to the SDF‐1 promoter was analyzed by chromatin immunoprecipitation and dual‐luciferase assay. The rescue experiment was performed using the recombinant SDF‐1 protein and KLF9 pcDNA. KLF9 was downregulated in the RCC cells. KLF9 knockdown induced the proliferation, invasion, and migration of RCC cells, whereas KLF9 overexpression elicited the opposite roles. Mechanically, KLF9 bound to the SDF‐1 promoter, repressed SDF‐1 transcription, and reduced the SDF‐1/CXCR4 expression levels. Activation of the SDF‐1/CXCR4 axis attenuated the inhibitory role of KLF9 overexpression in RCC cell growth. Ordinarily, KLF9 suppressed the proliferation, invasion, and migration of RCC cells by repressing the SDF‐1/CXCR4 signaling.
Latent and active myofascial trigger points (MTrPs) in knee-associated muscles may play a key role in pain management among patients with knee osteoarthritis (KOA). The aim of this study was to ...investigate the effect of dry needling treatment on pain intensity, disability, and range of motion (ROM) in patients with KOA.
This randomized, single-blinded, clinical trial was carried out for 6 weeks of treatment and 6-month follow-up. A total of 98 patients met the entry criteria and were randomly assigned to the dry needling latent and active myofascial trigger point (MTrPs) with the stretching group or the oral diclofenacwith the stretching group. Numeric Pain Rating Scale (NPRS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and ROM were statistically analyzed before and after treatment and at the 6-month follow-up.
A total of 42 patients in the dry needling group (DNG) and 35 patients in the diclofenac group (DG), respectively, completed the study, and there was no significant difference in the general data between the two groups. After treatments, both the groups showed a good effect in knee pain, function, and ROM, However, the DNG showed a significantly better result than the DG. Especially in the results of the 6-month follow-up, the DNG showed much better results than the DG.
Dry needling on latent and active MTrPs combined with stretching and oral diclofenac combined with stretching can effectively relieve pain, improve function, and restore knee ROM affected by KOA. However, the effects of dry needling and stretching are better and longer lasting than those of oral diclofenac and stretching for at least 6 months.
Registered in the Chinese Clinical Trial Registry ( www.chictr.org.cn ) in 17/11/2017 with the following code: ChiCTR-INR-17013432.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Myofascial pain syndrome (MPS) is characterized by myofascial trigger points and fascial constrictions. At present, domestic and foreign scholars have not reached a consensus on the etiology and ...pathogenesis of MPS. Due to the lack of specific laboratory indicators and imaging evidence, there is no unified diagnostic criteria for MPS, making it easy to confuse with other diseases. The Chinese Association for the Study of Pain organized domestic experts to formulate this Chinese Pain Specialist Consensus on the diagnosis and treatment of MPS. This article reviews relevant domestic and foreign literature on the definition, epidemiology, pathogenesis, clinical manifestation, diagnostic criteria and treatments of MPS. The consensus is intended to normalize the diagnosis and treatment of MPS and be used by first-line doctors, including pain physicians to manage patients with MPS.
To investigate the effects of trigger point dry needling (TrP-DN) on exercise-induced patellofemoral pain syndrome (PFPS).
In this randomized, single-blind, parallel-group trial, 50 patients with ...PFPS were randomly allocated to the following two groups: the TrP-DN group (n = 25) and the Sham needling group (n = 25). Patients in both groups were asked to perform a stretching exercise of the quadriceps daily after needling. The needling group received a single session of TrP-DN to trigger points (TrPs) in the vastus medialis oblique (VMO), vastus lateralis (VL), and rectus femoris muscles (once a week for 6 weeks), and the Sham group received placebo needling. Visual analogue scale (VAS) for pain intensity and Kujala questionnaire for the functional status were assessed before treatment, 3 and 6 weeks after treatment, and at the 3-month follow-up. The ratio of the myoelectric amplitude of the vastus medialis oblique and vastus lateralis muscles (VMO/VL) was assessed before treatment and 6 weeks after treatment.
There was no significant difference in the general data between the two groups. The VAS scores and Kujala scores in the TrP-DN group were significantly improved and increased at the 3-week treatment visit, 6-week treatment visit, and 3-month follow-up compared to the scores before treatment; and the scores in the Sham group were only significantly improved at the 3-week treatment visit, and 6-week treatment visit. VAS scores in the TrP-DN group were significantly lower and Kujala scores were significantly higher at the 6-week treatment visit and the 3-month follow-up compared to those in the Sham group. The VMO/VL ratio in the TrP-DN group was significantly increased at the 6-week treatment visit compared to that before treatment.
TrP-DN at the quadriceps combined with stretch can reduce the pain, and improves the clinical symptoms and function, the VMO/VL ratio, and the coordination of VMO and VL in patients with PFPS.
As angiogenesis and vasculogenesis involve the complex network structures of various types of cells, extracellular matrix components, and cytokines, it is still difficult to exactly mimic the ...microenvironment of vascularization in vivo. In our study, we constructed a complex containing highly proliferative fibroblasts that can secrete extracellular matrix components and growth factors to chemotaxize endothelial progenitor cells (EPCs) in an attempt to create an ideal microenvironment for quick vascularization. Amniotic membrane microparticles (mAM) rich in type IV collagen (COL IV) and laminin (LN) were prepared, and human dermal fibroblasts (HDF) were infected with lentivirus (LV) of overexpression of SDF-1α to construct SDF-1αovHDF. Using the rotary cell culture system (RCCS), mAM was loaded with HDF or SDF-1αovHDF to construct HDF-mAM and SDF-1αovHDF-mAM complexes. The complexes were able to secrete various types of active peptides (IL-6, IL-8, TGF-β, and bFGF) during in vitro culture. In addition, SDF-1αovHDF-mAM complex highly expressed SDF-1α. Transwell assay showed SDF-1αovHDF-mAM complex had an apparent chemotactic effect on EPCs. Transplantation of complexes onto full-thickness skin defects of C57BL mice further demonstrated that SDF-1α expression and the number of peripheral EPCs at days 3, 5, and 7 in the SDF-1αovHDF-mAM group were significantly higher than that in other groups (p < 0.01). The local microvascular density at day 10 of transplantation showed that the microvascular density in the SDF-1αovHDF-mAM group was significantly higher than that in HDF-mAM group (p < 0.01). In conclusion, HDF-mAM had a strong proliferative activity and could be used to create a sound microenvironment for quick vascularization by secreting multiple cytokines and extracellular matrix components. Overexpression of SDF-1α could chemotaxize EPCs to reach local wounds, thus further accelerating angiogenesis in the transplant site. The technique described may prove to be a new model for accelerating vascularization of tissue and organ transplants and chronic ischemic wounds.
Summary
Introduction
The delta opioid peptide D‐Ala2, D‐Leu5enkephalin (DADLE) plays a key role in neuronal protection against both hypoxic and ischemic conditions. However, the cellular mechanisms ...of action of DADLE under these conditions remain unclear.
Methods
Ischemia was simulated with perfusing the brain slices with glucose‐free artificial cerebrospinal fluid. Apoptosis was examined using an in situ cell death detection kit and expressed as the percentage of positively labeled neurons relative to total number of neurons. PCR was performed by adding cDNA, 5 pm dNTP, 1 μL Taqase, and primers. PCR products were separated with electrophoresis, stained with ethidium bromide, and visualized under ultraviolet light.
Aims
To investigate the potential effects of DADLE in an ex vivo model of cerebral ischemia/reperfusion.
Results
DADLE attenuated lactic dehydrogenase release and neuronal apoptosis in a concentration‐dependent manner. The protective effects of DADLE were attenuated by representative selective delta2, but not delta1 opioid antagonists. Treatment with PD98059, a selective inhibitor of ERK kinase (MEK), also blocked the protective effect of DADLE as well as ERK phosphorylation induced by DADLE.
Conclusions
Endogenous opioid peptides could promote cell survival via delta2 opioid receptors, possibly through the downstream MEK‐ERK pathway.
The ability to effectively detect bacterial infection in human tissues is important for the timely treatment of the infection. However, traditional techniques fail to visualize bacterial species ...adhered to host cells in situ in a target-specific manner. Dihydropteroate synthase (DHPS) exclusively exists in bacterial species and metabolically converts p-aminobenzoic acid (PABA) to folic acid (FA). By targeting this bacterium-specific metabolism, we have developed a fluorescent imaging probe, PABA-DCM, based on the conjugation of PABA with a long-wavelength fluorophore, dicyanomethylene 4H-pyran (DCM). We confirmed that the probe can be used in the synthetic pathway of a broad spectrum of Gram-positive and negative bacteria, resulting in a significantly extended retention time in bacterial over mammalian cells. We validated that DHPS catalytically introduces a dihydropteridine group to the amino end of the PABA motif of PABA-DCM, and the resulting adduct leads to an increase in the FA levels of bacteria. We also constructed a hydrogel dressing containing PABA-DCM and graphene oxide (GO), termed PABA-DCM@GO, that achieves target-specific fluorescence visualization of bacterial infection on the wounded tissues of mice. Our research paves the way for the development of fluorescent imaging agents that target species-conserved metabolic pathways of microorganisms for the in situ monitoring of infections in human tissues.
Tetranuclear complexes constructed from asymmetrical N,N′-bis(substituted)oxamide have been synthesized and characterized by X-ray single-crystal diffraction. The cytotoxicities and reactivities ...towards DNA of the two complexes have been investigated. Display omitted
► Two tetranuclear complexes have been synthesized and characterized. ► The two complexes exhibit cytotoxicities against SMMC-7721 and A549 cell lines. ► The DNA-binding abilities are consistent with cytotoxicities in the order 2>1. ► The terminal ligands are very important in the DNA-binding and cytotoxic properties.
Two new circular tetranuclear copper(II) complexes, Cu4(dmoxba)2(bpy)2(CH3OH)2(pic)2·2H2O (1) and Cu4(dmoxba)2(phen)2(pic)2·2CH3OH (2), where dmoxba, pic, bpy and phen stand for the anion of 2-{N′-2-(dimethylamino)ethyloxamido}benzoate, picrate, 2,2′-bipyridine and 1,10-phenanthroline, respectively, have been synthesized and structurally characterized by X-ray single-crystal diffraction. Both the complexes have embedded inversion centers and similar complex cations assembled by the oxamide-bridges and carboxylate-bridges of two cis-dmoxba3− ligands. The Cu⋯Cu separations through the oxamide-bridge and the carboxylato-bridge are 5.1991(4) and 5.4674(4)Å in 1 and 5.1843(5) and 5.2138(5)Å in 2, respectively. Both copper(II) ions are in square-pyramidal environments in 1. While in complex 2, the inner and exo copper(II) ions have square-planar and square-pyramidal coordination geometries, respectively. In both the crystals, three-dimensional supramolecular structures are formed by hydrogen bonds and π–π stacking interactions. The DNA-binding properties and anticancer activities of the two complexes were investigated. The results suggest that the two complexes interact with HS-DNA in the mode of intercalation with the intrinsic binding constants 5.0×104M−1 (1) and 6.7×104M−1 (2). The influence of structural variation of the terminal ligands in the tetranuclear complexes on DNA-binding properties is preliminarily discussed.
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