Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α-XBP1s pathway.

Periprosthetic osteolysis and subsequent aseptic loosening are the primary causes of failure following total joint arthroplasty. Wear particle-induced osteogenic impairment is recognized as an important contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress emerging as a pivotal underlying mechanism. Hence, searching for potential therapeutic targets and agents capable of modulating ER stress in osteoblasts is crucial for preventing aseptic loosening. Kaempferol (KAE), a natural flavonol compound, has shown promising osteoprotective effects and anti-ER stress properties in diverse diseases. However, the influence of KAE on ER stress-mediated osteogenic impairment induced by wear particles remains unclear. In this study, we observed that KAE effectively relieved TiAl6V4 particles-induced osteolysis by improving osteogenesis in a mouse calvarial model. Furthermore, we demonstrated that KAE could attenuate ER stress-mediated apoptosis in osteoblasts exposed to TiAl6V4 particles, both in vitro and in vivo. Mechanistically, our results revealed that KAE mitigated ER stress-mediated apoptosis by upregulating the IRE1α-XBP1s pathway while concurrently partially inhibiting the IRE1α-regulated RIDD and JNK activation. Collectively, our findings suggest that KAE is a prospective therapeutic agent for treating wear particle-induced osteolysis and highlight the IRE1α-XBP1s pathway as a potential therapeutic target for preventing aseptic loosening.

A Low Systemic Inflammatory Response Index Is Associated With Improved Survival in Adenoid Cystic Carcinoma Patients.

BACKGROUND: Predicting the long-term survival in adenoid cystic carcinoma (ACC) patients remains challenging. Inflammatory cell-based indices are emerging as prognostic indicators of oncology. PURPOSE: This study aimed to determine the associations between the preoperative systemic inflammatory response index (SIRI) and the systemic immunoinflammatory index (SII) and the 10-year survival rates in patients with ACC of the head and neck (ACCHN). STUDY DESIGN, SETTING, SAMPLE: This retrospective cohort study comprised ACCHN patients treated at the Chinese People's Liberation Army General Hospital between November 2003 and December 2020. PREDICTOR VARIABLE: The inflammatory response, assessed using the SIRI and SII, was the predictor variable. The optimal cutoff values were based on the maximum Youden index values (sensitivity ＋ specificity－1). The patients were divided into two groups each, based on the SIRI (low, ≤ 0.15) and (high, > 0.15), and SII (low, ≤ 562.8 and high, > 562.8) values. MAIN OUTCOME VARIABLE(S): Overall survival (OS), or the number of days, weeks, or months between treatment initiation and death (or the last follow-up date), was the primary outcome variable. COVARIATES: The covariates were classified as demographic (age, gender, body mass index), medical (hypertension, diabetes), inflammatory (neutrophils, lymphocytes, monocytes, platelets, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, neutrophil-lymphocyte ratio), and perioperative (tumor stage, lymph node metastasis, tumor size, treatment type). ANALYSES: Descriptive, univariate, and multivariate Cox proportional risk regression analyses were performed to determine whether the SIRI and SII were independent prognostic factors for OS. Kaplan-Meier survival curves and log-rank tests were used to determine their associations with the OS. RESULTS: The study sample comprised 162 patients (mean age, 52 ± 14; males, 39.5%). The median follow-up time was 6.81 ± 0.23, and the 10-year OS rate was 7.68 ± 0.25. The low and high SIRI groups comprised 109 and 53 patients, while the low and high SII groups comprised 116 and 46 patients, respectively. SIRI was identified as a prognostic factor (P < .01; hazard ratio, 2.45; 95% confidence interval, 1.35-4.45). CONCLUSION AND RELEVANCE: The SIRI has the advantages of reproducibility, convenience, noninvasiveness, and affordability, making it a promising prognostic inflammatory index for patients with ACCHN.

Protective Effects of Total Alkaloids from Menispermum dauricum against Airway Inflammation in Asthmatic Mice.

Menispermum dauricum is widely used to treat respiratory inflammation, including laryngopharyngitis, tonsillitis, tracheitis, and bronchitis. Total alkaloids isolated from M. dauricum have shown a variety of beneficial bioactivities. However, available data on the effects of M. dauricum total alkaloids against allergic asthma has not been reported. In present study, the protective effect of M. dauricum total alkaloids was evaluated by using an ovalbumin-induced in vivo model of asthma. The asthma model was prepared by sensitizing and challenging mice with ovalbumin, and M. dauricum total alkaloids (100, 200, and 400 mg/kg) were administrated to asthmatic mice by gavage. Histopathological analysis of pulmonary changes was detected by hematoxylin and eosin, and periodic acid-schiff staining. Inflammatory cell counts were determined in bronchoalveolar lavage fluid. Total immunoglobulin E and ovalbumin-specific immunoglobulin E levels in serum, and T-helper 2 cytokines and chemokine levels in bronchoalveolar lavage fluid were detected by an ELISA. Histological results demonstrated that M. dauricum total alkaloids significantly attenuated pulmonary inflammation in asthmatic mice. M. dauricum total alkaloid treatment exhibited marked effects on asthmatic mice in reducing inflammatory cell counts, decreasing interleukin-4, interleukin-5, and interleukin-13 concentrations, and downregulating TNF-α and eotaxin levels in bronchoalveolar lavage fluid. In addition, M. dauricum total alkaloids could also inhibit the elevated serum levels of total immunoglobulin E and ovalbumin-specific immunoglobulin E. These findings confirmed that M. dauricum total alkaloids could suppress airway inflammation in ovalbumin-induced asthma through regulating the T-helper 2 response and chemokine level. M. dauricum total alkaloids may be a potential ethnopharmacological agent for asthmatic patients.

Correction to: Bilobalide protects against ischemia/reperfusion-induced oxidative stress and inflammatory responses via the MAPK/NF-κB pathways in rats.

An amendment to this paper has been published and can be accessed via the original article.

Bilobalide protects against ischemia/reperfusion-induced oxidative stress and inflammatory responses via the MAPK/NF-íœ B pathways in rats.

BACKGROUND: Clinically, skeletal muscle ischemia/reperfusion injury is a life-threatening syndrome that is often caused by skeletal muscle damage and is characterized by oxidative stress and inflammatory responses. Bilobalide has been found to have antioxidative and anti-inflammatory effects. However, it is unclear whether bilobalide can protect skeletal muscle from ischemia/reperfusion injury. METHODS: The effects of bilobalide on ischemia/reperfusion-injured skeletal muscle were investigated by performing hematoxylin and eosin staining and assessing the wet weight/dry weight ratio of muscle tissue. Then, we measured lipid peroxidation, antioxidant activity and inflammatory cytokine levels. Moreover, Western blotting was conducted to examine the protein levels of MAPK/NF-휅B pathway members. RESULTS: Bilobalide treatment could protected hind limb skeletal muscle from ischemia/reperfusion injury by alleviating oxidative stress and inflammatory responses via the MAPK/NF-휅B pathways. CONCLUSIONS: Bilobalide may be a promising drug for I/R-injured muscle tissue. However, the specific mechanisms for the protective effects still need further study.

miR-181c-5p mediates simulated microgravity-induced impaired osteoblast proliferation by promoting cell cycle arrested in the G2 phase.

Impaired osteoblast proliferation plays fundamental roles in microgravity-induced bone loss, and cell cycle imbalance may result in abnormal osteoblast proliferation. However, whether microgravity exerts an influence on the cell cycle in osteoblasts or what mechanisms may underlie such an effect remains to be fully elucidated. Herein, we confirmed that simulated microgravity inhibits osteoblast proliferation. Then, we investigated the effect of mechanical unloading on the osteoblast cell cycle and found that simulated microgravity arrested the osteoblast cell cycle in the G2 phase. In addition, our data showed that cell cycle arrest in osteoblasts from simulated microgravity was mainly because of decreased cyclin B1 expression. Furthermore, miR-181c-5p directly inhibited cyclin B1 protein translation by binding to a target site in the 3'UTR. Lastly, we demonstrated that inhibition of miR-181c-5p partially counteracted cell cycle arrest and decreased the osteoblast proliferation induced by simulated microgravity. In conclusion, our study demonstrates that simulated microgravity inhibits cell proliferation and induces cell cycle arrest in the G2 phase in primary mouse osteoblasts partially through the miR-181c-5p/cyclin B1 pathway. This work may provide a novel mechanism of microgravity-induced detrimental effects on osteoblasts and offer a new avenue to further investigate bone loss induced by mechanical unloading.

Simulated microgravity reduces intracellular-free calcium concentration by inhibiting calcium channels in primary mouse osteoblasts.

Calcium homeostasis in osteoblasts plays fundamental roles in the physiology and pathology of bone tissue. Various types of mechanical stimuli promote osteogenesis and increase bone formation elicit increases in intracellular-free calcium concentration in osteoblasts. However, whether microgravity, a condition of mechanical unloading, exerts an influence on intracellular-free calcium concentration in osteoblasts or what mechanisms may underlie such an effect are unclear. Herein, we show that simulated microgravity reduces intracellular-free calcium concentration in primary mouse osteoblasts. In addition, simulated microgravity substantially suppresses the activities of L-type voltage-sensitive calcium channels, which selectively allow calcium to cross the plasma membrane from the extracellular space. Moreover, the functional expression of ryanodine receptors and inositol 1,4,5-trisphosphate receptors, which mediate the release of calcium from intracellular storage, decreased under simulated microgravity conditions. These results suggest that simulated microgravity substantially reduces intracellular-free calcium concentration through inhibition of calcium channels in primary mouse osteoblasts. Our study may provide a novel mechanism for microgravity-induced detrimental effects in osteoblasts, offering a new avenue to further investigate bone loss induced by mechanical unloading.

Costal Cartilage Assessment in Surgical Timing of Microtia Reconstruction.

BACKGROUND: Rib cartilage growth is closely related to age and determines the feasibility and outcomes of auricular reconstruction. Ear reconstruction is performed as early as age 6 in efforts to treat children before school matriculation while allowing for sufficient rib growth. But there is controversy over the optimal timing of microtia reconstruction. This study employs CT imaging and surface scanning to guide the timing of auricular reconstruction in children. METHODS: A retrospective analysis was performed on 6-year-old microtia patients between January 2016 and June 2016. A total of 37 patients were underwent preoperative 3D rib-cage CT measurements and normal auricle scanning measurement including: the length of 6th, 7th, and 8th costal cartilage, the width of 6th,and 7th costal cartilage, and the length of normal auricle. Then the data of costal cartilage were compared with the data of the auricle. RESULTS: The average length of the 6th, 7th, and 8th rib cartilage on the right was 76.1 ±â€Š9.2 mm (range, 61.1-94.9 mm), 102.6 ±â€Š9.9 mm (range, 84.5-119.1 mm), and 75.4 ±â€Š19.3 mm (range, 47.3-118.5 mm), respectively, and the the average helical length was 90.5 ±â€Š6.8 mm (range, 76.9-101.5 mm). Comparing the above data, it was revealed that the age of 6 years was an optimal time for ear reconstruction with tissue-expanding technique. CONCLUSIONS: 3D rib-cage CT for preoperative measurement of costal cartilage could be a useful method for planning microtia reconstruction. According to our study, the amount of costal cartilage of almost all 6-year-old microtia patients is enough for ear reconstruction. So age 6 years is the optimal timing of auricular reconstruction with tissue-expanding method.

The secreted fructose 1,6-bisphosphate aldolase as a broad spectrum vaccine candidate against pathogenic bacteria in aquaculture.

The development of aquaculture has been hampered by different aquatic pathogens that can cause edwardsiellosis, vibriosis, or other diseases. Therefore, developing a broad spectrum vaccine against different fish diseases is necessary. In this study, fructose 1,6-bisphosphate aldolase (FBA), a conserved enzyme in the glycolytic pathway, was demonstrated to be located in the non-cytoplasmic components of five aquatic pathogenic bacteria and exhibited remarkable protection and cross-protection against these pathogens in turbot and zebrafish. Further analysis revealed that sera sampled from vaccinated turbot had a high level of specific antibody and bactericidal activity against these pathogens. Meanwhile, the increased expressions of immune response-related genes associated with antigen recognition and presentation indicated that the adaptive immune response was effectively aroused. Taken together, our results suggest that FBA can be utilized as a broad-spectrum vaccine against various pathogenic bacteria of aquaculture in the future.

Experimental study on determining the degree of bone healing by wall thickness ratio analysis.

To verify the reliability and accuracy of wall thickness ratio analysis to determine the degree of bone healing, fracture models were established with 6 beagles. X-ray, micro-CT, and CT scans were performed at 24 weeks. The healthy side and the affected side were used to simulate the three-dimensional geometric model after internal fixation, and the mesh was divided. The mean and median CT wall thickness values were obtained through the wall thickness analysis. X-ray, CT, micro-CT, and gross appearance were used to determine the degree of bone healing, which was compared with wall thickness analysis. There was a positive correlation between the average CT value and the median wall thickness. The correlation coefficient analysis of the median wall thickness ratio (R2) and healing index ratio (R3) showed a positive correlation. The results of the wall thickness ratio (R2) and the healing index ratio (R3) were used to determine bone healing, and the results were consistent with the results of the actual mechanical test and image analysis. The results of wall thickness ratio analysis were significantly correlated with the degree of bone healing. This method is simple, rapid, and practical to analyze and judge the degree of bone healing.

Pretreatment with a modified St. Thomas' solution in patients with severe upper limb injuries: Four case reports.

BACKGROUND: This study aims to describe the application of a modified St. Thomas' solution in patients with severe limb injuries. CASE SUMMARY: Four patients who sustained a high-energy trauma and underwent complete upper limb amputation were pretreated with a modified St. Thomas' solution before upper limb replantation. After the perfusion solution stopped flowing from the blood vessel, the amputated upper limb amputation was replanted. The patients were instructed to perform functional rehabilitation training after the operation. All 4 patients were followed up for 5 years. All the severed upper limbs survived. Routine re-examination after the operation showed that the function of the affected limb was restored. All the patients were satisfied with the sensory and functional recovery of the affected limb. CONCLUSION: The modified St. Thomas' solution can effectively improve the success rate of limb salvage surgery and the recovery of limb function in patients with a severe limb injury.

Particle-induced osteolysis is mediated by endoplasmic reticulum stress-associated osteoblast apoptosis.

Osteoblast dysfunction plays a crucial role in periprosthetic osteolysis and aseptic loosening, and endoplasmic reticulum (ER) stress is recognized as an important causal factor of wear particle-induced osteolysis. However, the influence of ER stress on osteoblast activity during osteolysis and its underlying mechanisms remain elusive. This study aims to investigate whether ER stress is involved in the detrimental effects of wear particles on osteoblasts. Through our investigation, we observed elevated expression levels of ER stress and apoptosis markers in particle-stimulated bone specimens and osteoblasts. To probe further, we employed the ER stress inhibitor, 4-PBA, to treat particle-stimulated osteoblasts. The results revealed that 4-PBA effectively alleviated particle-induced osteoblast apoptosis and mitigated osteogenic reduction. Furthermore, our study revealed that wear particle-induced ER stress in osteoblasts coincided with mitochondrial damage, calcium overload, and oxidative stress, all of which were effectively alleviated by 4-PBA treatment. Encouragingly, 4-PBA administration also improved bone formation and attenuated osteolysis in a mouse calvarial model. In conclusion, our results demonstrate that ER stress plays a crucial role in mediating wear particle-induced osteoblast apoptosis and impaired osteogenic function. These findings underscore the critical involvement of ER stress in wear particle-induced osteolysis and highlight ER stress as a potential therapeutic target for ameliorating wear particle-induced osteogenic reduction and bone destruction.

Bone and soft tissue reaction to Co(II)/Cr(III) ions stimulation in a murine calvaria model: A pioneering in vivo study.

Metal ions released during wear and corrosion of the artificial knee/hip joints are considered to contribute to aseptic implant failure. However, there are few convincing in vivo studies that demonstrate the effects of metal ions on bone and soft tissue. This study examined the in vivo effects of Co(II)/Cr(III) ions on mouse calvaria and the supra-calvaria soft tissue in an original mouse model. With the implantation of a helmet-like structure, we set up a subcutaneous cavity on the calvaria in which Co(II) Chloride or Cr(III) Chloride solutions were administered respectively. A layer of interface membrane formed on the calvaria along with the implantation of the helmet. The administered Cr(III) ions accumulated in the interface membranes while Co(II) disseminated into the circulation. Accumulated Cr(III) and related products induced local massive macrophage infiltration and skewed the bone metabolic balance. At last, we revealed that lymphocyte aggregates, which are the pathologic hallmark of human periprosthetic tissue, could be caused by either Co(II) or Cr(III) stimulation. These in vivo results may shed light on the effects and pathogenic mechanism of the Co(II)/Cr(III) ions released from the joint prosthesis. STATEMENT OF SIGNIFICANCE: Macrophage infiltration and lymphocyte aggregates are hallmarks of human joint periprosthetic tissue. We chronically administered Co(II)/Cr(III) ions on mouse calvaria and reproduced these two histopathologic hallmarks on mouse tissue based on an implanted helmet-like structure. Our results reveal that Cr(III) ions are locally accumulated and are effective in inducing macrophage infiltration and they can be phagocytosed and stored. However, the lymphocytes aggregates could be induced by both Co(II), Cr(III) and other unspecific inflammatory stimuli.

Inhibitory effects of Formononetin on CoCrMo particle-induced osteoclast activation and bone loss through downregulating NF-κB and MAPK signaling.

Wear particle-induced osteoclast over-activation is a major contributor to periprosthetic osteolysis and aseptic loosening, which can cause pathological bone loss and destruction. Hence, inhibiting excessive osteoclast-resorbing activity is an important strategy for preventing periprosthetic osteolysis. Formononetin (FMN) has been shown to have protective effects against osteoporosis, but no previous study has evaluated the effects of FMN on wear particle-induced osteolysis. In this study, we found that FMN alleviated CoCrMo alloy particles (CoPs)-induced bone loss in vivo and inhibited the formation and bone-resorptive function of osteoclasts in vitro. Moreover, we revealed that FMN exerted inhibitory effects on the expression of osteoclast-specific genes via the classical NF-κB and MAPK signaling pathways in vitro. Collectively, FMN is a potential therapeutic agent for the prevention and treatment of periprosthetic osteolysis and other osteolytic bone diseases.

Jujuboside A Exhibits an Antiepileptogenic Effect in the Rat Model via Protection against Traumatic Epilepsy-Induced Oxidative Stress and Inflammatory Responses.

Traumatic brain injuries (TBI) are the greatest source of death in trauma, and post-traumatic epilepsy (PTE) is one of the common complications of TBI. Oxidative stress and inflammatory responses play an important role in the process of PTE. Many studies have shown that Jujuboside A has powerful antioxidant and anti-inflammatory properties. However, it is not known whether Jujuboside A has an anti-epileptic effect. The influences of Jujuboside A in the experimental FeCl3-induced model of PTE were tested by estimating the grade of seizures and performing behavioral tests. Following that, we detected oxidative stress indicators and inflammatory factors. Additionally, western blotting was used to test the protein levels of signaling molecules in MAPK pathways. In this study, Jujuboside A was found to have improved the recognition deficiency and epilepsy syndromes in the experimental rat model. Moreover, oxidative stress and inflammatory responses induced by FeCl3 injection were relieved by Jujuboside A. In addition, Jujuboside A was found to be capable of reducing the increased expression of p-P38 and p-ERK1/2 caused by iron ions. Collectively, our results demonstrated that Jujuboside A exhibits an antiepileptogenic effect by alleviating oxidative stress and inflammatory responses via the p38 and ERK1/2 pathways.

Enteropathogenic Escherichia coli Mediates CoCrMo Particle-Induced Peri-Implant Osteolysis by Increasing Peripheral 5-HT.

The human gut microbiota has been proven to have great effects on the regulation of bone health. However, the association between gut microbiota and particle-induced osteolysis, which is the primary cause of aseptic loosening, is still unknown. In this study, we used a combination of wide-spectrum antibiotics to eliminate the majority of gut microbiota and found that reduction of gut commensal bacteria significantly alleviated the progression of osteolysis, in which anaerobe was the biggest culprit in the exacerbation of osteolysis. Furthermore, colonization of enteropathogenic Escherichia coli (EPEC), a subspecies of anaerobe, could promote the development of particle-induced osteolysis by increasing the secretion of peripheral 5-hydroxytryptamine (5-HT) from the colon. Elevated 5-HT level decreased the phosphorylation of CREB and inhibited the proliferation of osteoblasts. Collectively, these results indicated EPEC colonization suppressed the bone formation and aggravated particle-induced osteolysis in vivo. Thus, clearance of EPEC is expected to become a potential preventive approach to treat debris-induced osteolysis and aseptic loosening.