Artemisinin relieves osteoarthritis by activating mitochondrial autophagy through reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling in cartilage.

Osteoarthritis (OA) is a widespread chronic degenerative joint disease characterized by the degeneration of articular cartilage or inflamed joints. Our findings indicated that treatment with artemisinin (AT) downregulates the protein levels of MMP3, MMP13, and ADAMTS5, which are cartilage degradation-related proteins in OA, and inhibits the expression of inflammatory factors in interleukin-1ß (IL-1ß)-stimulated chondrocytes. However, the mechanism of the role of AT in OA remains unclear. Here, we performed gene sequencing and bioinformatics analysis in control, OA, and OA + AT groups to demonstrate that several mRNA candidates were enriched in the PI3K/AKT/mTOR signaling pathway, and TNFSF11 was significantly downregulated after AT treatment. TNFSF11 was downregulated in the OA + AT group, whereas it was upregulated in rat OA tissues and OA chondrocytes. Therefore, we confirmed that TNFSF11 was the target gene of AT. In addition, our study revealed that AT relieved cartilage degradation and defection by activating mitochondrial autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in IL-1ß-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. Injecting AT into the knee joints of OA rat alleviated surgical resection-induced cartilage destruction. Thus, these findings revealed that AT relieves OA by activating mitochondrial autophagy by reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling.

A Subpopulation of Luminal Progenitors Secretes Pleiotrophin to Promote Angiogenesis and Metastasis in Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer characterized by rapidly arising diffuse erythema and edema. Genomic studies have not identified consistent alterations and mechanisms that differentiate IBC from non-IBC tumors, suggesting that the microenvironment could be a potential driver of IBC phenotypes. Here, using single-cell RNA sequencing, multiplex staining, and serum analysis in patients with IBC, we identified enrichment of a subgroup of luminal progenitor (LP) cells containing high expression of the neurotropic cytokine pleiotrophin (PTN) in IBC tumors. PTN secreted by the LP cells promoted angiogenesis by directly interacting with the NRP1 receptor on endothelial tip cells located in both IBC tumors and the affected skin. NRP1 activation in tip cells led to recruitment of immature perivascular cells in the affected skin of IBC, which are correlated with increased angiogenesis and IBC metastasis. Together, these findings reveal a role for cross-talk between LPs, endothelial tip cells, and immature perivascular cells via PTN-NRP1 axis in the pathogenesis of IBC, which could lead to improved strategies for treating IBC. SIGNIFICANCE: Nonmalignant luminal progenitor cells expressing pleiotrophin promote angiogenesis by activating NRP1 and induce a prometastatic tumor microenvironment in inflammatory breast cancer, providing potential therapeutic targets for this aggressive breast cancer subtype.

The features of male breast cancer in China: A real-world study.

BACKGROUND: Male breast cancer (MBC) is a rare disease. Although several large-scale studies have investigated MBC patients in other countries, the features of MBC patients in China have not been fully explored. This study aims to explore the features of Chinese MBC patients comprehensively. METHODS: We retrospectively collected data of MBC patients from 36 centers in China. Overall survival (OS) was evaluated by the Kaplan-Meier method, log-rank test, and Cox regression analyses. Multivariate Cox analyses were used to identify independent prognostic factors of the patients. RESULTS: In total, 1119 patients were included. The mean age at diagnosis was 60.9 years, and a significant extension over time was observed (P < 0.001). The majority of the patients (89.1 %) received mastectomy. Sentinel lymph node biopsy was performed in 7.8 % of the patients diagnosed in 2009 or earlier, and this percentage increased significantly to 38.8 % in 2020 or later (P < 0.001). The five-year OS rate for the population was 85.5 % [95 % confidence interval (CI), 82.8 %-88.4 %]. Multivariate Cox analysis identified taxane-based [T-based, hazard ratio (HR) = 0.32, 95 % CI, 0.13 to 0.78, P = 0.012] and anthracycline plus taxane-based (A + T-based, HR = 0.47, 95 % CI, 0.23 to 0.96, P = 0.037) regimens as independent protective factors for OS. However, the anthracycline-based regimen showed no significance in outcome (P = 0.175). CONCLUSION: As the most extensive MBC study in China, we described the characteristics, treatment and prognosis of Chinese MBC population comprehensively. T-based and A + T-based regimens were protective factors for OS in these patients. More research is required for this population.

Statistical analysis of human papillomavirus in a subset of upper aerodigestive tract tumors.

Human papilloma virus (HPV) has been detected in some upper aerodigestive tract tumors, but the correlation between HPV and these tumors is not well understood. There is also some controversy regarding this correlation because a large variation in the prevalence of HPV in these tumors has been reported. To discuss the impact of HPV infection on upper aerodigestive tract tumors, this review estimated systematically the prevalence and risk of HPV in upper aerodigestive tract tumors from studies published between 1982 and 2012. In total, 418 articles were selected, which included 273 studies on the head and neck and 145 studies on esophageal squamous cell carcinoma. The overall prevalence of HPV in the 5,467 head and neck squamous cell carcinoma specimens was 36.3%. HPV was detected more frequently in the Americas (40%), than in Asia (38.6%), Europe (32%), or others regions (30.5%). The prevalence of HPV was significantly higher in oropharyngeal (48.5%) than in oral (32.5%), laryngeal (30.7%), and unselected head and neck squamous cell carcinoma (33.3%) (P < 0.001). The pooled prevalence of HPV in the 6,912 esophageal squamous cell carcinoma cases was 38.9% and it was significantly higher in China (44%) versus other regions (31.3%) (P < 0.05). Meta-analysis showed that head and neck and esophageal squamous cell carcinoma are associated with HPV infection (combined OR: 3.58, OR for head and neck and esophageal squamous cell carcinoma: 4.20). These findings suggest that HPV might be linked etiologically to the development of some upper aerodigestive tract tumors.

Predicting survival of patients with bone metastasis of unknown origin.

Purpose: Bone metastasis of unknown origin is a rare and challenging situation, which is infrequently reported. Therefore, the current study was performed to analyze the clinicopathologic features and risk factors of survival among patients with bone metastasis of unknown origin. Patients and methods: We retrospectively analyzed the clinical data for patients with bone metastasis of unknown origin between 2010 and 2016 based on the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were first analyzed by applying univariable Cox regression analysis. Then, we performed multivariable analysis to confirm independent survival predictors. Results: In total, we identified 1224 patients with bone metastasis of unknown origin for survival analysis, of which 704 males (57.5%) and 520 females (42.5%). Patients with bone metastasis of unknown origin had a 1-year OS rate of 14.50% and CSS rate of 15.90%, respectively. Race, brain metastasis, liver metastasis, radiotherapy, and chemotherapy were significant risk factors of OS on both univariable and multivariable analyses (p <0.05). As for CSS, both univariable and multivariable analyses revealed that no brain metastasis, no liver metastasis, radiotherapy, and chemotherapy were associated with increased survival (p <0.05). Conclusion: Patients with bone metastasis of unknown origin experienced an extremely poor prognosis. Radiotherapy and chemotherapy were beneficial for prolonging the survival of those patients.

Inhibition of HDAC6 by Tubastatin A reduces chondrocyte oxidative stress in chondrocytes and ameliorates mouse osteoarthritis by activating autophagy.

The aim of this study was to determine the effect of HDAC6 inhibition using the selective inhibitor Tubastatin A (TubA) on the regulation of tert-butyl hydroperoxide (TBHP)-treated chondrocytes and a mouse OA model. Using conventional molecular biology methods, our results showed that the level of HDAC6 increases both in the cartilage of osteoarthritis (OA) mice and TBHP-treated chondrocytes in vitro. TubA treatment effectively inhibits the expression of HDAC6, attenuates oxidative stress, reduces the level of apoptotic proteins to maintain chondrocyte survival, and suppresses the extracellular matrix (ECM) degradation. In addition, our results also revealed that HDAC6 inhibition by TubA activates autophagy in chondrocytes, whereas the protective effects of TubA were abolished by autophagy inhibitor intervention. Subsequently, the positive effects of HDAC6 inhibition by TubA were also found in a mouse OA model. Therefore, our study provide evidence that HDAC6 inhibition prevents OA development, and HDAC6 could be applied as a potential therapeutic target for OA management.

Biological homeostasis-inspired light-excited multistage nanocarriers induce dual apoptosis in tumors.

In the microenvironment of an organism, each element always regulates and compensates for each other's defects, finally achieving biostable equilibrium. Herein, inspired by the balance of biological homeostasis and the interconstraint of elements, light-responsive nanoparticle with anti-vascularization and oxygen-supplying ability such like a homeostasis body is constructed by the electrostatic adsorption of reactive oxygen species (ROS)-responsive copolymers with photosensitizers and oxygen donors, which act as the elements of homeostasis body can interact through multistage reactions forming a balance that induces double apoptosis including those caused by the photosensitizer itself and those induced after oxygenation. In this homeostasis body, the element photosensitizer can simultaneously generate hyperthermia and ROS. The former can not only inhibit the growth of blood vessels and promote cell necrosis, but induce the thermally responsive release of oxygen to alleviate tumor hypoxia for enhanced PDT. And the latter will induce rapid depolymerization of nanoparticles, promote the penetration and finally induce double apoptosis through multistage reactions. Immunofluorescence data further demonstrate that the nanoparticles significantly alleviated tumor hypoxia upon photoexcitation. Thus, such nanoparticles with multistage synergistic effects have demonstrated excellent effects in achieving biostable equilibrium to induce dual apoptosis and may also be a good strategy in hypoxic tumors therapy.

The Development of Inhibitors Targeting the Mixed Lineage Leukemia 1 (MLL1)-WD Repeat Domain 5 Protein (WDR5) Protein- Protein Interaction.

Mixed Lineage Leukemia 1 (MLL1), an important member of Histone Methyltransferases (HMT) family, is capable of catalyzing mono-, di-, and trimethylation of Histone 3 lysine 4 (H3K4). The optimal catalytic activity of MLL1 requires the formation of a core complex consisting of MLL1, WDR5, RbBP5, and ASH2L. The Protein-Protein Interaction (PPI) between WDR5 and MLL1 plays an important role in abnormal gene expression during tumorigenesis, and disturbing this interaction may have a potential for the treatment of leukemia harboring MLL1 fusion proteins. In this review, we will summarize recent progress in the development of inhibitors targeting MLL1- WDR5 interaction.

Magnolol induces human Ewing sarcoma SK-ES-1 cell apoptosis via the mitochondrial and death receptor pathways.

New treatments for Ewing's sarcoma (ES) are urgently needed. Magnolol, an active ingredient in Magnolia officinalis, shows anti-oxidative, anti-microbial, and anti-tumor effects, but its effect on ES is unknown. We examined the effect of magnolol on ES cell proliferation and apoptosis in vitro as well as the mechanism of its anticancer effect. The results demonstrated that magnolol inhibited the proliferation of ES and induced ES cell apoptosis through the mitochondrial and death receptor pathways. Magnolol reduced MEK1/2, ERK1/2, and STAT3 phosphorylation in ES cells, suggesting that the MAPK/ERK and JAK/STAT3 signal transduction pathways are involved in the inhibition of ES cell growth by magnolol. In short, magnolol is a potential anti-ES drug.

Cell Membrane-Inspired Polymeric Vesicles for Combined Photothermal and Photodynamic Prostate Cancer Therapy.

Photothermal therapy (PTT) and photodynamic therapy (PDT) have emerged as highly prospective therapeutic modalities in cancer therapy. Notwithstanding, a critical challenge still remains in the exploration of an effective strategy to maximize the synergistic efficacy of PTT and PDT due to low photoconversion efficiency. Herein, inspired by the phospholipid bimolecular structure of the cell membrane, bionic cell membrane polymeric vesicles with photothermal/photodynamic synergy for prostate cancer therapy at one wavelength's excitation are constructed in one step by the coordination of hexadecyl trimethyl ammonium bromide (CTAB) from the surface of hydrophobic gold nanorods (AuNRs) with indocyanine green (ICG) and polycaprolactone (PCL), achieving their self-assembly in aqueous solutions. Importantly, the aggregation of the assembly improves the stability of the vesicles, realizing the synergistic effect of PTT and PDT for prostate cancer therapy. After being assembled within polymeric vesicles, bifunctional photosensitizer ICG can generate reactive oxygen species (ROS) and photothermal effect under light treatment. Their ROS not only induce PDT efficacy but also destroy the integrity of the lysosomal membrane, promoting the translocation of ICG and another photosensitizer called gold nanorods (AuNRs) into the cytosol. Moreover, their photothermal effects produced by both photosensitizers are able to engender greater damage to the tumor cells because of the close distance with organelles. This structure manifests good cellular uptake, highly effective tumor accumulation, high photothermal conversion efficiency, and excellent properties of enhanced photobleaching resistance, which are beneficial to ICG-based fluorescence tumor imaging. Using the same near-infrared (NIR) wavelength for excitation, the AuNR/ICG vesicles can reduce the side effect rate of photodamage on the skin. In addition, by generating reactive oxygen species (ROS) and double photothermal effect, the vesicles under NIR excitation can promote the apoptosis of PC3 tumor cells. Taken together, the spontaneous self-assembled AuNR/ICG vesicles exhibit huge potential in advanced-stage prostate cancer therapy, especially for the prostate-specific membrane antigen (PSMA)-negative castration-resistant subtype.

Th9 Cell Differentiation and Its Dual Effects in Tumor Development.

With the improved understanding of the molecular pathogenesis and characteristics of cancers, the critical role of the immune system in preventing tumor development has been widely accepted. The understanding of the relationship between the immune system and cancer progression is constantly evolving, from the cancer immunosurveillance hypothesis to immunoediting theory and the delicate balance in the tumor microenvironment. Currently, immunotherapy is regarded as a promising strategy against cancers. Although adoptive cell therapy (ACT) has shown some exciting results regarding the rejection of tumors, the effect is not always satisfactory. Cellular therapy with CD4+ T cells remains to be further explored since the current ACT is mainly focused on CD8+ cytotoxic T lymphocytes (CTLs). Recently, Th9 cells, a subgroup of CD4+ T helper cells characterized by the secretion of IL-9 and IL-10, have been reported to be effective in the elimination of solid tumors and to exhibit superior antitumor properties to Th1 and Th17 cells. In this review, we summarize the most recent advances in the understanding of Th9 cell differentiation and the dual role, both anti-tumor and pro-tumor effects, of Th9 cells in tumor progression.

MicroRNA-451 blockade promotes osteoblastic differentiation and skeletal anabolic effects by promoting YWHAZ-mediated RUNX2 protein stabilization.

Background: senile osteoporosis researchers are now seeking to promote osteoblastogenesis and resultant bone formation to directly counteract age-related bone loss. Targeting microRNA (miRNA) activity in adult osteoblasts may be a successful therapeutic strategy for age-related bone loss. We investigated the mechanism(s) by which miRNAs negatively regulate osteoblastogenesis and bone formation in vitro and in vivo. Methods: we performed a miRNA microarray screen followed by PCR validation in adult bone marrow-derived mesenchymal stem cells during the proliferation-to-mineralization transition to identify downregulated miRNAs, most notably miR-451. Primary human calvarial pre-osteoblasts were isolated and transfected with miR-451's agomir or antagomir for in vitro assays. Bioinformatics analysis and in vitro experiments verified YWHAZ as a miR-451 target gene. We next investigated the effects of YWHAZ knockdown on osteoblastic differentiation. To examine the effects of miR-451's antagomir in vivo, we injected ovariectomized (OVX) or sham-operated mice with miR-451's antagomir over a period of six weeks. We isolated stromal cells from murine bone marrow on week six for further ex vivo experimentation. Results: miR-451's antagomir stimulated pre-osteoblast differentiation into a more differentiated, mineralized phenotype. This phenotype was associated with upregulated RUNX2, ALP, and COL1A1 protein expression. miR-451's antagomir derepresses YWHAZ expression, thereby enhancing RUNX2 protein stability and promoting osteoblastic differentiation. When injected in vivo, miR-451's antagomir promotes osteoblastogenesis and mineralization, reversed OVX-induced bone loss, and increased bone strength in OVX and sham-operated mice. Conclusions: miR-451 suppresses osteoblastogenesis in vitro and in vivo. miR-451 inhibition may serve as an effective anabolic therapeutic strategy in senile osteoporosis patients.

[Case-control study on the effect of core strength training on the function of anterior cruciate ligament reconstruction].

OBJECTIVE: To observe the effect of core strength training on knee joint function and postural stability after anterior cruciate ligament reconstruction (ACLR). METHODS: A total of 80 ACLR patients were randomly allocated into conventional rehabilitation training group and core strength training group from May 2013 to May 2015 with 40 patients in each group. The patients in conventional rehabilitation training group underwent conventional ACLR rehabilitation training, in which 28 males and 12 females. The mean age was(30.5±5.2) years old(ranged, 22 to 42 years old). The mean BMI was(23.8±2.4) kg/m²(ranged, 18.2 to 25.9 kg/m²). Thirty patients had injuries on the dominant side and 10 patients had injuries on the non-dominant side. The core strength training group received conventional ACLR rehabilitation training and core strength training, in which 31 males and 9 females. The mean age was(31.1±4.8) years old(ranged, 21 to 45 years old). The mean BMI was(24.1±2.7) kg/m²(ranged, 18.5 to 26.1 kg/m²) . Twenty-seven patients had injuries on the dominant side and 13 patients had injuries on the non-dominant side. The Lysholm score, tibial anterior transition measured by KT-1000 before and after treatment, and the Star Excursion Balance Test results after treatment were compared between the two groups. RESULTS: Six months after rehabilitation training, the tibial anterior transition of the conventional rehabilitation training group and the core strength training group were(3.4±1.0) mm and(3.3±1.2) mm respectively, which were less than(12.1±1.8) mm and(12.5±2.0) mm before treatment. But there was no significant difference in anterior tibial translation between two groups(P>0.05). The Lysholm score of the conventional rehabilitation training group and the core strength training group were 91.8±4.3 and 92.1±3.9 individually, which were higher than 69.2±5.8 and 70.2±5.1 before treatment. But there was no significant difference in Lysholm score between two groups(P>0.05). Six months after rehabilitation training, the results of Star Excursion Balance Test showed the reach distance with the support in the injured side and healthy side in the core strength training group were greater than that of the conventional rehabilitation training group in the eight directions(P<0.05). CONCLUSIONS: The core strength training could improve the dynamic balance of ACLR patients.