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Osteoarthritis (OA), a common degenerative joint disease, is characterized by the progressive degradation of articular cartilage and inflammation. Hederagenin (HE) is a pentacyclic triterpenoid saponin extracted from many herb plants. It has anti-inflammatory, anti-lipid peroxidative, anti-cancer, and neuroprotective activities. However, its effect on OA has not been investigated. Our study found that HE may be a potential anti-OA drug. In vitro, HE could suppress extracellular matrix (ECM) degradation via up-regulating aggrecan and Collagen II levels as well as downregulating MMPs and ADAMTS5 levels. It could also reduce proinflammatory and inflammatory cytokines or enzymes production, including TNF-α, IL-6, iNOS, COX-2, NO, and PGE

Purpose This study aimed to investigate the interactions between posaconazole (POS) and intravenously/orally administered Cyclosporine A (CsA) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Methods We included 118 allogeneic HSCT patients who received CsA and POS simultaneously between January 2017 and June 2020 this study. The ratio of CsA blood concentration (ng/mL) to dosage (mg/day) (C/D) before and after POS initiation was compared. Results After the initiation of POS, the level of CsA increased 1 to 2 times in 66% (78/118) of patients compared to those without POS. However, the CsA C/D ratio increased by more than threefold in 6% (7/118) of patients after POS initiation, with an increase of more than fourfold in two patients. The median C/D ratio of CsA increased from 0.89 to 1.23 (P

Recently, the role of the gut microbiota in diseases, including cardiovascular disease (CVD), has gained considerable research attention. Trimethylamine-N-oxide (TMAO), which is formed during ʟ-carnitine metabolism, promotes the formation of atherosclerotic plaques, causing thrombosis. Here, we elucidated the anti-atherosclerotic effect and mechanism of ginger (Zingiber officinale Roscoe) essential oil (GEO) and its bioactive compound citral in Gubra Amylin NASH (GAN) diet with ʟ-carnitine-induced atherosclerosis female ApoE−/− mice. Treatment with GEO at both low and high doses and citral inhibited the formation of aortic atherosclerotic lesions, improved plasma lipid profile, reduced blood sugar, improved insulin resistance, decreased plasma TMAO levels, and inhibited plasma inflammatory cytokines, especially interleukin-1β. Additionally, GEO and citral treatment modulated gut microbiota diversity and composition by increasing the abundance of beneficial microbes and decreasing the abundance of CVD-related microbes. Overall, these results showed that GEO and citral may serve as potential dietary supplements for CVD prevention by improving gut microbiota dysbiosis.

Background The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Methods Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Results Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen. Conclusion Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.

Guidelines recommend primary prophylactic (PP) granulocyte colony stimulating factor (G-CSF) for prevention of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy with high risk (HR: 20%), or intermediate risk (IR:10-20%) of FN and ≥ 1 patient risk factor (e.g., age ≥ 65y). The current retrospective cohort study describes patterns of PP-G-CSF in older Medicare patients undergoing myelosuppressive chemotherapy with HR/IR of FN.Patients aged ≥ 66y initiating chemotherapy regimens with HR/IR of FN to treat breast, colorectal, lung, or ovarian cancer, or Non-Hodgkin's Lymphoma were selected using Medicare 20% sample (2013-2015) and 100% cancer patient (2014-2017) data. PP-G-CSF use was identified in the first cycle. Timing of pegfilgrastim pre-filled syringe (PFS) administration, proportion of patients completing all cycles (adherence) with pegfilgrastim PFS or on-body injector (OBI), and duration of short-acting G-CSF (sG-CSF) was described across all cycles.Of 64,893 patients receiving HR/IR for FN, 71% received HR and 29% IR regimens. Overall, PP-G-CSF use in the first cycle was 53% (HR: 74%; IR: 44%) and varied across cancers. Adherence with pegfilgrastim was slightly higher among OBI initiators (78%) than PFS (74%). Number of PP-sG-CSF administrations (mean [SD]) per cycle was 5.1 (SD: 2.7) overall, 5.4 (2.6) for HR, and 4.9 (2.7) for IR.Despite cancer treatment guidelines recommending PP-G-CSF use to reduce risk of FN associated with HR and IR (with ≥ 1 patient risk-factor) regimens, PP-G-CSF remains underutilized in older patients, across cancer types and regimens. Opportunities exist for improvement in use of PP-G-CSF.

Nucleus pulposus (NP) cells play a critical role in maintaining intervertebral disc integrity through producing the components of extracellular matrix (ECM). NP cell dysfunction, including senescence and hyper-apoptosis, has been regarded as critical events during intervertebral disc degeneration development. In the present study, we found that Transcription Factor 7-Like 2 (TCF7L2) was overexpressed within degenerative intervertebral disc tissue samples, and TCF7L2 silencing improved lipopolysaccharide (LPS)-induced repression on NP cell proliferation, ECM synthesis, and LPS-induced NP cell senescence. miR-1260b directly targeted TCF7L2 and inhibited TCF7L2 expression. miR-1260b overexpression improved LPS-induced degenerative changes in NP cells; more importantly, TCF7L2 overexpression significantly reversed the effects of miR-1260b overexpression on LPS-stimulated degenerative changes within NP cells. For the first time, we demonstrated the function of the miR-1260b/TCF7L2 axis on the phenotypic maintenance of chondrocyte-like NP cells and ECM synthesis by NP cells under LPS stimulation.

Purpose To explore the outcomes of bone augmentation in the aesthetic zone of the anterior teeth using computer-aided design and a 3D-printed template. Methods Ten patients with severe bone defects in the aesthetic zone of anterior teeth were included in the study; CT data were collected before surgery. The design of the osteotomy line in the bone defect area was determined under computer simulation. The position parameters and osteotomy line of the free bone were determined via virtual surgery. A 3D-printed template was prepared to guide the accurate placement of the bone graft. Reexamination was conducted to evaluate the position of the bone graft immediately after the operation and the resorbed capacity of the bone graft before implant restoration. Results The position of the bone graft was consistent with the preoperative design. The amount of bone graft resorbed was within the acceptable range three months after the operation, and the effect of implant restoration was satisfactory. Clinical significance Use of computer-aided design and a 3D-printed template can be an effective approach for accurate bone augmentation in the aesthetic zone of the anterior teeth.

Purpose To evaluate and compare different surgical approaches for the treatment of Helveston syndrome and provide further information for preoperative planning. Methods From February 2008 to December 2018, data of 52 patients with Helveston syndrome were retrospectively reviewed. Different surgical approaches were selected based on the extent of A-pattern exotropia, dissociated vertical deviation (DVD), and both superior oblique muscle overaction (SOOA) with fundus photograph intorsion. Eye position, A-pattern, DVD, superior oblique muscle function, and binocular vision function were evaluated pre- and postoperatively. The average follow-up duration was 20.5 months. Results Nine cases underwent simultaneous horizontal deviation correction with bilateral superior rectus recession, 24 underwent simultaneous horizontal deviation correction with bilateral superior oblique muscle lengthening, and 19 underwent two stages of horizontal deviation correction with superior oblique muscle lengthening, and later bilateral superior rectus recession. A-pattern, DVD, SOOA, and fundus intorsion were all collapsed in all patients postoperatively. Forty-five patients had an orthophoric eye position with considerably aligned ocular movements postoperatively. The total success rate was 86.5%. Postoperatively, eight of the 10 patients with diplopia experienced a recovery of binocular single vision and three had a recovery of rudimentary stereopsis (Titmus 3000–400 s of arc). The compensatory head posture of patients improved significantly postoperatively. Conclusions The surgical planning of Helveston syndrome should be designed based on the degree of the A-pattern, SOOA, DVD, and the intorsion in fundus photographs, and the appropriate approach should be selected to improve patient satisfaction.