Dihydrotanshinone I inhibits gallbladder cancer growth by targeting the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation.

BACKGROUND: Gallbladder cancer (GBC) poses a significant risk to human health. Its development is influenced by numerous factors, particularly the homeostasis of reactive oxygen species (ROS) within cells. This homeostasis is crucial for tumor cell survival, and abnormal regulation of ROS is associated with the occurrence and progression of many cancers. Dihydrotanshinone I (DHT I), a biologically effective ingredient isolated from Salvia miltiorrhiza, has exhibited cytotoxic properties against various tumor cells by inducing apoptosis. However, the precise molecular mechanisms by which dht I exerts its cytotoxic effects remain unclear. PURPOSE: To explore the anti-tumor impact of dht I on GBC and elucidate the potential molecular mechanisms. METHODS: The proliferation of GBC cells, NOZ and SGC-996, was assessed using various assays, including CCK-8 assay, colony formation assay and EdU staining. We also examined cell apoptosis, cell cycle progression, ROS levels, and alterations in mitochondrial membrane potential to delve into the intricate molecular mechanism. Quantitative PCR (qPCR), immunofluorescence staining, and Western blotting were performed to evaluate target gene expression at both the mRNA and protein levels. The correlation between nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1) were examined using co-immunoprecipitation. Finally, the in vivo effect of dht I was investigated using a xenograft model of gallbladder cancer in mice. RESULTS: Our research findings indicated that dht I exerted cytotoxic effects on GBC cells, including inhibiting proliferation, disrupting mitochondrial membrane potential, inducing oxidative stress and apoptosis. Our in vivo studies substantiated the inhibition of dht I on tumor growth in xenograft nude mice. Mechanistically, dht I primarily targeted Nrf2 by promoting Keap1 mediated Nrf2 degradation and inhibiting protein kinase C (PKC) induced Nrf2 phosphorylation. This leads to the suppression of Nrf2 nuclear translocation and reduction of its target gene expression. Moreover, Nrf2 overexpression effectively counteracted the anti-tumor effects of dht I, while Nrf2 knockdown significantly enhanced the inhibitory effect of dht I on GBC. Meanwhile, PKC inhibitors and nuclear import inhibitors increased the sensitivity of GBC cells to dht I treatment. Conversely, Nrf2 activators, proteasome inhibitors, antioxidants and PKC activators all antagonized dht I induced apoptosis and ROS generation in NOZ and SGC-996 cells. CONCLUSION: Our findings indicated that dht I inhibited the growth of GBC cells by regulating the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation. These insights provide a strong rationale for further investigation of dht I as a potential therapeutic agent for GBC treatment.

Intestinal microbiota and biliary system diseases.

Introduction: The incidence of biliary system diseases has been continuously increasing in the past decade. Biliary system diseases bring a heavy burden to humanity and society. However, the specific etiology and pathogenesis are still unknown. The biliary system, as a bridge between the liver and intestine, plays an indispensable role in maintaining the physiological metabolism of the body. Therefore, prevention and treatment of biliary diseases are crucial. It is worth noting that the microorganisms participate in the lipid metabolism of the bile duct, especially the largest proportion of intestinal bacteria. Methods: We systematically reviewed the intestinal microbiota in patients with gallstones (GS), non-calculous biliary inflammatory, and biliary tract cancer (BTC). And searched Pubmed, Embase and Web of science for research studies published up to November 2023. Results: We found that the abundance of Faecalibacterium genus is decreased in GS, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and BTC. Veillonella, Lactobacillus, Streptococcus and Enterococcus genus were significantly increased in PSC, PBC and BTC. Interestingly, we found that the relative abundance of Clostridium was generally reduced in GS, PBC and BTC. However, Clostridium was generally increased in PSC. Discussion: The existing research mostly focuses on exploring the mechanisms of bacteria targeting a single disease. Lacking comparison of multiple diseases and changes in bacteria during the disease process. We hope to provide biomarkers forearly diagnosis of biliary system diseases and provide new directions for the mechanism of intestinal microbiota in biliary diseases.

Gallbladder cancer: surgical treatment, immunotherapy, and targeted therapy.

Gallbladder cancer is a common type of biliary tract tumor. Optimal management for early stage cases typically involves radical excision as the primary treatment modality. Various surgical techniques, including laparoscopic, robotic, and navigational surgery, have demonstrated favorable clinical outcomes in radical gallbladder excision. Unfortunately, most patients are ineligible for surgical intervention because of the advanced stage of the disease upon diagnosis. Consequently, non-surgical interventions, such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have become the mainstay of treatment for patients in advanced stages. This review focuses on elucidating various surgical techniques as well as advancements in immunotherapy and targeted therapy in the context of recent advancements in gallbladder cancer research.

Knee and hip arthroplasty joint surgical site wound infection in end-stage renal disease subjects who underwent dialysis or a kidney transplant: A meta-analysis.

A meta-analysis study to assess the knee and hip arthroplasty joint surgical site wound infection (SSWI) in end-stage renal disease (ESRD) subjects who underwent dialysis or a kidney transplant (KT). A comprehensive literature examination till February 2023 was implemented and 1046 linked studies were appraised. The picked studies contained 5 471 898 subjects with total joint arthroplasty (TJA) at the baseline, 13 049 of them were haemodialysis or renal transplant, and 5 458 849 were control. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of knee and hip arthroplasty SSWI in ESRD subjects who underwent dialysis or a KT by the dichotomous and continuous styles and a fixed or random model. Haemodialysis or renal transplant had a significantly higher postoperative SSWI (OR, 2.13; 95% CI, 1.73-2.62, P < .001) compared with control in TJA subjects. However, no significant difference was observed between haemodialysis and renal transplant in postoperative SSWI (OR, 0.93; 95% CI, 0.16-5.54, P = .94) and between haemodialysis or renal transplant and control in prosthetic joint infection (OR, 1.07; 95% CI, 0.25-4.55, P = .93) in TJA subjects. Haemodialysis had a significantly higher prosthetic joint infection (OR, 1.92; 95% CI, 1.21-3.03, P = .005) compared with renal transplant in TJA subjects. Haemodialysis or renal transplant had a significantly higher postoperative SSWI in TJA subjects. Also, haemodialysis had a significantly higher prosthetic joint infection compared with renal transplant in TJA subjects. Although precautions should be taken when commerce with the consequences because a low number of selected studies was picked for certain comparisons in this meta-analysis.

Unilateral biportal endoscopic lumbar interbody fusion assisted by intraoperative O-arm total navigation for lumbar degenerative disease: A retrospective study.

Background: Recently, unilateral biportal endoscopic lumbar interbody fusion (BE-LIF) has been successfully applied for degenerative diseases of the lumbar spine, with good clinical results reported. However, the drawbacks include radiation exposure, limited field of view, and steep learning curves. Objective: This retrospective study aimed to compare the results between navigation and non-navigation groups and explore the benefits of BE-LIF assisted by intraoperative O-arm total navigation. Methods: A total of 44 patients were retrospectively analyzed from August 2020 to June 2021. Perioperative data were collected, including operative time, estimated intraoperative blood loss, postoperative drainage, postoperative hospital stay, radiation dose, and duration of radiation exposure. In addition, clinical outcomes were evaluated using postoperative data, such as the Oswestry Disability Index (ODI), visual analog scale (VAS), modified MacNab criteria, Postoperative complications and fusion rate. Results: The non-navigation and navigation groups included 23 and 21 patients, respectively. All the patients were followed up for at least 12 months. No significant differences were noted in the estimated intraoperative blood loss, postoperative drainage, postoperative hospital stay, fusion rate, or perioperative complications between the two groups. The radiation dose was significantly lower in the navigation group than in the non-navigation group. The average total operation time in the navigation group was lower than that in the non-navigation group (P < 0.01). All clinical outcomes showed improvement at different time points postoperatively, with no significant difference noted between the two groups (P > 0.05). Conclusions: Compared with the non-navigation approach, O-arm total navigation assistive BE-LIF technology not only has similar clinical results, but also can provide accurate intraoperative guidance and help spinal surgeons achieve accurate decompression. Furthermore, it can reduce radiation exposure to surgeons and operation time, which improve the efficiency and safety of surgery.

Radiation Dose Reduction and Surgical Efficiency Improvement in Endoscopic Transforaminal Lumbar Interbody Fusion Assisted by Intraoperative O-arm Navigation: A Retrospective Observational Study.

OBJECTIVE: Endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) has gained increasing popularity among spine surgeons. However, with the use of fluoroscopy, intraoperative radiation exposure remains a major concern. Here, we aim to introduce Endo-TLIF assisted by O-arm-based navigation and compare the results between O-arm navigation and fluoroscopy groups. METHODS: Sixty-four patients were retrospectively analyzed from May 2019 to September 2020; the nonnavigation group comprised 34 patients, and the navigation group comprised 30 patients. Data on radiation dose, blood loss, postoperative drains, surgery time, complications, and length of hospital stay (LOS) were collected. Clinical outcomes were evaluated from postoperative data such as fusion rate, Oswestry Disability Index (ODI), and visual analogue scale (VAS). Radiation dose and surgery time were selected as primary outcomes; the others were second outcomes. RESULTS: All patients were followed up for at least 12 months. No significant differences were detected in intraoperative hemorrhage, postoperative drains, hospital LOS, or complications between the 2 groups. The radiation dose was significantly lower in the navigation group compared with the nonnavigation group. The time of cannula placement and pedicle screw fixation was significantly reduced in the navigation group. No significant differences were detected between the clinical outcomes in the 2 groups (VAS and ODI scores). CONCLUSION: The present study demonstrates that O-arm-assisted Endo-TLIF is efficient and safe. Compared with fluoroscopy, O-arm navigation could reduce the radiation exposure and surgical time in Endo-TLIF surgery, with similar clinical outcomes. However, the higher doses exposed to patients remains a negative effect of this technology.

Injectable cartilage matrix hydrogel loaded with cartilage endplate stem cells engineered to release exosomes for non-invasive treatment of intervertebral disc degeneration.

Low back pain, mainly caused by intervertebral disc degeneration (IVDD), is a common health problem; however, current surgical treatments are less than satisfactory. Thus, it is essential to develop novel non-invasive surgical methods for IVDD treatment. Here, we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage (ECM-Gels) that are loaded with cartilage endplate stem cells (CESCs). After loaded with CESCs overexpressing Sphk2 (Lenti-Sphk2-CESCs) and injected near the cartilage endplate (CEP) of rats in vivo, ECM-Gels produced Sphk2-engineered exosomes (Lenti-Sphk2-Exos). These exosomes penetrated the annulus fibrosus (AF) and transported Sphk2 into the nucleus pulposus cells (NPCs). Sphk2 activated the phosphatidylinositol 3-kinase (PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs, ultimately ameliorating IVDD. This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.

A Modified Endoscopic Transforaminal Lumbar Interbody Fusion Technique: Preliminary Clinical Results of 96 Cases.

Background: As a newly emerging technique, endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) has become an increasingly popular procedure of interest. The purpose of this study was to introduce a modified Endo-TLIF system and share our preliminary clinical experiences and outcomes in treating lumbar degenerative disease with this procedure. Methods: Ninety-six patients (thirty-seven men and fifty-nine women; mean age 55.85 ± 11.03 years) with lumbar degenerative diseases who underwent Endo-TLIF in our hospital were enrolled. The surgical time, volume of intraoperative blood loss, postoperative hospitalization time and postoperative drainage were documented. Clinical outcomes were evaluated by visual analog scale (VAS) scores, Oswestry Disability Index (ODI) scores, and modified MacNab criteria. Bone fusion was identified through computerized tomography (CT) scans or X-ray during the follow-up period. Results: All patients were followed up for at least 12 months, and the average follow-up time was 17.03 ± 3.27 months. The mean operative time was 136.79 ± 30.14 minutes, and the mean intraoperative blood loss was 53.06 ± 28.89 ml. The mean VAS scores of low back pain and leg pain were 5.05 ± 1.37 and 6.25 ± 1.03, respectively, before surgery, which improved to 2.27 ± 0.66 and 2.22 ± 0.55, respectively, after the operation (P < 0.05). The final VAS scores of low back pain and leg pain were 0.66 ± 0.60 and 0.73 ± 0.66, respectively (P < 0.05). The preoperative ODI score (49.06 ± 6.66) also improved significantly at the 3-month follow-up (13.00 ± 7.37; P < 0.05). The final ODI score was 8.03 ± 6.13 (P < 0.05). There were 10 cases of non-fusion (nine women and one man) at the 12-month follow-up, but no cases of non-union were identified by imaging at the final follow-up. Conclusions: The present study demonstrated satisfactory clinical and radiologic results among patients who received Endo-TLIF treatment from our institution. This indicates that Endo-TLIF is efficient and safe for select patients.

How Much Benefit Can Patients Acquire from Enhanced Recovery After Surgery Protocols with Percutaneous Endoscopic Lumbar Interbody Fusion?

PURPOSE: We aimed to explore the role of enhanced recovery after surgery (ERAS) in patients who underwent percutaneous endoscopic lumbar interbody fusion (PELIF). PATIENTS AND METHODS: We performed a retrospective, observational, cohort study on 91 patients who underwent PELIF for degenerative disc disease. The primary outcomes were postoperative opioid consumption, hospital length of stay (LOS), and hospital cost. RESULTS: Forty-six patients comprised the ERAS group, and 45 patients comprised the pre-ERAS group (control group). The groups had comparable demographic characteristics. Good compliance with the ERAS pathway was observed in the ERAS group. Patients in the ERAS group used significantly fewer morphine equivalents compared with the pre-ERAS group (25.0 vs 33.3, respectively; p = 0.017). Hospital LOS did not decrease significantly in the ERAS group compared with the pre-ERAS group (3.1days vs 3.4 days, respectively; p = 0.096). Likewise, there was no significant difference in hospital cost between the pre-ERAS group and the ERAS group ($10,598.60 vs $10,384.50, respectively; p = 0.468). CONCLUSION: In the present study, the benefit of ERAS in the context of PELIF was limited. Although a multidisciplinary ERAS protocol can improve analgesia and decrease opioid consumption, no significant reduction in hospital LOS and cost was observed.

Cartilage Endplate Stem Cells Transdifferentiate Into Nucleus Pulposus Cells via Autocrine Exosomes.

Stem cells derived from cartilage endplate (CEP) cells (CESCs) repair intervertebral disc (IVD) injury; however, the mechanism remains unclear. Here, we evaluated whether CESCs could transdifferentiate into nucleus pulposus cells (NPCs) via autocrine exosomes and subsequently inhibit IVD degeneration. Exosomes derived from CESCs (CESC-Exos) were extracted and identified by ultra-high-speed centrifugation and transmission electron microscopy. The effects of exosomes on the invasion, migration, and differentiation of CESCs were assessed. The exosome-activating hypoxia-inducible factor (HIF)-1α/Wnt pathway was investigated using lenti-HIF-1α and Wnt agonists/inhibitors in cells and gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis in normal and degenerated human CEP tissue. The effects of GATA binding protein 4 (GATA4) on transforming growth factor (TGF)-ß expression and on the invasion, migration, and transdifferentiation of CESCs were investigated using lenti-GATA4, TGF-ß agonists, and inhibitors. Additionally, IVD repair was investigated by injecting CESCs overexpressing GATA4 into rats. The results indicated that CESC-Exos promoted the invasion, migration, and differentiation of CESCs by autocrine exosomes via the HIF-1α/Wnt pathway. Additionally, increased HIF-1α enhanced the activation of Wnt signaling and activated GATA4 expression. GATA4 effectively promoted TGF-ß secretion and enhanced the invasion, migration, and transdifferentiation of CESCs into NPCs, resulting in promotion of rat IVD repair. CESCs were also converted into NPCs as endplate degeneration progressed in human samples. Overall, we found that CESC-Exos activated HIF-1α/Wnt signaling via autocrine mechanisms to increase the expression of GATA4 and TGF-ß1, thereby promoting the migration of CESCs into the IVD and the transformation of CESCs into NPCs and inhibiting IVDD.

Simulating magnetic nanotubes using a chain of ellipsoid-rings model with a magnetization reversal process by fanning rotation.

Recently, magnetic nanotubes have attracted great attention owing to the advantages of tubular geometry. Of all the physical properties of magnetic nanotubes, the magnetic behavior plays a pivotal role in potential applications, particularly in biotechnology. Modeling magnetic nanotubes provides an effective way to determine the geometry dependent magnetic properties. In the present article, we model the nanotube as a chain of ellipsoid-rings; thus the magnetic behavior of nanotubes is simulated by the fanning rotation of magnetic moments. Based on this model, we further discuss the influence of tubular geometric parameters on the magnetic properties. The calculated magnetic properties of Fe, Co, Ni, Fe3O4 and CoFe2O4 nanotubes are all consistent with their experimental data. Consequently, our model provides an easy and general approach to magnetic nanotubes.