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International Journal of Molecular... Jun 2024The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin...
The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin connective tissue diseases, increasing evidence from clinical and animal experiments suggests that TLRs (Toll-like receptors) play an important role in several diseases. This study aimed to determine the role of TLR7 (Toll-like receptor 7) and TLR9 (Toll-like receptor 9) in the mechanisms of immune abnormalities and fibrosis in SSc. This study used TLR7-KO mice (TLR7-knockout mice with a balb/c background) and TLR9-KO mice (TLR9-knockout mice with a balb/c background) as well as WT mice (wild-type balb/c mice). All three kinds of mice were induced by BLM (bleomycin) in a scleroderma model as the experimental group; meanwhile, WT mice treated with PBS (phosphate-buffered saline) were used as the control group. We analyzed the fibrotic phenotype and the immunological abnormality phenotype of TLR7-deficient and TLR9-deficient mice in the SSc disease model using flow cytometry, RT-PCR (reverse transcription-polymerase chain reaction), a histological examination, and IHC (immunohistochemical staining). In a mouse model of SSc disease, the deletion of TLR7 attenuated skin and lung fibrosis, while the deletion of TLR9 exacerbated skin and lung fibrosis. The deletion of TLR7 resulted in a relative decrease in the infiltration and expression of various pro-inflammatory and fibrotic cells and cytokines in the skin. On the other hand, the deletion of TLR9 resulted in a relative increase in the infiltration and expression of various pro-inflammatory and cytokine-inhibiting cells and cytokines in the skin. Under the influence of pDCs (plasmacytoid dendritic cells), the balances of Beff/Breg (IL-6 + CD19 + B cell/IL-10 + CD19 + B cell), Th17/Treg (IL-17A + CD4 + T cell/Foxp3 + CD25 + CD4 + T cell), M1/M2 (CD86 + macrophage/CD206 + macrophage), and Th1/Th2 (TNFα + CD3 + CD4 + T cell/IL-4 + CD3 + CD4 + T cell) were biased towards the suppression of inflammation and fibrosis as a result of the TLR7 deletion. Comparatively, the balance was biased towards promoting inflammation and fibrosis due to the TLR9 deletion. In the SSc model, TLR7 promoted inflammation and fibrosis progression, while TLR9 played a protective role. These results suggest that TLR7 and TLR9 play opposite roles in triggering SSc to produce immune system abnormalities and skin fibrosis.
Topics: Animals; Toll-Like Receptor 7; Scleroderma, Systemic; Toll-Like Receptor 9; Mice; Mice, Knockout; Disease Models, Animal; Bleomycin; Mice, Inbred BALB C; Cytokines; Skin; Fibrosis; Pulmonary Fibrosis; Membrane Glycoproteins
PubMed: 38892317
DOI: 10.3390/ijms25116133 -
International Journal of Molecular... May 2024Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have...
Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups ( > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.
Topics: Animals; Liraglutide; Doxorubicin; Cardiotoxicity; Male; Rats; Rats, Wistar; Oxidative Stress; Myocardium; NF-kappa B; Tumor Necrosis Factor-alpha; Heart
PubMed: 38892020
DOI: 10.3390/ijms25115833 -
International Journal of Molecular... May 2024Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in family members have also been...
Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, -deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.
Topics: Podocytes; Animals; Mice; Humans; Mice, Knockout; Doxorubicin; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing; Apoptosis; Nephrotic Syndrome; Male; Tumor Suppressor Proteins
PubMed: 38891998
DOI: 10.3390/ijms25115808 -
Nature Communications Jun 2024Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly...
Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Acetylation; Poly(ADP-ribose) Polymerase Inhibitors; Spliceosomes; Cell Line, Tumor; Phthalazines; Exons; Piperazines; Animals; BRCA1 Protein; Depsipeptides; Mice; DNA Damage; Gene Expression Regulation, Neoplastic
PubMed: 38890388
DOI: 10.1038/s41467-024-49573-7 -
Open Heart Jun 2024For high bleeding-risk patients (HBR) undergoing percutaneous coronary intervention (PCI), the LEADERS FREE (LF) and LEADERS FREE II (LF II) trials established the... (Comparative Study)
Comparative Study
BACKGROUND
For high bleeding-risk patients (HBR) undergoing percutaneous coronary intervention (PCI), the LEADERS FREE (LF) and LEADERS FREE II (LF II) trials established the safety and efficacy of a stainless steel polymer-free biolimus-coated stent (SS-BCS) with 30 days of dual antiplatelet treatment (DAPT). The LEADERS FREE III (LF III) trial investigated clinical outcomes after PCI with the next-generation cobalt-chromium thin-strut polymer-free biolimus-coated stent (CoCr-BCS) in HBR patients.
AIMS
To report the final 3-year results of the LF III trial and compare them to LF II.
METHODS
LF III was a prospective, multicentre, open-label single-arm study to evaluate the safety and efficacy of the CoCr-BCS stent. The primary safety endpoint was the composite of cardiac death (CD), myocardial infarction(MI) or definite/probable stent thrombosis (ST). The primary efficacy endpoint was clinically driven target lesion revascularisation (cd-TLR). We performed a propensity-matched comparison to the 3-year outcomes of LF II.
RESULTS
After 3 years, CD/MI/ST had occurred in 57 patients (15%, 95% CI 11.8% to 19%) and cd-TLR in 23 (6.2%, 95% CI 4.1% to 9.2%) patients. In a propensity-matched comparison of patients treated with the CoCr-BCS versus the SS-BCS, there were similar rates of CD (6.6% vs 7.8%, p=0.50), MI (7.1% vs 8.3%, p=0.47) and definite/probable ST (1.1% vs 2%, HR 0.56, 95% CI 0.16 to 1.93, p=0.35). The rates of cd-TLR were 5.3% with CoCr-BCS versus 9.8% with SS-BCS (HR 0.54, 95% CI 0.31 to 0.96, p=0.03).
CONCLUSION
LF III confirms the long-term safety and efficacy of the CoCr-BCS in HBR patients treated with 1 month of DAPT.
TRIAL REGISTRATION NUMBER
NCT02843633, NCT03118895.
Topics: Humans; Drug-Eluting Stents; Male; Prospective Studies; Female; Percutaneous Coronary Intervention; Prosthesis Design; Sirolimus; Treatment Outcome; Coronary Artery Disease; Aged; Time Factors; Middle Aged; Follow-Up Studies; Platelet Aggregation Inhibitors; Risk Factors
PubMed: 38890129
DOI: 10.1136/openhrt-2024-002679 -
Clinical Cardiology Jun 2024Long-term follow-up results of various trials comparing Zotarolimus eluting stents (ZES) with Everolimus eluting stents (EES) have been published recently. Additionally,... (Comparative Study)
Comparative Study Meta-Analysis
Temporal Trends in the Outcomes of Percutaneous Coronary Intervention With Zotarolimus Eluting Stents Versus Everolimus Eluting Stents: A Meta-Analysis of Randomized Controlled Trials.
INTRODUCTION
Long-term follow-up results of various trials comparing Zotarolimus eluting stents (ZES) with Everolimus eluting stents (EES) have been published recently. Additionally, over the last decade, there have been new trials comparing the ZES with various commercially available EES. We aim to conduct an updated meta-analysis in light of new evidence from randomized controlled trials (RCTs) to provide comprehensive evidence regarding the temporal trends in the clinical outcomes.
METHODS
A comprehensive literature search was conducted across PubMed, Cochrane, and Embase. RCTs comparing ZES with EES for short (<2 years), intermediate (2-3 years), and long-term follow-ups (3-5 years) were included. Relative risk was used to pool the dichotomous outcomes using the random effects model employing the inverse variance method. All statistical analysis was conducted using Revman 5.4.
RESULTS
A total of 18 studies reporting data at different follow-ups for nine trials (n = 14319) were included. At short-term follow-up (<2 years), there were no significant differences between the two types of stents (all-cause death, cardiac death, Major adverse cardiovascular events (MACE), target vessel myocardial infarction, definite or probable stent thrombosis or safety outcomes (target vessel revascularization, target lesion revascularization, target vessel failure, target lesion failure). At intermediate follow-up (2-3 years), EES was superior to ZES for reducing target lesion revascularization (RR = 1.28, 95% CI = 1.05-1.58, p < 0.05). At long-term follow-up (3-5 years), there were no significant differences between the two groups for any of the pooled outcomes (p > 0.05).
CONCLUSION
ZES and EES have similar safety and efficacy at short, intermediate, and long-term follow-ups.
Topics: Humans; Cardiovascular Agents; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Percutaneous Coronary Intervention; Prosthesis Design; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; Time Factors; Treatment Outcome
PubMed: 38888152
DOI: 10.1002/clc.24306 -
BMC Pulmonary Medicine Jun 2024Rapamycin has been extensively utilized for coating coronary artery stents to reduce the occurrence of restenosis, yet there has been limited research on the potential...
BACKGROUND
Rapamycin has been extensively utilized for coating coronary artery stents to reduce the occurrence of restenosis, yet there has been limited research on the potential harms of rapamycin-eluting stents. Herein, We report a case of eosinophilia and interstitial pneumonia caused by a cobalt-based alloy stent eluted with rapamycin.
CASE PRESENTATION
The patient was admitted due to fever, cough, and expectoration symptoms. Previously, the patient had undergone a procedure of percutaneous coronary stent implantation in our hospital's cardiology department, which led to a gradual rise in blood eosinophil count. This time, the eosinophil count was higher than the previous admission. A chest CT scan revealed multiple flocculent density increases in both lungs and bronchiectasis. The rapamycin-eluting stents may have caused eosinophilia and interstitial pneumonia, which improved after administering corticosteroids. A systematic review of relevant literature was conducted to summarize the characteristics of interstitial pneumonia caused by drug-eluting stents.
CONCLUSION
Paclitaxel, everolimus, zotarolimus, and rapamycin are the types of drugs that can lead to drug-eluting stents, and because of the rarity of their onset, clinical doctors must be precise and prompt in diagnosing suspected cases to avoid misdiagnosis and delayed treatment.
Topics: Humans; Lung Diseases, Interstitial; Drug-Eluting Stents; Sirolimus; Eosinophilia; Male; Tomography, X-Ray Computed; Percutaneous Coronary Intervention; Aged
PubMed: 38886703
DOI: 10.1186/s12890-024-03101-x -
Vascular Health and Risk Management 2024Kaposiform hemangioendothelioma(KHE) without Kasabach-Merritt phenomenon is a rare tumor primarily observed in pediatric patients; however, its documentation in the... (Review)
Review
Kaposiform hemangioendothelioma(KHE) without Kasabach-Merritt phenomenon is a rare tumor primarily observed in pediatric patients; however, its documentation in the literature remains limited. We reported about a 1-year-old boy diagnosed with superficial KHE who received oral propranolol in combination with topical sirolimus and reviewed relevant reports and treatment of superficial KHE.
Topics: Humans; Infant; Male; Administration, Oral; Biopsy; Hemangioendothelioma; Propranolol; Sarcoma, Kaposi; Sirolimus; Treatment Outcome
PubMed: 38883398
DOI: 10.2147/VHRM.S461505 -
International Journal of Nanomedicine 2024While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still...
BACKGROUND
While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still an essential problem.
METHODS
We exploited nanoparticle coordination between ferric (Fe) ions and telomerase-targeting hairpin DNA structures to encapsulate doxorubicin (DOX) and fabricated Fe-DNA@DOX nanoparticles (BDDF NPs). This work studied the NIR fluorescence imaging and pharmacokinetic studies targeting the ability and biodistribution of BDDF NPs. In vitro and vivo studies investigated the nano formula's toxicity, imaging, and synergistic therapeutic effects.
RESULTS
The enhanced permeability and retention (EPR) effect and tumor targeting resulted in prolonged blood circulation times and high tumor accumulation. Significantly, BDDF NPs could reduce DOX-mediated cardiac toxicity by improving the antioxidation ability of cardiomyocytes based on the different telomerase activities and iron dependency in normal and tumor cells. The synergistic treatment efficacy is enhanced through Fe-mediated ferroptosis and the β-catenin/p53 pathway and improved the tumor inhibition rate.
CONCLUSION
Harpin DNA-based nanoplatforms demonstrated prolonged blood circulation, tumor drug accumulation via telomerase-targeting, and synergistic therapy to improve antitumor drug efficacy. Our work sheds new light on nanomaterials for future synergistic chemotherapy.
Topics: Doxorubicin; Animals; Humans; Telomerase; Cell Line, Tumor; Mice; DNA; Tissue Distribution; Nanoparticles; Neoplasms; Ferroptosis; Antibiotics, Antineoplastic; Mice, Inbred BALB C; Drug Carriers
PubMed: 38882546
DOI: 10.2147/IJN.S461774 -
Drug Design, Development and Therapy 2024Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from...
Extracellular Vesicles Derived from HO-Stimulated Adipose-Derived Stem Cells Alleviate Senescence in Diabetic Bone Marrow Mesenchymal Stem Cells and Restore Their Osteogenic Capacity.
INTRODUCTION
Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from diabetic patients is compromised, possibly due to hyperglycemia-induced senescence. The objective of this study was to assess the preconditioning effects of extracellular vesicles derived from HO-stimulated adipose-derived stem cells (ADSCs) and non-modified ADSCs on the osteogenic potential of diabetic bone marrow mesenchymal stem cells (BMSCs).
METHODS
Sprague-Dawley (SD) rats were experimentally induced into a diabetic state through a high-fat diet followed by an injection of streptozotocin, and diabetic BMSCs were collected from the bone marrow of these rats. Extracellular vesicles (EVs) were isolated from the conditioned media of ADSCs, with or without hydrogen peroxide (HO) preconditioning, using density gradient centrifugation. The effects of HO preconditioning on the morphology, marker expression, and particle size of the EVs were analyzed. Furthermore, the impact of EV-pretreatment on the viability, survivability, migration ability, osteogenesis, cellular senescence, and oxidative stress of diabetic BMSCs was examined. Moreover, the expression of the Nrf2/HO-1 pathway was also assessed to explore the underlying mechanism. Additionally, we transplanted EV-pretreated BMSCs into calvarial defects in diabetic rats to assess their in vivo bone formation and anti-senescence capabilities.
RESULTS
Our study demonstrated that pretreatment with EVs from ADSCs significantly improved the viability, senescence, and osteogenic differentiation potential of diabetic BMSCs. Moreover, in-vitro experiments revealed that diabetic BMSCs treated with HO-activated EVs exhibited increased viability, reduced senescence, and enhanced osteogenic differentiation compared to those treated with non-modified EVs. Furthermore, when transplanted into rat bone defects, diabetic BMSCs treated with HO-activated EVs showed improved bone regeneration potential and enhanced anti-senescence function t compared to those treated with non-modified EVs. Both HO-activated EVs and non-modified EVs upregulated the expression of the Nrf2/HO-1 pathway in diabetic BMSCs, however, the promoting effect of HO-activated EVs was more pronounced than that of non-modified EVs.
CONCLUSION
Extracellular vesicles derived from HO-preconditioned ADSCs mitigated senescence in diabetic BMSCs and enhanced their bone regenerative functions via the activation of the Nrf2/HO-1 pathway.
Topics: Animals; Hydrogen Peroxide; Extracellular Vesicles; Rats, Sprague-Dawley; Mesenchymal Stem Cells; Rats; Osteogenesis; Diabetes Mellitus, Experimental; Cellular Senescence; Male; Cells, Cultured; Adipose Tissue; Oxidative Stress; Streptozocin
PubMed: 38882044
DOI: 10.2147/DDDT.S454509