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Molecular Medicine (Cambridge, Mass.) Apr 2024Bleomycin, a potent antitumor agent, is limited in clinical use due to the potential for fatal pulmonary toxicity. The accelerated DNA damage and senescence in alveolar...
BACKGROUND
Bleomycin, a potent antitumor agent, is limited in clinical use due to the potential for fatal pulmonary toxicity. The accelerated DNA damage and senescence in alveolar epithelial cells (AECs) is considered a key factor in the development of lung pathology. Understanding the mechanisms for bleomycin-induced lung injury is crucial for mitigating its adverse effects.
METHODS
Human lung epithelial (A549) cells were exposed to bleomycin and subsequently assessed for cellular senescence, DNA damage, and double-strand break (DSB) repair. The impact of Rad51 overexpression on DSB repair and senescence in AECs was evaluated in vitro. Additionally, bleomycin was intratracheally administered in C57BL/6 mice to establish a pulmonary fibrosis model.
RESULTS
Bleomycin exposure induced dose- and time-dependent accumulation of senescence hallmarks and DNA lesions in AECs. These effects are probably due to the inhibition of Rad51 expression, consequently suppressing homologous recombination (HR) repair. Mechanistic studies revealed that bleomycin-mediated transcriptional inhibition of Rad51 might primarily result from E2F1 depletion. Furthermore, the genetic supplement of Rad51 substantially mitigated bleomycin-mediated effects on DSB repair and senescence in AECs. Notably, decreased Rad51 expression was also observed in the bleomycin-induced mouse pulmonary fibrosis model.
CONCLUSIONS
Our works suggest that the inhibition of Rad51 plays a pivotal role in bleomycin-induced AECs senescence and lung injury, offering potential strategies to alleviate the pulmonary toxicity of bleomycin.
Topics: Bleomycin; Rad51 Recombinase; Animals; Cellular Senescence; Humans; Mice; DNA Repair; Mice, Inbred C57BL; Pulmonary Fibrosis; Disease Models, Animal; Down-Regulation; A549 Cells; DNA Damage; DNA Breaks, Double-Stranded; E2F1 Transcription Factor; Alveolar Epithelial Cells
PubMed: 38649802
DOI: 10.1186/s10020-024-00821-y -
Radiology Case Reports Jul 2024Testicular seminoma commonly occurs in young men aged between 15 and 45 years old. Those with testicular cancer may present with a lump or swelling in the testicle. If...
Testicular seminoma commonly occurs in young men aged between 15 and 45 years old. Those with testicular cancer may present with a lump or swelling in the testicle. If treated and managed early, patients can expect a greater than 95% success rate. However, advanced stages of testicular seminoma can lead to eventual metastasis. We present a 45-year-old male patient with a prior history of testicular seminoma who was admitted to the emergency department with abdominal distension and acute abdominal pain. The CT identified a rather sizable abdominal mass and the biopsy confirmed metastatic testicular seminoma. Lymphoma was considered as the other differential diagnosis. Abdominal metastasis is rare in patients with testicular seminoma and usually leads to a poor survival outcome. Our patient did not attend follow-up appointments postorchidectomy, likely resulting in abdominal metastasis of testicular seminoma. This demonstrates the importance of ongoing surveillance of seminoma patients, and the challenges associated with differentiating large abdominal conglomerate mass in the CT scan. This patient is currently on active chemotherapy with bleomycin, cisplatin, and etoposide.
PubMed: 38645951
DOI: 10.1016/j.radcr.2024.03.012 -
Animal Cells and Systems 2024Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by skin and internal organ fibrosis and obliterative vasculopathy. Few effective treatments are...
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by skin and internal organ fibrosis and obliterative vasculopathy. Few effective treatments are currently available for fibrosis in SSc, therefore, demand persists for novel therapies. Although use of extract (GBE) has been reported to improve blood circulation and alleviate liver and lung fibrosis, its effect on skin fibrosis in SSc remains unclear. In this study, the effects and underlying mechanisms of GBE on skin fibrosis in bleomycin (BLM)-induced mouse model of SSc was investigated. GBE significantly reduced dermal thickness and protein levels of profibrotic factors in the BLM-induced SSc mouse model. Moreover, GBE inhibited the gene expression of profibrotic factors, such as COL1A1, α-SMA, and connective tissue growth factor (CTGF), in fibroblasts by suppressing transforming growth factor (TGF)-β signaling. Furthermore, GBE inhibited the transdifferentiation of adipocytes into myofibroblasts. Thus, our findings suggest that GBE is a promising therapeutic candidate for the treatment of SSc.
PubMed: 38645438
DOI: 10.1080/19768354.2024.2337761 -
Molecular Medicine (Cambridge, Mass.) Apr 2024Skin fibrosis affects the normal function of the skin. TGF-β1 is a key cytokine that affects organ fibrosis. The latency-associated peptide (LAP) is essential for...
BACKGROUND
Skin fibrosis affects the normal function of the skin. TGF-β1 is a key cytokine that affects organ fibrosis. The latency-associated peptide (LAP) is essential for TGF-β1 activation. We previously constructed and prepared truncated LAP (tLAP), and confirmed that tLAP inhibited liver fibrosis by affecting TGF-β1. SPACE peptide has both transdermal and transmembrane functions. SPACE promotes the delivery of macromolecules through the stratum corneum into the dermis. This study aimed to alleviate skin fibrosis through the delivery of tLAP by SPACE.
METHODS
The SPACE-tLAP (SE-tLAP) recombinant plasmid was constructed. SE-tLAP was purified by nickel affinity chromatography. The effects of SE-tLAP on the proliferation, migration, and expression of fibrosis-related and inflammatory factors were evaluated in TGF-β1-induced NIH-3T3 cells. F127-SE-tLAP hydrogel was constructed by using F127 as a carrier to load SE-tLAP polypeptide. The degradation, drug release, and biocompatibility of F127-SE-tLAP were evaluated. Bleomycin was used to induce skin fibrosis in mice. HE, Masson, and immunohistochemistry were used to observe the skin histological characteristics.
RESULTS
SE-tLAP inhibited the proliferation, migration, and expression of fibrosis-related and inflammatory factors in NIH-3T3 cells. F127-SE-tLAP significantly reduced ECM production, collagen deposition, and fibrotic pathological changes, thereby alleviating skin fibrosis.
CONCLUSION
F127-SE-tLAP could increase the transdermal delivery of LAP, reduce the production and deposition of ECM, inhibit the formation of dermal collagen fibers, and alleviate the progression of skin fibrosis. It may provide a new idea for the therapy of skin fibrosis.
Topics: Animals; Mice; Bleomycin; Collagen; Fibrosis; Hydrogels; Polyethylenes; Polypropylenes; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Skin Diseases; Smad Proteins; Skin
PubMed: 38641575
DOI: 10.1186/s10020-024-00815-w -
Cellular and Molecular Life Sciences :... Apr 2024Idiopathic pulmonary fibrosis (IPF) poses significant challenges due to limited treatment options despite its complex pathogenesis involving cellular and molecular...
Idiopathic pulmonary fibrosis (IPF) poses significant challenges due to limited treatment options despite its complex pathogenesis involving cellular and molecular mechanisms. This study investigated the role of transient receptor potential ankyrin 1 (TRPA1) channels in regulating M2 macrophage polarization in IPF progression, potentially offering novel therapeutic targets. Using a bleomycin-induced pulmonary fibrosis model in C57BL/6J mice, we assessed the therapeutic potential of the TRPA1 inhibitor HC-030031. TRPA1 upregulation was observed in fibrotic lungs, correlating with worsened lung function and reduced survival. TRPA1 inhibition mitigated fibrosis severity, evidenced by decreased collagen deposition and restored lung tissue stiffness. Furthermore, TRPA1 blockade reversed aberrant M2 macrophage polarization induced by bleomycin, associated with reduced Smad2 phosphorylation in the TGF-β1-Smad2 pathway. In vitro studies with THP-1 cells treated with bleomycin and HC-030031 corroborated these findings, highlighting TRPA1's involvement in fibrotic modulation and macrophage polarization control. Overall, targeting TRPA1 channels presents promising therapeutic potential in managing pulmonary fibrosis by reducing pro-fibrotic marker expression, inhibiting M2 macrophage polarization, and diminishing collagen deposition. This study sheds light on a novel avenue for therapeutic intervention in IPF, addressing a critical need in the management of this challenging disease.
Topics: Animals; Mice; Acetanilides; Bleomycin; Collagen; Cytoskeletal Proteins; Idiopathic Pulmonary Fibrosis; Macrophages; Mice, Inbred C57BL; Purines; TRPA1 Cation Channel
PubMed: 38635081
DOI: 10.1007/s00018-024-05219-x -
International Journal of Radiation... Apr 2024Combined modality treatment with chemotherapy followed by consolidation radiation therapy (RT) provides excellent outcomes for patients with early-stage Hodgkin...
Involved-site Radiation Therapy is Equally Effective and Less Toxic Than Involved-field Radiation Therapy in Patients Receiving Combined Modality Treatment for Early-stage Unfavorable Hodgkin Lymphoma-An Analysis of the Randomized Phase 3 HD17 Trial of the German Hodgkin Study Group.
PURPOSE
Combined modality treatment with chemotherapy followed by consolidation radiation therapy (RT) provides excellent outcomes for patients with early-stage Hodgkin lymphoma. The international standard of care for consolidation RT, involved-site/involved-node radiation therapy (ISRT/INRT), has never been evaluated in a randomized phase 3 trial against the former standard involved-field radiation therapy (IFRT).
METHODS AND MATERIALS
In the multicenter phase 3 GHSG (German Hodgkin Study Group) HD17 trial, patients with early-stage unfavorable Hodgkin lymphoma were randomized between the standard Combined modality treatment group and a positron-emission tomography (PET)-guided group. In the standard group, patients received 2 cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy IFRT. In the experimental group, patients received no further therapy if postchemotherapy PET was negative and 30 Gy GHSG INRT, comparable to and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET-positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT.
RESULTS
A total of 1100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival were 96.8% (95% CI, 91.6%-98.8%) in the IFRT group and 95.4% (95% CI, 89.9%-97.9%; HR, 1.40; 95% CI, 0.44-4.42) in the ISRT group. The pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade 3/4 toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (P = .03).
CONCLUSIONS
For the first time, consolidation INRT/ISRT was randomly compared with IFRT in a phase 3 trial. Regarding progression-free survival, no advantage of IFRT could be demonstrated. In summary, our data confirm the status of INRT/ISRT as the current standard of care.
PubMed: 38631539
DOI: 10.1016/j.ijrobp.2024.04.015 -
Biomedicine & Pharmacotherapy =... May 2024Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression...
Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5 mg/kg) and treated with CCM (25 mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff-Van Gieson, Picro sirius red, and Masson's trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.
Topics: Animals; MicroRNAs; Curcumin; Mice, Inbred C57BL; Mitochondria; DNA Methyltransferase 3A; Extracellular Matrix; Humans; Mice; Male; Fibroblasts; Bleomycin; Pulmonary Fibrosis; Lung; DNA (Cytosine-5-)-Methyltransferases; Idiopathic Pulmonary Fibrosis; Disease Models, Animal
PubMed: 38626519
DOI: 10.1016/j.biopha.2024.116572 -
Biomolecules & Biomedicine Apr 2024Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic disease that significantly impacts patient quality of life, and its incidence is on the rise. The...
Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic disease that significantly impacts patient quality of life, and its incidence is on the rise. The pathogenesis of IPF remains poorly understood. Alveolar type 2 (AT2) cells are crucial in the onset and progression of IPF, yet the specific mechanisms involved are not well defined. Lon protease 1 (LONP1), known for its critical roles in various diseases, has an unclear function in IPF. Our research investigated the impact of Lonp1 gene deletion on AT2 cell functionality and its subsequent effect on IPF development. We generated a bleomycin-induced pulmonary fibrosis mouse model with a targeted Lonp1 knockout in AT2 cells and assessed the consequences on AT2 cell function and fibrosis progression. Additionally, we constructed the MLE12 cells with stable Lonp1 knockdown and utilized transcriptome sequencing to identify pathways altered by the Lonp1 knockdown. Our results indicated that mice with AT2 cell-specific Lonp1 knockout exhibited more severe fibrosis compared to controls. These mice exhibited a reduction in AT2 and AT1 cell populations, along with an increase in p53- and p21-positive AT2 cells. Lonp1 knockdown in MLE12 cells led to the upregulation of aging-associated pathways, with fibroblast growth factor 2 (Fgf2) gene emerging as a central gene interconnecting these pathways. Therefore, loss of Lonp1 appears to promote AT2 cell aging and exacerbate bleomycin-induced pulmonary fibrosis. Fgf2 emerges as a pivotal downstream gene associated with cellular senescence. This study uncovers the role of the Lonp1 gene in pulmonary fibrosis, presenting a novel target for investigating the pathological mechanisms and potential therapeutic approaches for IPF.
PubMed: 38625722
DOI: 10.17305/bb.2024.10429 -
Infectious Agents and Cancer Apr 2024Little is known about the outcome for HIV-associated Hodgkin lymphoma (HIV-HL) as this is less common than HIV-negative lymphoma. Therefore, we performed a multi-center...
Outcome in patients with HIV-associated Hodgkin lymphoma treated with chemotherapy using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the combination antiretroviral therapy (cART) era: results of a multicenter study from China.
Little is known about the outcome for HIV-associated Hodgkin lymphoma (HIV-HL) as this is less common than HIV-negative lymphoma. Therefore, we performed a multi-center study to analyze the clinical characteristics and outcomes of HIV-HL patients in China. Nineteen cases of HIV-HL were diagnosed and treated at three center and including the sixth people's hospital of Zhengzhou, Peking union medical college hospital, and Chongqing university cancer hospital, between December 2013 and June 2022. Data on the clinical features, laboratory results, response, and prognosis were collected and analyzed. The median age at diagnosis was 43(22-74) years. All patients were infected with HIV through sexual transmission, with ten cases transmitted through man having sex with man (MSM) and nine cases transmitted through heterosexual transmission. Seven patients were diagnosed with lymphoma and found to be infected with HIV. Four cases were in stage III, and fifteen cases were in stage IV. After a median follow up of 46.8(4.0-112.9) months, 17 cases were alive after ABVD regimen chemotherapy combined with combination antiretroviral therapy (cART). The 5-year progression-free survival (PFS) and overall survival (OS) rate were 83.9% and 89.5%,respectively. HIV-HL exhibits an invasive process in clinical practice, and cART combined with ABVD regimen chemotherapy can achieve long-term survival for patients.
PubMed: 38622727
DOI: 10.1186/s13027-024-00571-w -
Scientific Reports Apr 2024Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some...
Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some approaches such as combination therapy may be applicable for increasing therapeutic efficacy of PFD. Losartan (LOS), an angiotensin II receptor antagonist, could be a suitable candidate for combination therapy because of its stabilizing effect on the pulmonary function of IPF patients. Therefore, this study aimed to investigate the effects of LOS in combination with PFD on bleomycin (BLM)-induced lung fibrosis in rats. BLM-exposed rats were treated with LOS alone or in combination with PFD. The edema, pathological changes, level of transforming growth factor-β (TGF-β1), collagen content, and oxidative stress parameters were assessed in the lung tissues. Following BLM exposure, the inflammatory response, collagen levels, and antioxidant markers in rat lung tissues were significantly improved by PFD, and these effects were improved by combination with LOS. The findings of this in vivo study suggest that the combined administration of PFD and LOS may provide more potent protection against IPF than single therapy through boosting its anti-inflammatory, anti-fibrotic, and anti-oxidant effects. These results hold promise in developing a more effective therapeutic strategy for treating of lung fibrosis.
Topics: Humans; Rats; Animals; Losartan; Bleomycin; Lung; Idiopathic Pulmonary Fibrosis; Antioxidants; Transforming Growth Factor beta1; Collagen; Pyridones
PubMed: 38622264
DOI: 10.1038/s41598-024-59395-8