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1.
J Immunother ; 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38557756

RESUMO

Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.

2.
Anticancer Drugs ; 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38527238

RESUMO

Glioblastoma (GBM) is the most common primary malignant brain tumour and lacks therapeutic options with significant effects. The aberrant activation of STAT3 is a critical factor in glioma progression via activating multiple signalling pathways that promote glioma. Among them, the antiapoptotic gene Bcl-2 could be upregulated by p-STAT3, which is an important reason for the continuous proliferation of glioma. We previously reported that bergaptol, a natural furanocoumarin widely found in citrus products, exerts antineuroinflammatory effects by inhibiting the overactivation of STAT3. Here, we aimed to evaluate whether bergaptol could promote glioma apoptosis by inhibiting the STAT3/Bcl-2 pathway. This study found that bergaptol inhibited the proliferation and migration of GBM cell lines (U87 and A172) and promoted apoptosis in vitro. We also found that bergaptol significantly inhibited the STAT3/Bcl-2 pathway in GBM cells. U87 cells were implanted intracranially into nude mice to establish a glioma model, and glioma-bearing mice were treated with bergaptol (40 mg/kg). Bergaptol treatment significantly inhibited glioma growth and prolonged the glioma-bearing mice's survival time. In addition, bergaptol administration also significantly inhibited the STAT3/Bcl-2 pathway of tumour tissue in vivo. Overall, we found that bergaptol could effectively play an antiglioma role by inhibiting STAT3/Bcl-2 pathway, suggesting the potential efficacy of bergaptol in treating glioma.

4.
J Med Chem ; 67(1): 479-491, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38110353

RESUMO

The platinum(IV) prodrug strategy is attractive for the synergistic antitumor effect. High levels (>400 nM) of nitric oxide (NO) exert promising cancer inhibition effects via multiple mechanisms. Herein, we designed and synthesized a new group of integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs bearing long alkyl chains to enhance the stability in circulation, while the cytoplasmic reductants trigger cascade activation to release Pt and NO in tumor cells. Specifically, compound 10c exhibited an improved stability, favorable pharmacokinetic properties (AUC(0-t) of 2210.10 h*ng/mL), potent anti-triple-negative breast cancer (TNBC) effects (71.08% tumor growth inhibition (TGI) against the MDA-MB-231 xenograft model), potent in vivo anti-TNBC lung metastasis activity, and acceptable low toxicity. Importantly, NO released from 10c leads to the S-nitrosation of metal transporters Atox1&ATP7a in TNBC cells, which increases the Pt retention and inhibits lysyl oxidase, generating synergistic tumoricidal and antimetastatic activity. These results may inspire further study on the synergistical therapy of Pt and NO for the treatment of TNBC.


Assuntos
Antineoplásicos , Pró-Fármacos , Neoplasias de Mama Triplo Negativas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Platina , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Catálise , Linhagem Celular Tumoral
5.
Med Res Rev ; 44(3): 975-1012, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38126568

RESUMO

Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long-term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti-IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti-IS drugs/agents are briefly provided to move the field forward.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/tratamento farmacológico , AVC Isquêmico/etiologia , Terapia Trombolítica/efeitos adversos , Trombectomia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Resultado do Tratamento
6.
Aging (Albany NY) ; 15(23): 14411-14421, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38059889

RESUMO

MicroRNAs (miRNAs) are essential to the tumour growth and metastasis of several cancers. However, the implied functions of miR-211-5p in pancreatic cancer (PC) remains poorly known. In the present study, we discovered that miR-211-5p was a significantly downregulated miRNA in PC tissues compared to adjacent non-tumour tissues. Moreover, we revealed that miR-211-5p overexpression suppressed the proliferation and metastasis of PC cells. Mechanistically, miR-211-5p directly bond to 3'UTR of bone morphogenetic protein-2 (BMP2) and negatively regulated its expression. Rescue experiments showed that the biological function of miR-211-5p was reversed by BMP-2 overexpression in PC cells. Clinical data indicated that BMP2 expression was negatively correlated with miR-211-5p levels in PC patients. Our study provided evidence that miR-211-5p served as a significant suppressor in PC, provided potential targets for prognosis and treatment of patients with PC.


Assuntos
MicroRNAs , Neoplasias Pancreáticas , Humanos , Linhagem Celular Tumoral , Invasividade Neoplásica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Pancreáticas/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo
7.
J Med Chem ; 66(24): 16680-16693, 2023 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-38069814

RESUMO

Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted ß-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.


Assuntos
Equinococose , Echinococcus granulosus , Camundongos , Animais , Harmina/farmacologia , Harmina/uso terapêutico , Equinococose/tratamento farmacológico , Echinococcus granulosus/ultraestrutura , Albendazol/farmacocinética , Albendazol/uso terapêutico
8.
Eur J Med Chem ; 262: 115912, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37931330

RESUMO

Ischemic stroke (IS) is a life-threatening disease worldwide. Nitric oxide (NO) derived from l-arginine catalyzed by NO synthase (NOS) is closely associated with IS. Three isomers of NOS (nNOS, eNOS and iNOS) produce different concentrations of NO, resulting in quite unlike effects during IS. Of them, n/iNOSs generate high levels of NO, detrimental to brain by causing nerve cell apoptosis and/or necrosis, whereas eNOS releases small amounts of NO, beneficial to the brain via increasing cerebral blood flow and improving nerve function. As a result, a large variety of NO regulators (NO donors or n/iNOS inhibitors) have been developed for fighting IS. Regrettably, up to now, no review systematically introduces the progresses in this area. This article first outlines dynamic variation rule of NOS/NO in IS, subsequently highlights advances in NO regulators against IS, and finally presents perspectives based on concentration-, site- and timing-effects of NO production to promote this field forward.


Assuntos
AVC Isquêmico , Óxido Nítrico , Humanos , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Arginina
9.
ACS Omega ; 8(43): 40260-40276, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37929119

RESUMO

Baicalin (BAI), the main active component of Scutellaria baicalensis, has significant anti-inflammatory and antibacterial effects. Echinacoside (ECH), an active component from Echinacea purpurea, has significant antiangiogenesis and antioxidant effects. In previous studies, BAI or ECH has been used for some skin inflammation problems by topical treatment. Psoriasis (PSO) is a common inflammatory skin disease with typical features such as excessive inflammatory response and vascular proliferation in skin lesions. Because of the anti-inflammatory effect of BAI and the antiangiogenic activity of ECH, it is proposed that the combination of BAI and ECH can ameliorate psoriatic skin lesions better than a single component. This study aims to explore the effects and potential mechanisms of BAI combined with ECH on imiquimod (IMQ)-induced psoriatic skin lesions by topical treatment. Transcriptome analysis first showed that the TNF signaling pathway and the VEGF signaling pathway were significantly enriched in IMQ-induced psoriatic skin lesions. Topical application of BAI combined with ECH could ameliorate IMQ-induced skin lesions in mice, especially the better effects of B2-E1 (BAI/ECH = 2:1). Network pharmacology analysis and molecular docking indicated that BAI-treated PSO on the skin by regulating the TNF signaling pathway, and ECH treated PSO on the skin by regulating the VEGF signaling pathway. Meanwhile, the ELISA test and the qPCR assay showed that BAI combined with ECH could inhibit the expression of key cytokines and genes related to the TNF signaling pathway and the VEGF signaling pathway. Zebrafish experiments demonstrated the anti-inflammatory and antiangiogenic effects of BAI combined with ECH and revealed the potential mechanisms associated with regulating the inflammation-related TNF signaling pathway and the angiogenesis-related VEGF signaling pathway. This suggested that BAI combined with ECH may be a promising topical agent to ameliorate psoriatic skin lesions in the future.

10.
Ther Clin Risk Manag ; 19: 853-863, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37899984

RESUMO

Purpose: To evaluate the clinical outcomes of lenvatinib plus PD-1 inhibitors (LP) and regorafenib (R) in patients with advanced hepatocellular carcinoma (HCC) after sorafenib failure. Methods: From June 2018 to September 2021, 68 patients from a single center who received lenvatinib combined with PD-1 inhibitors or regorafenib after sorafenib treatment failure were analyzed. The tumor response and survival outcomes were compared between the LP group and R group. Prognostic factors for OS and PFS were determined using Cox proportional hazard regression models. Results: The ORR increased in the LP group (19.5% vs 7.4%, p =0.294), and the DCR was better in the R group (73.2% vs 44.4%, p =0.017). Additionally, median PFS and OS were not significantly different between the LP group and R two groups in survival analysis (PFS: 5.3 months vs 3.0 months, p =0.633; OS: 11.8 months vs 8.0 months, p =0.699). The common adverse events (≥grade 3) were hand-foot skin reactions (13.1%). In multivariate analyses, AFP≥400 ng/mL and ECOG PS 2 were independent risk factors for poor prognosis. Conclusion: The LP group appeared to have a trend of greater tumor response and a higher disease control rate than the R group among patients with sorafenib-resistant HCC, although PFS and OS did not differ significantly between the two groups.

11.
J Med Chem ; 66(20): 14221-14240, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37820326

RESUMO

Invasive fungal infections (IFIs) such as cryptococcal meningitis (CM) remain a serious health issue worldwide due to drug resistance closely related to biofilm formation. Unfortunately, available antifungal drugs with ideal safety and promising potency are still lacking; thus, the research of new candidate and therapeutic approach is urgently needed. As an important gas messenger molecule, nitric oxide (NO) shows vital inhibition on various microorganism biofilms. Hence, three series of novel NO-donating azole derivatives were designed and synthesized, and the in vitro antifungal activity as well as the mechanism of action was investigated. Among them, 3a and 3e displayed excellent antifungal activity against Cryptococcus neoformans and biofilm depending on the release of NO. Moreover, a more stable analogue 3h of 3a demonstrated markedly anti-CM effects via intranasal dropping, avoiding the first-pass effects and possessing a better brain permeability bypass blood-brain barrier. These results present a promising antifungal candidate and intranasal dropping approach for the treatment of CM, warranting further studies.


Assuntos
Criptococose , Cryptococcus neoformans , Meningite Criptocócica , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Azóis/farmacologia , Criptococose/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Testes de Sensibilidade Microbiana
12.
Mol Breed ; 43(3): 17, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37313295

RESUMO

Mushroom leaves (MLs) are malformed leaves that develop from the leaf veins in some of Chinese kale genotypes. To study the genetic model and molecular mechanism of ML development in Chinese kale, the F2 segregation population was constructed by two inbred lines, genotype Boc52 with ML and genotype Boc55 with normal leaves (NL). In the present study, we have identified for the first time that the development of mushroom leaves may be affected by the change of adaxial-abaxial polarity of leaves. Examination of the phenotypes of F1 and F2 segregation populations suggested that ML development is controlled by two dominant major genes inherited independently. BSA-seq analysis showed that a major quantitative trait locus (QTL) qML4.1 that controls ML development is located within 7.4 Mb on chromosome kC4. The candidate region was further narrowed to 255 kb by linkage analysis combined with insertion/deletion (InDel) markers, and 37 genes were predicted in this region. According to the expression and annotation analysis, a B3 domain-containing transcription factor NGA1-like gene, BocNGA1, was identified as a key candidate gene for controlling ML development in Chinese kale. Fifteen single nucleotide polymorphisms (SNPs) were found in coding sequences and 21 SNPs and 3 InDels found in the promoter sequences of BocNGA1 from the genotype Boc52 with ML. The expression levels of BocNGA1 in ML genotypes are significantly lower than in the NL genotypes, which suggests that BocNGA1 may act as a negative regulator for ML genesis in Chinese kale. This study provides a new foundation for Chinese kale breeding and for the study of the molecular mechanism of plant leaf differentiation. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01364-6.

13.
Liver Cancer ; 12(2): 116-128, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37325495

RESUMO

Introduction: Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population. Methods: In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety. Results: As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9-54.3) in group A and 14.3% (95% CI, 3.0-36.3) in group B. Median duration of response was not reached (95% CI, 3.3-not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9-NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4-5.5) and 4.1 months (95% CI, 1.5-NE), and median overall survival was 11.6 months (95% CI, 6.4-NE) and 14.3 months (95% CI, 8.2-NE) in groups A and B, respectively. Conclusion: Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.

14.
Phys Chem Chem Phys ; 25(26): 17657-17666, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37366159

RESUMO

In the field of membrane separation, the environmental concerns caused by spent membranes are becoming increasingly serious, which contradicts the concept of sustainable development. Based on this, a biodegradable poly(butylene adipate-co-terephthalate) (PBAT) membrane was used for the first time in the pervaporation separation of phenol, a high boiling point organic compound (HBOC). By using the PBAT membrane, outstanding separation efficiency was achieved, and environmental pollution and disposal issues were also avoided. The separation process and mechanism of the PBAT membrane were systematically studied through the experiment together with molecular dynamics (MD) simulation. The swelling experiment and intermolecular interaction energy calculation demonstrated that the PBAT membrane had a strong affinity for phenol. Further simulation concluded that higher phenol concentration increased the number of hydrogen bonds so that the membrane was more greatly swollen. Meanwhile, the simulations on the adsorption, diffusion and permeation predicted that the PBAT membrane had excellent separation performance for phenol. Besides MD simulation, the influences of feed concentration and temperature on pervaporation performance were also investigated by experiment. The results showed that the flux of each component increased with the feed concentration. This phenomenon was attributed to the preferential adsorption of phenol by the PBAT membrane, which resulted in large free volumes and cavities within the membrane, accelerating the diffusion of molecules. In addition, it was found that the optimal operating temperature was 333 K with the best separation performance. This study confirms that the biodegradable PBAT membrane is valuable for the recovery of high boiling point organic compounds (HBOCs) such as phenol.

15.
ACS Biomater Sci Eng ; 9(6): 3335-3347, 2023 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-37144723

RESUMO

Fragrances, which are commonly used in food, textiles, consumer products, and medical supplies, are volatile compounds that require stabilization and controlled release due to their sensitivity to environmental conditions such as light, oxygen, temperature, and humidity. Encapsulation in various material matrices is a desired technique for these purposes, and there is a growing interest in using sustainable natural materials to reduce environmental impact. In this study, fragrance encapsulation in microspheres made from silk fibroin (SF) was investigated. Fragrance-loaded silk fibroin microspheres (Fr-SFMSs) were prepared by adding fragrance/surfactant emulsions to silk solutions, followed by mixing them with polyethylene glycol under ambient conditions. The study investigated eight different fragrances, where citral, beta-ionone, and eugenol showed higher binding affinities to silk than the other five fragrances, resulting in better microsphere formation with uniform sizes and higher fragrance loading (10-30%). Citral-SFMSs showed characteristic crystalline ß-sheet structures of SF, high thermal stability (initial weight loss at 255 °C), long shelf life at 37 °C (>60 days), and sustained release (∼30% of citral remained after incubation at 60 °C for 24 h). When citral-SFMSs with different sizes were used to treat cotton fabrics, about 80% of the fragrance remained on the fabrics after one wash, and the duration of release from the treated fabrics was significantly longer than that of control samples treated with citral alone (no microspheres). This method of preparing Fr-SFMSs has potential applications in textile finishing, cosmetics, and the food industry.


Assuntos
Fibroínas , Seda , Seda/química , Odorantes , Preparações de Ação Retardada
16.
ACS Biomater Sci Eng ; 9(6): 3643-3659, 2023 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-37142304

RESUMO

The conventional method of applying local medications for treating wound infections is often ineffective because of the dilution of drugs by the excess wound exudate. In addition, there have been insufficient studies investigating the adhesion between drug-loaded nanomaterials and cells or tissue. To address this intractable problem, berberine-silk fibroin microspheres (Ber@MPs) with an extracellular matrix-anchoring function were developed in this study. The microspheres were prepared from silk fibroin using the polyethylene glycol emulsion precipitation method. Subsequently, berberine was loaded onto the microspheres. Our results revealed that Ber@MPs firmly anchored to cells, continuously releasing berberine in the microenvironment. Moreover, both Ber@MPs and Ber@MPs-cell complexes exerted a strong and long-lasting antibacterial effect against Staphylococcus aureus and Staphylococcus epidermidis in the microenvironment, despite the large amount of wound exudate. In addition, Ber@MPs effectively resisted the inflammatory response induced by lipopolysaccharides and accelerated the migration of fibroblasts and neovascularization of endothelial cells cultured in inflammation-induced media. Finally, the in vivo experiments confirmed that the Ber@MP spray accelerated the healing of infected wounds via its antibacterial and anti-inflammatory effects. Therefore, this study provides a novel strategy for treating infected wounds in the presence of excess exudate.


Assuntos
Berberina , Fibroínas , Fibroínas/farmacologia , Berberina/farmacologia , Microesferas , Células Endoteliais , Cicatrização , Antibacterianos/farmacologia , Matriz Extracelular , Anti-Inflamatórios/farmacologia
17.
Chem Biol Drug Des ; 102(2): 395-407, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37062588

RESUMO

The decrease in angiogenesis that occurs with aging significantly contributes to the higher incidence and mortality of cardiovascular diseases among the elderly. This decline in angiogenesis becomes more pronounced with increasing age and is closely linked to abnormal function and senescence of endothelial cells. Enhancing angiogenesis in aging and targeting senescent endothelial cells have gained considerable attention. Nitric oxide (NO) has been thoroughly investigated for its function in regulating angiogenesis and is an important factor that can counteract endothelial cell senescence. This review summarizes the mechanisms of reduced angiogenesis during aging and therapeutic strategies targeting senescent cells. We also discuss the potential of combining the current approaches with NO in promoting angiogenesis in aging vessels.


Assuntos
Células Endoteliais , Óxido Nítrico , Humanos , Idoso , Endotélio Vascular , Envelhecimento , Senescência Celular/fisiologia
18.
ACS Appl Mater Interfaces ; 15(10): 12696-12707, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36855948

RESUMO

Wound dressings are important for wound repair. The morphology of the biomaterials used in these dressings, and in particular, the pore structure affects tissue regeneration by facilitating attachment and proliferation of cells due to the hierarchical multiscale, water absorbance, and nutrient transport. In the present study, silk fibroin (SF) sponges with walls containing nanopores (SFNS) were prepared from SF nanoparticles generated during the autoclaving of SF solutions, followed by leaching the SF nanoparticles from the freeze-dried sponges of SF. The nano/microporous structure, biofluid absorbance, and porosity of the SF sponges with and without nanopores were characterized. In vitro cell proliferation, in vivo biocompatibility, and wound healing were evaluated with the sponges. The results demonstrated that SFNS had significantly increased porosity and water permeability, as well as cell attachment and proliferation when compared with SF sponges without the nanopores (SFS). Wound dressings were assessed in a rat skin wound model, and SFNS was superior to SFS in accelerating wound healing, supported by vascularization, deposition of collagen, and increased epidermal thickness over 21 days. Hence, such a dressing material with a hierarchical multiscale pore structure could promote cell migration, vascularization, and tissue regeneration independently without adding any growth factor, which would offer a new strategy to design and engineer better-performed wound dressing.


Assuntos
Fibroínas , Nanoporos , Ratos , Animais , Fibroínas/química , Cicatrização , Colágeno/metabolismo , Água , Seda
19.
Curr Oncol ; 30(3): 2653-2672, 2023 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-36975415

RESUMO

The Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing (CMTM) family, comprising nine members, is involved in the tumorigenesis and progression of various cancers. However, the expression profiles and clinical significance of CMTM family members in hepatocellular carcinoma (HCC) are not fully clarified. In this study, the RNA-sequencing and clinical data were downloaded from The Cancer Genome Atlas (TCGA) databases. The Kaplan-Meier method and the Cox proportional hazards regression analysis were used to evaluate the prognostic significance of CMTM family members. Single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithms were employed to explore the relationship between CMTM family genes and the tumor microenvironment in HCC. Finally, the prognostic CMTM family gene expression was further validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining in clinical HCC tissue specimens. The results indicated that, compared with normal tissues, the expression of CKLF, CMTM1, CMTM3, CMTM4, CMTM7, and CMTM8 were significantly upregulated in HCC, while the expression of CMTM2, CMTM5, and CMTM6 were significantly downregulated in HCC. Univariate and multivariate Cox regression analysis demonstrated that CKLF was an independent prognostic biomarker for the overall survival (OS) of HCC patients. In HCC, the expression of CKLF was found to be correlated with immune cell infiltration, immune-related functions, and immune checkpoint genes. The qRT-PCR and IHC confirmed that CKLF was highly expressed in HCC. Overall, this research suggested that CKLF is involved in immune cell infiltration and may serve as a critical prognostic biomarker, which provides new light on the therapeutics for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Prognóstico , Neoplasias Hepáticas/genética , Algoritmos , Biomarcadores , Microambiente Tumoral , Quimiocinas/genética , Proteínas com Domínio MARVEL/genética
20.
Signal Transduct Target Ther ; 8(1): 58, 2023 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-36750721

RESUMO

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/métodos , Estudos de Coortes , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Estudos Retrospectivos
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