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1.
Eur J Med Chem ; 275: 116638, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38950489

RESUMO

The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway promotes antitumor immune responses by sensing cytosolic DNA fragments leaked from nucleus and mitochondria. Herein, we designed a highly charged ruthenium photosensitizer (Ru1) with a ß-carboline alkaloid derivative as the ligand for photo-activating of the cGAS-STING pathway. Due to the formation of multiple non-covalent intermolecular interactions, Ru1 can self-assemble into carrier-free nanoparticles (NPs). By incorporating the triphenylphosphine substituents, Ru1 can target and photo-damage mitochondrial DNA (mtDNA) to cause the cytoplasmic DNA leakage to activate the cGAS-STING pathway. Finally, Ru1 NPs show potent antitumor effects and elicit intense immune responses in vivo. In conclusion, we report the first self-assembling mtDNA-targeted photosensitizer, which can effectively activate the cGAS-STING pathway, thus providing innovations for the design of new photo-immunotherapeutic agents.

2.
Adv Sci (Weinh) ; : e2405327, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38952072

RESUMO

Stimuli-responsive materials exhibiting exceptional room temperature phosphorescence (RTP) hold promise for emerging technologies. However, constructing such systems in a sustainable, scalable, and processable manner remains challenging. This work reports a bio-inspired strategy to develop RTP nanofiber materials using bacterial cellulose (BC) via bio-fermentation. The green fabrication process, high biocompatibility, non-toxicity, and abundant hydroxyl groups make BC an ideal biopolymer for constructing durable and stimuli-responsive RTP materials. Remarkable RTP performance is observed with long lifetimes of up to 1636.79 ms at room temperature. Moreover, moisture can repeatedly quench and activate phosphorescence in a dynamic and tunable fashion by disrupting cellulose rigidity and permeability. With capabilities for repeatable moisture-sensitive phosphorescence, these materials are highly suitable for applications such as anti-counterfeiting and information encryption. This pioneering bio-derived approach provides a reliable and sustainable blueprint for constructing dynamic, scalable, and processable RTP materials beyond synthetic polymers.

3.
Fish Shellfish Immunol ; 151: 109730, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38942250

RESUMO

RLR helicases RIG-I and MDA5, which are known as pattern recognition receptors to sense cytoplasmic viral RNAs and trigger antiviral immune responses, are DExD/H-box helicases. In teleost, whether and how non-RLR helicases regulate RLR helicases to affect viral infection remains unclear. Here, we report that the non-RLR helicase DHX40 from grass carp (namely gcDHX40) is a negative regulator of grass carp reovirus (GCRV) infection and RLR-mediated type I IFN production. GcDHX40 was a cytoplasmic protein. Ectopic expression of gcDHX40 facilitated GCRV replication and suppressed type I IFN production induced by GCRV infection and by those genes involved the RLR antiviral signaling pathway. Mechanistically, gcDHX40 promoted the generation of viral inclusion bodies (VIBs) by interacting with the NS38 protein of GCRV. Additionally, gcDHX40 interacted with RLR helicase, and impaired the formation of RLR-MAVS functional complexes. Taken together, our results indicate that gcDHX40 is a novel important proviral host factor involving in promoting the generation of GCRV VIBs and inhibiting the production of RLR-mediated type I IFNs.

4.
Endocrine ; 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38922479

RESUMO

Fracture risk in type 2 diabetes (T2D) patients is paradoxically increased despite no decrease in areal bone mineraldensity (BMD). This phenomenon, known as the "diabetic bone paradox", has been attributed to various factorsincluding alterations in bone microarchitecture and composition, hyperinsulinemia and hyperglycemia, advancedglycation end products (AGEs), and comorbidities associated with T2D. Zhao et al. recently investigated therelationship between T2D and fracture risk using both genetic and phenotypic datasets. Their findings suggest thatgenetically predicted T2D is associated with higher BMD and lower fracture risk, indicating that the bone paradox isnot observed when confounding factors are controlled using Mendelian randomization (MR) analysis. However, inprospective phenotypic analysis, T2D remained associated with higher BMD and higher fracture risk, even afteradjusting for confounding factors. Stratified analysis revealed that the bone paradox may disappear when T2Drelatedrisk factors are eliminated. The study also highlighted the role of obesity in the relationship between T2Dand fracture risk, with BMI mediating a significant portion of the protective effect. Overall, managing T2D-relatedrisk factors may be crucial in preventing fracture risk in T2D patients.

5.
J Affect Disord ; 361: 589-595, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38908558

RESUMO

BACKGROUND: This study aimed to explore and evaluate the development trends and differential changes in the prevalence of mental and behavioral disorders among the earthquake survivors in exposure groups (highly hard-hit areas) and control groups (general disaster areas) from 2015 to 2019, as well as to investigate the potential influencing factors. METHODS: Data was obtained from the Sichuan Health Information System and the Sichuan Health Yearbook, the prevalence of the exposure group and the control group were calculated, the difference between the two groups was evaluated using the prevalence rate ratio, and a fixed effect model was developed to investigate the potential influencing factors of the prevalence. RESULTS: The prevalence by gender and age in the exposure group was always greater than those in the control group (RR>1), although the disparity between the two proceeded to diminish with time. The urbanization rate (ß = 0.0448, P < 0.05) and disaster area levels (ß = 0.0104, P < 0.05) were risk factors for the prevalence of mental and behavioral disorders. LIMITATIONS: The study only collected data at the group level following the Wenchuan earthquake. Consequently, the findings are only applicable at the group level. Furthermore, diagnostic criteria for various types of mental and behavioral disorders diseases were not provided. CONCLUSIONS: The earthquake has a significant long-term impact on mental health. It is necessary to continuously monitor the mental health of Wenchuan earthquake survivors and take appropriate post-disaster intervention measures.

6.
J Immunother Cancer ; 12(6)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38908856

RESUMO

BACKGROUND: Tertiary lymphoid structures (TLSs) serve as organized lymphoid aggregates that influence immune responses within the tumor microenvironment. This study aims to investigate the characteristics and clinical significance of TLSs and tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC). METHODS: TLSs and TILs were analyzed comprehensively in 754 ccRCC patients from 6 academic centers and 532 patients from The Cancer Genome Atlas. Integrated analysis was performed based on single-cell RNA-sequencing datasets from 21 ccRCC patients to investigate TLS heterogeneity in ccRCC. Immunohistochemistry and multiplex immunofluorescence were applied. Cox regression and Kaplan-Meier analyses were used to reveal the prognostic significance. RESULTS: The study demonstrated the existence of TLSs and TILs heterogeneities in the ccRCC microenvironment. TLSs were identified in 16% of the tumor tissues in 113 patients. High density (>0.6/mm2) and maturation of TLSs predicted good overall survival (OS) (p<0.01) in ccRCC patients. However, high infiltration (>151) of scattered TILs was an independent risk factor of poor ccRCC prognosis (HR=14.818, p<0.001). The presence of TLSs was correlated with improved progression-free survival (p=0.002) and responsiveness to therapy (p<0.001). Interestingly, the combination of age and TLSs abundance had an impact on OS (p<0.001). Higher senescence scores were detected in individuals with immature TLSs (p=0.003). CONCLUSIONS: The study revealed the contradictory features of intratumoral TLSs and TILs in the ccRCC microenvironment and their impact on clinical prognosis, suggesting that abundant and mature intratumoral TLSs were associated with decreased risks of postoperative ccRCC relapse and death as well as favorable therapeutic response. Distinct spatial distributions of immune infiltration could reflect effective antitumor or protumor immunity in ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Linfócitos do Interstício Tumoral , Estruturas Linfoides Terciárias , Microambiente Tumoral , Humanos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Estruturas Linfoides Terciárias/imunologia , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/genética , Feminino , Masculino , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Prognóstico , Estudos de Coortes , Idoso
7.
Nat Commun ; 15(1): 4846, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844481

RESUMO

The collective light-matter interaction of chiral supramolecular aggregates or molecular ensembles with confined light fields remains a mystery beyond the current theoretical description. Here, we programmably and accurately build models of chiral plasmonic complexes, aiming to uncover the entangled effects of excitonic correlations, intra- and intermolecular charge transfer, and localized surface plasmon resonances. The intricate interplay of multiple chirality origins has proven to be strongly dependent on the site-specificity of chiral molecules on plasmonic nanoparticle surfaces spanning the nanometer to sub-nanometer scale. This dependence is manifested as a distinct circular dichroism response that varies in spectral asymmetry/splitting, signal intensity, and internal ratio of intensity. The inhomogeneity of the surface-localized plasmonic field is revealed to affect excitonic and charge-transfer mixed intermolecular couplings, which are inherent to chirality generation and amplification. Our findings contribute to the development of hybrid classical-quantum theoretical frameworks and the harnessing of spin-charge transport for emergent applications.

8.
Front Immunol ; 15: 1376096, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38863707

RESUMO

Bispecific T-cell-engaging antibodies are a growing class of therapeutics with numerous molecules being tested in clinical trials and, currently, seven of them have received market approval. They are structurally complex and function as adaptors to redirect the cytotoxicity of T cells to kill tumor cells. T-cell-engaging bispecific antibodies can be generally divided into two categories: IgG/IgG-like and non-IgG-like formats. Different formats may have different intrinsic potencies and physiochemical properties, and comprehensive studies are needed to gain a better understanding of how the differences in formats impact on structural and functional characteristics. In this study, we designed and generated bispecific T-cell-engaging antibodies with IgG-like (DVD-Ig) and non-IgG (BiTE) formats. Both target the same pair of antigens (EGFR and CD3) to minimize the possible influence of targets on functional characterization. We performed a side-by-side comparison to assess differences in the physiochemical and biological properties of these two bispecific T-cell-engaging antibodies using a variety of breast and ovarian cancer cell-based functional assays to delineate the structural-functional relationships and anti-tumor activities/potency. We found that the Fc portion of T-cell-engaging bispecific antibodies can significantly impact antigen binding activity, potency, and stability in addition to eliciting different mechanisms of action that contribute the killing of cancer cells.


Assuntos
Anticorpos Biespecíficos , Imunoglobulina G , Linfócitos T , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/imunologia , Humanos , Imunoglobulina G/imunologia , Linfócitos T/imunologia , Complexo CD3/imunologia , Linhagem Celular Tumoral , Receptores ErbB/imunologia , Feminino , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia
9.
Nat Commun ; 15(1): 4907, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851760

RESUMO

Perovskite/silicon tandem solar cells hold great promise for realizing high power conversion efficiency at low cost. However, achieving scalable fabrication of wide-bandgap perovskite (~1.68 eV) in air, without the protective environment of an inert atmosphere, remains challenging due to moisture-induced degradation of perovskite films. Herein, this study reveals that the extent of moisture interference is significantly influenced by the properties of solvent. We further demonstrate that n-Butanol (nBA), with its low polarity and moderate volatilization rate, not only mitigates the detrimental effects of moisture in air during scalable fabrication but also enhances the uniformity of perovskite films. This approach enables us to achieve an impressive efficiency of 29.4% (certified 28.7%) for double-sided textured perovskite/silicon tandem cells featuring large-size pyramids (2-3 µm) and 26.3% over an aperture area of 16 cm2. This advance provides a route for large-scale production of perovskite/silicon tandem solar cells, marking a significant stride toward their commercial viability.

10.
Regen Biomater ; 11: rbae050, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38872841

RESUMO

Pulp regeneration remains a crucial target in the preservation of natural dentition. Using decellularized extracellular matrix is an appropriate approach to mimic natural microenvironment and facilitate tissue regeneration. In this study, we attempted to obtain decellularized extracellular matrix from periapical lesion (PL-dECM) and evaluate its bioactive effects. The decellularization process yielded translucent and viscous PL-dECM, meeting the standard requirements for decellularization efficiency. Proteomic sequencing revealed that the PL-dECM retained essential extracellular matrix components and numerous bioactive factors. The PL-dECM conditioned medium could enhance the proliferation and migration ability of periapical lesion-derived stem cells (PLDSCs) in a dose-dependent manner. Culturing PLDSCs on PL-dECM slices improved odontogenic/angiogenic ability compared to the type I collagen group. In vivo, the PL-dECM demonstrated a sustained supportive effect on PLDSCs and promoted odontogenic/angiogenic differentiation. Both in vitro and in vivo studies illustrated that PL-dECM served as an effective scaffold for pulp tissue engineering, providing valuable insights into PLDSCs differentiation. These findings pave avenues for the clinical application of dECM's in situ transplantation for regenerative endodontics.

11.
Zool Res ; 45(3): 535-550, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38747058

RESUMO

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such as defects in the density and morphology of postsynaptic dendritic spines, underlie the pathology of various neuropsychiatric disorders. Protocadherin 17 (PCDH17) is associated with major mood disorders, including bipolar disorder and depression. However, the molecular mechanisms by which PCDH17 regulates spine number, morphology, and behavior remain elusive. In this study, we found that PCDH17 functions at postsynaptic sites, restricting the number and size of dendritic spines in excitatory neurons. Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety- and depression-like behaviors in mice. Mechanistically, PCDH17 interacts with actin-relevant proteins and regulates actin filament (F-actin) organization. Specifically, PCDH17 binds to ROCK2, increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3 (Ser3). Inhibition of ROCK2 activity with belumosudil (KD025) ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression, suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development. Hence, these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior, providing pathological insights into the neurobiological basis of mood disorders.


Assuntos
Citoesqueleto de Actina , Caderinas , Espinhas Dendríticas , Protocaderinas , Quinases Associadas a rho , Animais , Camundongos , Citoesqueleto de Actina/metabolismo , Caderinas/metabolismo , Caderinas/genética , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/fisiologia , Regulação da Expressão Gênica , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/genética , Protocaderinas/genética , Protocaderinas/metabolismo
12.
Zhongguo Zhong Yao Za Zhi ; 49(10): 2754-2765, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38812176

RESUMO

This study deciphered the ameliorating effect and molecular mechanism of the total glucosides of White Paeony Capsules(TGP) in the treatment of mice model with acute lung injury(ALI) via NOD-like receptor thermal protein domain associated protein 3(NLRP3) signaling pathway of the inflammasome. The study established an inflammasome activation model of primed bone marrow-derived macrophages(BMDMs), and its molecular mechanism was investigated by Western blot(WB), immunofluorescence staining, enzyme-linked immunosorbent assay(ELISA), and flow cytometry. C57BL/6J mice were randomly divided into a blank control group, a TGP group, a model group(LPS group), LPS+low-and high-dose TGP groups, LPS+MCC950 group, and LPS+MCC950+TGP group, with eight mice per group. The ALI model was induced in mice. Finally, bronchoalveolar lavage fluid(BALF) and lung tissue were collected. Lung index and lung weight wet-to-dry ratio were determined for each group of mice. The pathological changes in lung tissue were observed through hematoxylin-eosin(HE) staining. The number of neutrophils in the BALF of each group was detected using flow cytometry. The levels of interleukin(IL)-1ß, IL-6, and tumor necrosis factor(TNF)-α in the BALF were determined by ELISA. The expressions of IL-1ß, IL-18, IL-6, and TNF-α in the lung tissue were determined by real-time quantitative PCR(RT-qPCR). This study demonstrated that TGP dramatically blocked the activation of the NLRP3 inflammasome by inhibiting the production of upstream mitochondrial reactive oxygen species(mtROS) and the subsequent oligomerization of apoptosis-associated specks(ASC). Additionally, in the ALI mice model, compared with the blank control group, the model group showed alveolar structure rupture, thic-kening of alveolar septa, and dramatically increased lung index, lung weight wet-to-dry ratio in lung tissue, neutrophil count, and inflammatory factor levels. Compared with the model group, the pathological morphology of lung tissue was significantly ameliorated in the TGP and MCC950 groups, and the lung index and lung weight wet-to-dry ratio were significantly reduced. Neutrophil counts were reduced, and levels of inflammatory factors were significantly downregulated. Notably, compared with the MCC950 group, there was no significant difference in effect in the MCC950+TGP group. Collectively, the study reveals that TGP may ameliorate ALI in mice by inhibiting the activation of NLRP3 inflammasome, providing a safe and effective drug candidate for the prevention or treatment of ALI/ARDS.


Assuntos
Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas , Glucosídeos , Inflamassomos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Paeonia , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Glucosídeos/farmacologia , Glucosídeos/química , Camundongos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Masculino , Paeonia/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Cápsulas , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo
13.
Phys Chem Chem Phys ; 26(19): 14205-14215, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38689538

RESUMO

Graphitic carbon nitride (g-C3N4 or GCN) shows promise in photocatalytic water splitting, despite facing the challenge of rapid electron-hole recombination. In this study, we investigated the influence of boron/oxygen codoping on the photocatalytic performance of GCN systems for hydrogen generation. First-principles calculations and nonadiabatic molecular dynamics (NAMD) simulations were employed to reveal that the recombination time of photogenerated carriers could be increased by 16% to 64% in the codoped systems compared to the pristine GCN. The time-dependent density functional theory (TDDFT) scheme was utilized to select energy windows and initiate dynamics in cluster models of B/O co-doped heptazine with water molecules. Notably, we observed efficient direct photodissociation of hydrogen atoms from water molecules within 60 fs and proton hops within the hydrogen-bonded network within 80 fs in the co-doped system, diverging from the previously proposed mechanism for pristine heptazine in NAMD simulations. This discovery underscores the significant role of faster proton-coupled electron transfer (PCET) reactions and rapid radiationless relaxation in achieving high photocatalytic efficiency in water splitting. Our work enhances the understanding of the internal mechanism of highly efficient photocatalysts for water splitting and provides a new design strategy for doped GCN.

14.
Curr Microbiol ; 81(7): 182, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769214

RESUMO

Fusarium proliferatum is the main pathogen that causes Panax notoginseng root rot. The shortcomings of strong volatility and poor water solubility of Illicium verum essential oil (EO) limit its utilization. In this study, we prepared traditional emulsion (BDT) and nanoemulsion (Bneo) of I. verum EO by ultrasonic method with Tween-80 and absolute ethanol as solvents. The chemical components of EO, BDT, and Bneo were identified by gas chromatography-mass spectrometry (GC-MS) and the antifungal activity and mechanism were compared. The results show that Bneo has good stability and its particle size is 34.86 nm. The contents of (-) -anethole and estragole in Bneo were significantly higher than those in BDT. The antifungal activity against F. proliferatum was 5.8-fold higher than BDT. In the presence of I. verum EO, the occurrence of P. notoginseng root rot was significantly reduced. By combining transcriptome and metabolomics analysis, I. verum EO was found to be involved in the mutual transformation of pentose and glucuronic acid, galactose metabolism, streptomycin biosynthesis, carbon metabolism, and other metabolic pathways of F. proliferatum, and it interfered with the normal growth of F. proliferatum to exert antifungal effects. This study provide a theoretical basis for expanding the practical application of Bneo.


Assuntos
Antifúngicos , Emulsões , Fusarium , Illicium , Metabolômica , Óleos Voláteis , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Fusarium/efeitos dos fármacos , Fusarium/genética , Fusarium/metabolismo , Illicium/química , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Antifúngicos/química , Emulsões/química , Transcriptoma , Cromatografia Gasosa-Espectrometria de Massas , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Perfilação da Expressão Gênica
15.
Biomaterials ; 309: 122613, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38759485

RESUMO

Vascular restenosis following angioplasty continues to pose a significant challenge. The heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3, 5-triazinane-2, 4, 6-trione (TGIC)], known for its anticancer activity, was utilized as the parent ring to conjugate with a non-steroidal anti-inflammatory drug, resulting in the creation of the spliced conjugated compound BY1. We found that BY1 induced ferroptosis in VSMCs as well as in neointima hyperplasia. Furthermore, ferroptosis inducers amplified BY1-induced cell death, while inhibitors mitigated it, indicating the contribution of ferroptosis to BY1-induced cell death. Additionally, we established that ferritin heavy chain1 (FTH1) played a pivotal role in BY1-induced ferroptosis, as evidenced by the fact that FTH1 overexpression abrogated BY1-induced ferroptosis, while FTH1 knockdown exacerbated it. Further study found that BY1 induced ferroptosis by enhancing the NCOA4-FTH1 interaction and increasing the amount of intracellular ferrous. We compared the effectiveness of various administration routes for BY1, including BY1-coated balloons, hydrogel-based BY1 delivery, and nanoparticles targeting OPN loaded with BY1 (TOP@MPDA@BY1) for targeting proliferated VSMCs, for prevention and treatment of the restenosis. Our results indicated that TOP@MPDA@BY1 was the most effective among the three administration routes, positioning BY1 as a highly promising candidate for the development of drug-eluting stents or treatments for restenosis.


Assuntos
Ferroptose , Músculo Liso Vascular , Nanopartículas , Ferroptose/efeitos dos fármacos , Animais , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citologia , Humanos , Nanopartículas/química , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredutases/metabolismo , Ferritinas
16.
Cancer Lett ; 593: 216963, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38768682

RESUMO

Neoadjuvant tyrosine kinase inhibitor (TKI) therapy is an important treatment option for advanced renal cell carcinoma (RCC). Many RCC patients may fail to respond or be resistant to TKI therapy. We aimed to explore the key mechanisms of neoadjuvant therapy résistance. We obtained tumor samples from matched pre-treatment biopsy and post-treatment surgical samples and performed single-cell RNA sequencing. Sunitinib-resistant ccRCC cell lines were established. Ferroptosis was detected by ferrous ion and lipid peroxidation levels. Tumor growth and resistance to Sunitinib was validated in vitro and vivo. Immunohistochemistry was used to validate the levels key genes and lipid peroxidation. Multi-center cohorts were included, including TCGA, ICGC, Checkmate-025 and IMmotion151 clinical trial. Survival analysis was performed to identify the associated clinical and genomic variables. Intratumoral heterogeneity was first described in the whole neoadjuvant management. The signature of endothelial cells was correlated with drug sensitivity and progression-free survival. Ferroptosis was shown to be the key biological program in malignant cell resistance. We observed tissue lipid peroxidation was negatively correlated with IL6 and tumor response. TKI-resistant cell line was established. SLC7A11 knockdown promoted cell growth and lipid peroxidation, increased the ferroptosis level, and suppressed the growth of tumor xenografts significantly (P < 0.01). IL6 could reverse the ferroptosis and malignant behavior caused by SLC7A11 (-) via JAK2/STAT3 pathway, which was rescued by the ferroptosis inducer Erastin. Our data indicate that ferroptosis is a novel strategy for advanced RCC treatment, which activated by IL6, providing a new idea for resistance to TKIs.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Neoplasias Renais , Terapia Neoadjuvante , Sunitinibe , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Terapia Neoadjuvante/métodos , Sunitinibe/farmacologia , Animais , Linhagem Celular Tumoral , Camundongos , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Proteínas Quinases/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Feminino , Masculino , Terapia de Alvo Molecular , Interleucina-6/metabolismo , Interleucina-6/genética , Progressão da Doença
17.
Updates Surg ; 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38568357

RESUMO

PURPOSE: To compare the surgical safety and postoperative quality of life (QOL) between side overlap anastomosis (SOA) and double-tract anastomosis (DTA) after laparoscopic proximal gastrectomy (LPG). METHODS: This retrospective cohort study included 43 patients with proximal gastric cancer (PGC) who underwent LPG and were admitted to the Second Affiliated Hospital of Fujian Medical University between August 2020 and December 2022 were in. Their clinical and follow-up data were collected. The patients were divided into the modified SOA (mSOA) (n = 20) and DTA (n = 23) groups based on the anastomosis methods used. The main outcome measures included the QOL of patients 1 year after surgery, and the evaluation criteria were based on the postgastrectomy syndrome assessment scale. Secondary outcome measures included intraoperative and postoperative conditions, postoperative long-term complications and nutritional status 3, 6 and 12 months after surgery. RESULTS: No significant differences were observed in intraoperative and postoperative conditions (P > 0.05) between the mSOA and DTA groups. The mSOA group showed a decreased incidence of reflux esophagitis 1 year after surgery compared with the DTA group (P < 0.05), and no statistically significant differences were noticed between the two groups in terms of other postoperative complications (P > 0.05). The mSOA group showed better QOL when compared with the DTA group (P < 0.05). No significant differences were recorded in postoperative nutritional status between the two groups (P > 0.05). CONCLUSION: The efficacy and safety of LPG with mSOA for PGC were comparable. When compared with the DTA group, the mSOA group seems to show reduced incidence of gastroesophageal reflux and improved QOL, which makes mSOA one of the ideal surgical methods for PGC.

18.
Front Surg ; 11: 1348737, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38645508

RESUMO

Objective: To review and summarize the characteristics and therapy of paraganglioma of the urinary bladder (PUB). Method: Patients who underwent the operation in Peking Union Medical College Hospital between January 2012 and December 2021 were reviewed for this retrospective study. Results: A total of 29 patients, comprising 9 (31%) men and 20 (69%) women, were included. The main manifestations were hypertension, palpitation, and micturition syncope. Eight patients had an increased 24-h urinary catecholamine, and seven of them had increased norepinephrine. Normetanephrine in seven patients was increased. Six of 18 metaiodobenzylguanidine and 8 of 22 octreotide scans were positive. In total, 15 cases underwent laparoscopic partial cystectomy and 14 underwent transurethral resection of bladder tumor. In all patients, the immunohistochemical index of Melan-A, AE1/AE3, and α-inhibin were negative, and chromogranin A, S-100, and succinate dehydrogenase were positive. The Ki-67 of 28/29 cases was under 5%, and 1 case with a Ki-67 of 20% was diagnosed with malignant PUB. A total of 27 patients had a regular follow-up, 2 patients were lost during the follow-up, 3 patients had a recurrence, and 1 of these patients died within 1 year of surgery. The symptoms all disappeared or were relieved after the surgery. Conclusion: The transurethral surgery approach fits PUB tumors with a size <3 cm or that protrudes into the bladder and can significantly reduce the postoperative hospital stay. Early detection and treatment are effective, and regular review is necessary after the surgery.

19.
Virus Res ; 345: 199376, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38643856

RESUMO

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are antigenically related flaviviruses that co-circulate in many countries/territories. The interaction between the two viruses needs to be determined. Recent findings by ourselves and other labs showed that JEV-elicited antibodies (Abs) and CD8+T cells exacerbate and protect against subsequent ZIKV infection, respectively. However, the impact of JEV envelope (E) protein domain III (EDIII)-induced immune responses on ZIKV infection is unclear. We show here that sera from JEV-EDIII-vaccinated mice cross-react with ZIKV-EDIII in vitro, and transfer of the same sera to mice significantly decreases death upon lethal ZIKV infection at a dose-dependent manner. Maternally acquired anti-JEV-EDIII Abs also significantly reduce the mortality of neonatal mice born to JEV-EDIII-immune mothers post ZIKV challenge. Similarly, transfer of ZIKV-EDIII-reactive IgG purified from JEV-vaccinated humans increases the survival of ZIKV-infected mice. Notably, transfer of an extremely low volume of JEV-EDIII-immune sera or ZIKV-EDIII-reactive IgG does not mediate the Ab-mediated enhancement (ADE) of ZIKV infection. Similarly, transfer of JEV-EDIII-elicited CD8+T cells protects recipient mice against ZIKV challenge. These results demonstrate that JEV-EDIII-induced immune components including Abs and T cells have protective roles in ZIKV infection, suggesting EDIII is a promising immunogen for developing effective and safety JEV vaccine.


Assuntos
Anticorpos Antivirais , Linfócitos T CD8-Positivos , Proteção Cruzada , Vírus da Encefalite Japonesa (Espécie) , Proteínas do Envelope Viral , Infecção por Zika virus , Zika virus , Animais , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/imunologia , Linfócitos T CD8-Positivos/imunologia , Zika virus/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Proteínas do Envelope Viral/imunologia , Camundongos , Vírus da Encefalite Japonesa (Espécie)/imunologia , Proteção Cruzada/imunologia , Feminino , Reações Cruzadas , Encefalite Japonesa/prevenção & controle , Encefalite Japonesa/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Modelos Animais de Doenças , Imunização
20.
Carbohydr Res ; 539: 109120, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38669825

RESUMO

Xanthoceras sorbifolium Bunge, also known as Tu-Mu-Gua and Wen-Dan-Ge-Zi, has several applications. Clinical data and experimental studies have shown anti-tumor, anti-inflammatory, anti-bacterial, and anti-oxidant properties of Xanthoceras sorbifolium Bunge that inhibits prostate hyperplasia, lowers blood pressure and lipid level, and treats enuresis and urinary incontinence. It also has neuroprotective effects and can treat Alzheimer's disease and Parkinson's syndrome. The research on the chemical composition and pharmacological effects of Xanthoceras sorbifolium Bunge has been increasing. Triterpenoid and triterpenoid saponins are the main constituents in Xanthoceras sorbifolium Bunge and exhibit biological activities. In this review, we summarized the research progress on triterpenoids and their glycosides in Xanthoceras sorbifolia, including the chemical constituents, pharmacological activities, and biogenic pathways of triterpenoid mother nucleus. The results would provide a reference for further research and development of triterpenoids and their glycosides in Xanthoceras sorbifolia.


Assuntos
Saponinas , Triterpenos , Saponinas/química , Saponinas/farmacologia , Saponinas/isolamento & purificação , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/isolamento & purificação , Humanos , Sapindaceae/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação
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