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The dental implant market has experienced explosive growth, owing to the widespread acceptance of implants as the core of oral rehabilitation. Clinically, achieving simultaneous anti-infective effects and rapid osseointegration is a crucial but challenging task for implants. The demand for implants with long-term broad-spectrum antibacterial and immune-osteogenic properties is growing. Existing methods are limited by a lack of safety, efficiency, short-lasting anti-infective ability, and inadequate consideration of the immunomodulatory effects on osteogenesis. Herein, a ZnO/black TiO2-x heterojunction surface structure was designed as a near-infrared (NIR) light-responsive nanofilm immobilized on a titanium (Ti) implant surface. This nanofilm introduces abundant oxygen vacancies and heterojunctions, which enhance the photothermal and photoelectric abilities of Ti implants under NIR illumination by narrowing the band gap and improving interfacial charge transfer. The "photo-thermo-electric" implant exhibits excellent broad-spectrum antibacterial efficacy against three dental pathogenic bacteria (Porphyromonas gingivalis, Fusobacterium nucleatum, and Staphylococcus aureus, >99.4%) by destroying the bacterial membrane and increasing the production of intracellular reactive oxygen species. Additionally, the implant can effectively eliminate mature multispecies biofilms and kill bacteria inside the biofilms under NIR irradiation. Meanwhile, this implant can also induce the pro-regenerative transformation of macrophages and promote osteoblast proliferation and differentiation. Moreover, in vivo results confirmed the superior antibacterial and osteoimmunomodulatory properties of this dental implant. RNA sequencing revealed that the underlying osteogenic mechanisms involve activation of the Wnt/ß-catenin signaling pathway and bone development. Overall, this versatile "photo-thermo-electric" platform endows implants with anti-infection and bone integration performance simultaneously, which holds great potential for dental implants.
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OBJECTIVE: This study aimed to verify if intraoperative radiotherapy (IORT) can achieve the same survival outcome as whole-breast external beam radiotherapy (EBRT) in early breast cancer after breast-conserving surgery (BCS), and to explore the suitable candidates that can safely receive IORT after BCS. METHODS: Eligible post-BCS patients who received IORT or EBRT were included in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. Risk factors that affected 5-year overall survival (OS) or breast cancer specific survival (BCSS) were identified by Cox proportional hazards regression analysis. Clinical characteristics, OS, and BCSS were comparatively analyzed between the two treatment modalities. RESULTS: The survival analysis after propensity score matching confirmed that patients who received IORT (n = 2200) had a better 5-year OS than those who received EBRT (n = 2200) (p = 0.015). However, the two groups did not differ significantly in 5-year BCSS (p = 0.381). This feature persisted even after multivariate analyses that took into account numerous clinical characteristics. Although there was no significant difference in BCSS between different subgroups of patients treated with IORT or EBRT, patients over 55 years of age, with T1, N0, non-triple negative breast cancers, hormone receptor-positive, and histologic grade II showed a better OS after receiving IORT. CONCLUSION: In low-risk, early-stage breast cancer, IORT was not inferior to EBRT considering 5-year BCSS and OS. Considering the equivalent clinical outcome but less radiotoxicity, IORT might be a reasonable alternative to EBRT in highly selective patients undergoing BCS.
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Neoplasias de la Mama , Mastectomía Segmentaria , Programa de VERF , Humanos , Femenino , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Persona de Mediana Edad , Anciano , Radioterapia Adyuvante/métodos , Cuidados Intraoperatorios/métodos , Adulto , Puntaje de Propensión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19.IMPORTANCEIn addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.
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Enzima Convertidora de Angiotensina 2 , Receptores Histamínicos H1 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Internalización del Virus , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Animales , Enzima Convertidora de Angiotensina 2/metabolismo , Ratones , Internalización del Virus/efectos de los fármacos , Receptores Histamínicos H1/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/genética , COVID-19/virología , COVID-19/metabolismo , Células HEK293 , Tratamiento Farmacológico de COVID-19 , Receptores Virales/metabolismo , Unión Proteica , Antagonistas de los Receptores Histamínicos/farmacología , Antivirales/farmacologíaRESUMEN
Ferroptosis has been demonstrated a promising way to counteract chemoresistance of multiple myeloma (MM), however, roles and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis of MM cells remain elusive. Here, we uncovered that MM cells were more susceptible to ferroptotic induction under the interaction of BMSCs using in vitro and in vivo models. Mechanistically, BMSCs elevated the iron level in MM cells, thereby activating the steroid biosynthesis pathway, especially the production of lanosterol, a major source of reactive oxygen species (ROS) in MM cells. We discovered that direct coupling of CD40 ligand and CD40 receptor constituted the key signaling pathway governing lanosterol biosynthesis, and disruption of CD40/CD40L interaction using an anti-CD40 neutralizing antibody or conditional depletion of Cd40l in BMSCs successfully eliminated the iron level and lanosterol production of MM cells localized in the Vk*MYC Vk12653 or NSG mouse models. Our study deciphers the mechanism of BMSCs dictating ferroptosis of MM cells and highlights the therapeutic potential of non-apoptosis strategies for managing refractory or relapsed MM patients.
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Ferroptosis , Lanosterol , Células Madre Mesenquimatosas , Mieloma Múltiple , Mieloma Múltiple/patología , Mieloma Múltiple/metabolismo , Animales , Lanosterol/farmacología , Humanos , Ratones , Células Madre Mesenquimatosas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Hierro/metabolismo , Transducción de SeñalRESUMEN
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global pandemic, which severely endangers public health. Our and others' works have shown that the angiotensin-converting enzyme 2 (ACE2)-containing exosomes (ACE2-exos) have superior antiviral efficacies, especially in response to emerging variants. However, the mechanisms of how the virus counteracts the host and regulates ACE2-exos remain unclear. Here, we identified that SARS-CoV-2 nonstructural protein 6 (NSP6) inhibits the production of ACE2-exos by affecting the protein level of ACE2 as well as tetraspanin-CD63 which is a key factor for exosome biogenesis. We further found that the protein stability of CD63 and ACE2 is maintained by the deubiquitination of proteasome 26S subunit, non-ATPase 12 (PSMD12). NSP6 interacts with PSMD12 and counteracts its function, consequently promoting the degradation of CD63 and ACE2. As a result, NSP6 diminishes the antiviral efficacy of ACE2-exos and facilitates the virus to infect healthy bystander cells. Overall, our study provides a valuable target for the discovery of promising drugs for the treatment of coronavirus disease 2019. IMPORTANCE: The outbreak of coronavirus disease 2019 (COVID-19) severely endangers global public health. The efficacy of vaccines and antibodies declined with the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants. Angiotensin-converting enzyme 2-containing exosomes (ACE2-exos) therapy exhibits a broad neutralizing activity, which could be used against various viral mutations. Our study here revealed that SARS-CoV-2 nonstructural protein 6 inhibited the production of ACE2-exos, thereby promoting viral infection to the adjacent bystander cells. The identification of a new target for blocking SARS-CoV-2 depends on fully understanding the virus-host interaction networks. Our study sheds light on the mechanism by which the virus resists the host exosome defenses, which would facilitate the study and design of ACE2-exos-based therapeutics for COVID-19.
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COVID-19 , Exosomas , Humanos , COVID-19/metabolismo , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Exosomas/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Antivirales/farmacología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Unión ProteicaRESUMEN
Ageing and cell senescence of mesenchymal stem cells (MSCs) limited their immunomodulation properties and therapeutic application. We previously reported that nucleosome assembly protein 1-like 2 (Nap1l2) contributes to MSCs senescence and osteogenic differentiation. Here, we sought to evaluate whether Nap1l2 impairs the immunomodulatory properties of MSCs and find a way to rescue the deficient properties. We demonstrated that metformin could rescue the impaired migration properties and T cell regulation properties of OE-Nap1l2 BMSCs. Moreover, metformin could improve the impaired therapeutic efficacy of OE-Nap1l2 BMSCs in the treatment of colitis and experimental autoimmune encephalomyelitis in mice. Mechanistically, metformin was capable of upregulating the activation of AMPK, synthesis of l-arginine and expression of inducible nitric oxide synthase in OE-Nap1l2 BMSCs, leading to an increasing level of nitric oxide. This study indicated that Nap1l2 negatively regulated the immunomodulatory properties of BMSCs and that the impaired functions could be rescued by metformin pretreatment via metabolic reprogramming. This strategy might serve as a practical therapeutic option to rescue impaired MSCs functions for further application.
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Encefalomielitis Autoinmune Experimental , Inmunomodulación , Células Madre Mesenquimatosas , Metformina , Ratones Endogámicos C57BL , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Animales , Metformina/farmacología , Ratones , Inmunomodulación/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Colitis/tratamiento farmacológico , Colitis/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Reprogramación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Células Cultivadas , Movimiento Celular/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/citología , Reprogramación MetabólicaRESUMEN
Posttranslational modifications (PTMs) are crucial regulatory mechanisms for cellular differentiation and organismal development. Acylation modification is one of the main PTMs that plays a pivotal role in regulating the osteogenic differentiation of mesenchymal stem cells and is a focal point of research in bone tissue regeneration. However, its mechanism remains incompletely understood. This article aims to investigate the impact of protein crotonylation on osteogenic differentiation in periodontal ligament stem cells (PDLSCs) and elucidate its underlying mechanisms. Western blot analysis identified that the modification level of acetylation, crotonylation, and succinylation were significantly upregulated after osteogenic induction of PDLSCs. Subsequently, sodium crotonate (NaCr) was added to the medium and acyl-CoA synthetase short-chain family member 2 (ACSS2) was knocked down by short hairpin RNA plasmids to regulate the total level of protein crotonylation. The results indicated that treatment with NaCr promoted the expression of osteogenic differentiation-related factors in PDLSCs, whereas silencing ACSS2 had the opposite effect. In addition, mass spectrometry analysis was used to investigate the comprehensive analysis of proteome-wide crotonylation in PDLSCs under osteogenic differentiation. The analysis revealed that the level of protein crotonylation related to the PI3K-AKT signaling pathway was significantly upregulated in PDLSCs after osteogenic induction. Treatment with NaCr and silencing ACSS2 affected the activation of the PI3K-AKT signaling pathway. Collectively, our study demonstrates that protein crotonylation promotes osteogenic differentiation of PDLSCs via the PI3K-AKT pathway, providing a novel targeting therapeutic approach for bone tissue regeneration.
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Diferenciación Celular , Osteogénesis , Ligamento Periodontal , Transducción de Señal , Células Madre , Humanos , Diferenciación Celular/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Ligamento Periodontal/citología , Ligamento Periodontal/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Madre/metabolismo , Células Madre/citologíaRESUMEN
BACKGROUND: Obesity has emerged as a global epidemic. Recent research has indicated that diet-induced obesity can be prevented by promoting lacteal junction zippering. Berberine, which is derived from natural plants, is found to be promising in weight reduction, but the underlying mechanism remains unspecified. PURPOSE: To determine whether berberine protects against obesity by regulating the lacteal junction and to explore potential molecular mechanisms. METHODS: Following the induction of the diet-induced obese (DIO) model, mice were administered low and high doses of berberine for 4 weeks. Indicators associated with insulin resistance and lipid metabolism were examined. Various methods, such as Oil Red O staining, transmission electron microscopy imaging, confocal imaging and others were used to observe the effects of berberine on lipid absorption and the lacteal junction. In vitro, human dermal lymphatic endothelial cells (HDLECs) were used to investigate the effect of berberine on LEC junctions. Western Blot and immunostaining were applied to determine the expression levels of relevant molecules. RESULTS: Both low and high doses of berberine reduced body weight in DIO mice without appetite suppression and ameliorated glucolipid metabolism disorders. We also found that the weight loss effect of berberine might contribute to the inhibition of small intestinal lipid absorption. The possible mechanism was related to the promotion of lacteal junction zippering via suppressing the ras homolog gene family member A (RhoA)/Rho-associated kinase (ROCK) signaling pathway. In vitro, berberine also promoted the formation of stable mature junctions in HDLECs, involving the same signaling pathway. CONCLUSION: Berberine could promote lacteal junction zippering and ameliorate diet-induced obesity through the RhoA/ROCK signaling pathway.
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Berberina , Ratones , Humanos , Animales , Berberina/farmacología , Células Endoteliales/metabolismo , Transducción de Señal , Obesidad/tratamiento farmacológico , Dieta , Lípidos , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Excessive synthesis of triglycerides and cholesterol accelerates the progression of hepatic steatosis in metabolic-associated fatty liver disease (MAFLD). However, the precise mechanism by which 6-gingerol mitigates hepatic steatosis in MAFLD model mice has yet to be fully understood. The present study observed that 6-gingerol administration exhibited significant protective effects against obesity, insulin resistance, and hepatic steatosis in mice subjected to a high-fat diet (HFD), and mitigated lipid accumulation in HepG2 cells treated with palmitate (PA). Following the hepatic lipidomic analysis, we confirmed that the AMPK-SREBPs signaling pathway as the underlying molecular mechanism by which 6-gingerol inhibited triglyceride and cholesterol biosynthesis, both in vivo and in vitro, through Western blot and immunofluorescence assay. Additionally, the application of an AMPK agonist/inhibitor further validated that 6-gingerol promoted AMPK activation by increasing the phosphorylation level of AMPK in vitro. Notably, the inhibitory effect of 6-gingerol on cholesterol biosynthesis, rather than triglyceride biosynthesis, was significantly diminished after silencing SREBP2 using a lentiviral plasmid shRNA in HepG2 cells. Our study demonstrates that 6-gingerol mitigates hepatic triglyceride and cholesterol biosynthesis to alleviate hepatic steatosis by activating the AMPK-SREBPs signaling pathway, indicating that 6-gingerol may be a potential candidate in the therapy of MAFLD.
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Proteínas Quinasas Activadas por AMP , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Humanos , Triglicéridos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hígado , Metabolismo de los Lípidos , Transducción de Señal , Células Hep G2 , Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BLRESUMEN
Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants. Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited SARS-CoV-2 pseudovirus (PsV) infection at the early stage and potentially bound to the spike (S) protein of SARS-CoV-2, which may prevent the proteolytic cleavage of the S protein, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that phenothiazines can serve as a potential broad-spectrum therapeutic drug for the treatment of SARS-CoV-2 infection as well as the infection of future emerging human coronaviruses (HCoVs).
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COVID-19 , SARS-CoV-2 , Humanos , Fenotiazinas/farmacología , Glicoproteína de la Espiga del CoronavirusRESUMEN
In multiple myeloma (MM), bone marrow stromal cells (BMSC) shape a unique niche within the bone marrow, promoting T-cell dysfunction and driving MM progression; however, the precise underlying mechanisms remain elusive. Here, we show that BMSC-mediated reprogramming of MM cells led to heightened production of CXCL10. CXCL10 orchestrated the recruitment of γδ T cells into the bone marrow, and this was observed in both the Vk*MYC and 5TGM1 mouse models of MM, as well as in patients experiencing refractory or relapsed MM. Furthermore, the dysfunctional γδ T cells in the MM bone marrow niche exhibited increased PD-1 expression and IL17 production. In the Vk*MYC mouse model, MM-associated bone lesions and mortality were markedly alleviated in Tcrd-/- mice, and MM disease progression could be rescued in these mice upon transplantation of γδ T cells expanded from wild-type mice, but not from Il17-/- mice. Mechanistically, the hypoxic microenvironment prevailing in the MM bone marrow niche stimulated the expression of steroid receptor coactivator 3 (SRC-3) in γδ T cells, which in turn interacted with the transcriptional factor RORγt, promoting Il17 transcription. Pharmacologic inhibition of SRC-3 utilizing SI-2 effectively suppressed Il17A expression in γδ T cells, leading to alleviation of MM progression in the murine models and enhancing the anti-multiple myeloma efficacy of bortezomib. Our results illuminated the bone marrow microenvironment's involvement in provoking γδ T-cell dysfunction throughout MM progression and suggest SRC-3 inhibition as a promising strategy to enhance the effectiveness of immunotherapies targeting γδ T cells.
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Mieloma Múltiple , Humanos , Ratones , Animales , Mieloma Múltiple/patología , Médula Ósea/patología , Bortezomib , Receptores de Antígenos de Linfocitos T gamma-delta , Modelos Animales de Enfermedad , Linfocitos T/metabolismo , Microambiente Tumoral , Quimiocina CXCL10RESUMEN
Retroviruses, especially the pathogenic human immunodeficiency virus type 1 (HIV-1), have severely threatened human health for decades. Retroviruses can form stable latent reservoirs via retroviral DNA integration into the host genome, and then be temporarily transcriptional silencing in infected cells, which makes retroviral infection incurable. Although many cellular restriction factors interfere with various steps of the life cycle of retroviruses and the formation of viral latency, viruses can utilize viral proteins or hijack cellular factors to evade intracellular immunity. Many post-translational modifications play key roles in the cross-talking between the cellular and viral proteins, which has greatly determined the fate of retroviral infection. Here, we reviewed recent advances in the regulation of ubiquitination and SUMOylation in the infection and latency of retroviruses, focusing on both host defense- and virus counterattack-related ubiquitination and SUMOylation system. We also summarized the development of ubiquitination- and SUMOylation-targeted anti-retroviral drugs and discussed their therapeutic potential. Manipulating ubiquitination or SUMOylation pathways by targeted drugs could be a promising strategy to achieve a "sterilizing cure" or "functional cure" of retroviral infection.
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Infecciones por Retroviridae , Sumoilación , Humanos , Ubiquitinación , Proteínas Virales/metabolismo , Retroviridae/genética , Retroviridae/metabolismoRESUMEN
BACKGROUND: Immunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored. METHODS: The efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD.Cg-PrkdcscidIl2rgtm1Wjl /SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging. RESULTS: We report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2high MM cells in vitro and in vivo. CONCLUSION: This study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now.
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Mieloma Múltiple , Receptores de Ácido Retinoico , Ratones , Animales , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Inmunoterapia Adoptiva , Ratones Endogámicos NOD , Tretinoina/farmacología , Tretinoina/uso terapéutico , Tretinoina/metabolismo , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismoRESUMEN
Periodontitis is a chronic immune inflammatory disease that can lead to the destruction and loss of the tooth-supporting apparatus. During this process, the balance between bone absorption mediated by osteoclasts and bone formation mediated by osteoblasts is damaged. Consistent with previous studies, we observed that depletion of cylindromatosis (CYLD) resulted in an osteoporotic bone phenotype. However, the effect of CYLD deficiency on periodontitis is undetermined. Here, we investigated whether CYLD affects periodontal tissue homeostasis in experimental periodontitis in Cyld knockout (KO) mice, and we explored the underlying mechanisms. Interestingly, we discovered significant alveolar bone density loss and severely reduced alveolar bone height in Cyld KO mice with experimentally induced periodontitis. We observed increased osteoclast number and activity in both the femurs and alveolar bones, accompanied by the downregulation of osteogenesis genes and upregulation of osteoclastogenesis genes of alveolar bones in ligatured Cyld KO mice. Taken together, our findings demonstrate that the deletion of CYLD in mice plays a vital role in the pathogenesis of periodontal bone loss and suggest that CYLD might exert an ameliorative effect on periodontal inflammatory responses.
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Pérdida de Hueso Alveolar , Periodontitis , Ratones , Animales , Pérdida de Hueso Alveolar/genética , Osteogénesis , Osteoclastos/patología , Periodontitis/genética , Periodontitis/patología , Huesos/patología , Enzima Desubiquitinante CYLD/genéticaRESUMEN
Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.
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Antineoplásicos , Mieloma Múltiple , Humanos , Bortezomib/farmacología , Bortezomib/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Inhibidores de Proteasoma/farmacología , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Factores de Transcripción/farmacología , Antineoplásicos/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
The use of a cylindrical lens in femtosecond laser surface structuring is receiving attention to improve the processing efficiency. Here, we investigate the structures produced on a copper target, in air, by exploiting both spherical and cylindrical lenses for beam focusing, aiming at elucidating similarities and differences of the two approaches. The morphological features of the surface structures generated by ≈180 fs laser pulses at 1030 nm over areas of 8 × 8 mm2 were analyzed. For the spherical lens, micron-sized parallel channels are formed on the target surface, which is covered by subwavelength ripples and nanoparticles. Instead, the cylindrical lens leads to a surface decorated with ripples and nanoparticles with a negligible presence of micro-channels. Moreover, the morphological features achieved by focusing ≈180 fs laser pulses at 515 nm with the cylindrical lens and varying the scanning parameters were also studied. The experimental results evidence a direct effect of the hatch distance used in the scanning process on the target surface that contains dark and bright bands corresponding to regions where the rippled surface contains a richer decoration or a negligible redeposition of nanoparticles. Our findings can be of interest in large area surface structuring for the selection of the more appropriate focusing configuration according to the final application of the structured surface.
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Viruses have threatened human lives for decades, causing both chronic and acute infections accompanied by mild to severe symptoms. During the long journey of confrontation, humans have developed intricate immune systems to combat viral infections. In parallel, vaccines are invented and administrated to induce strong protective immunity while generating few adverse effects. With advancements in biochemistry and biophysics, different kinds of vaccines in versatile forms have been utilized to prevent virus infections, although the safety and effectiveness of these vaccines are diverse from each other. In this review, we first listed and described major pathogenic viruses and their pandemics that emerged in the past two centuries. Furthermore, we summarized the distinctive characteristics of different antiviral vaccines and adjuvants. Subsequently, in the main body, we reviewed recent advances of nanoparticles in the development of next-generation vaccines against influenza viruses, coronaviruses, HIV, hepatitis viruses, and many others. Specifically, we described applications of self-assembling protein polymers, virus-like particles, nano-carriers, and nano-adjuvants in antiviral vaccines. We also discussed the therapeutic potential of nanoparticles in developing safe and effective mucosal vaccines. Nanoparticle techniques could be promising platforms for developing broad-spectrum, preventive, or therapeutic antiviral vaccines.
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Lacteals are the central lymphatic vessels in the villi of the small intestine and perform nutrient absorption, especially dietary lipids, and the transportation of antigen and antigen-presenting cells. Remodeling, proliferation, and cell-cell junctions of lymphatic endothelial cells (LECs) in lacteals are the basis of the maintenance of lacteal integrity and dietary lipid absorption. Normal lipid absorption in the diet depends on sound lacteal development and proliferation, especially integrity maintenance, namely, maintaining the appropriate proportion of button-like and zipper-like junctions. Maintaining the integrity and transforming button-to-zipper junctions in lacteals are strongly connected with obesity, which could be regulated by intestinal flora and molecular signalings, such as vascular endothelial growth factor C-vascular endothelial growth receptor 3 (VEGFC-VEGFR3) signaling, Hippo signaling, Notch signaling, angiopoietin-TIE signaling, VEGF-A/VEGFR2 signaling, and PROX1. This manuscript reviews the molecular mechanism of development, integrity maintenance, and junction transformation in lacteal related to obesity.
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Vasos Linfáticos , Factor C de Crecimiento Endotelial Vascular , Humanos , Factor C de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales/metabolismo , Vasos Linfáticos/metabolismo , Grasas de la Dieta , ObesidadRESUMEN
Peri-implantitis, an infectious disease originating from dental biofilm that forms around dental implants, which causes the loss of both osseointegration and bone tissue. KN-17, a truncated cecropin B peptide, demonstrated efficacy against certain bacterial strains associated with peri-implantitis. This study aimed to assess the antibacterial and anti-inflammatory properties and mechanisms of KN-17. The effects of KN-17 on oral pathogenic bacteria were assessed by measuring its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Moreover, the cytotoxicity and anti-inflammatory effects of KN-17 were evaluated. KN-17 inhibited the growth of Streptococcus gordonii and Fusobacterium nucleatum during in vitro biofilm formation and possessed low toxicity to hBMSCs cells. KN-17 also caused RAW264.7 macrophages to transform from M1 to M2 by downregulating pro-inflammatory and upregulating anti-inflammatory factors. It inhibited the NF-κB signaling pathway by reducing IκBα and P65 protein phosphorylation while promoting IκBα degradation and nuclear P65 translocation. KN-17 might be an efficacious prophylaxis against peri-implant inflammation.
RESUMEN
The bacterial invasions and inflammatory responses after implant placement often affect osseointegration; the increased secretion of pro-inflammatory cytokines can lead to poor formation of bone and bone absorption. Previous research has shown that the antimicrobial peptide 6K-F17 has antibacterial and immunomodulatory properties. The objective of this study was to optimize KR-1 and KR-2, based on 6K-F17, to apply to the tissue around the oral implant. Our first objective is to study its antibacterial properties, and then we intend to further study its osteogenic ability to osteoblasts by modulating the immune response of macrophages. In this research, KR-1 and KR-2 can inhibit the formation of bacterial biofilm, and further kill bacteria S. gordonii and F. nucleatum by destroying the cell wall and cell membrane of bacteria. The novel peptides restrained the activation of the NF-κB signaling pathway by reducing the phosphorylation levels of IκBα and p65, inhibiting the degradation of IκBα and the nuclear translocation of p65, and increasing the percentage of M2 phenotype in macrophages. This suppressed the inflammatory response induced by lipopolysaccharides and enhanced the osteogenic activity of osteoblasts; this, in turn, promoted osteogenesis. The antimicrobial peptide KR-1 showed better performance. Our results demonstrate that KR-1 and KR-2 have antibacterial and bone immunomodulatory effects, and further promote osteogenesis by modulating the immune microenvironment, which provides the possibility for the adjuvant treatment of peri-implant diseases.