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1.
Life Sci Alliance ; 6(3)2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36625204

RESUMO

Baroreceptors are nerve endings located in the adventitia of the carotid sinus and aortic arch. They act as a mechanoelectrical transducer that can sense the tension stimulation exerted on the blood vessel wall by the rise in blood pressure and transduce the mechanical force into discharge of the nerve endings. However, the molecular identity of mechanical signal transduction from the vessel wall to the baroreceptor is not clear. We discovered that exogenous integrin ligands, such as RGD, IKVAV, YIGSR, PHSRN, and KNEED, could restrain pressure-dependent discharge of the aortic nerve in a dose-dependent and reversible manner. Perfusion of RGD at the baroreceptor site in vivo can block the baroreceptor reflex. An immunohistochemistry study showed the binding of exogenous RGD to the nerve endings under the adventitia of the rat aortic arch, which may competitively block the binding of integrins to ligand motifs in extracellular matrix. These findings suggest that connection of integrins with extracellular matrix plays an important role in the mechanical coupling process between vessel walls and arterial baroreceptors.


Assuntos
Mecanotransdução Celular , Pressorreceptores , Ratos , Animais , Pressorreceptores/fisiologia , Aorta/inervação , Artérias
2.
Cell Prolif ; : e13402, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36696967

RESUMO

Several studies have suggested the potential value of Houttuynia cordata as a therapeutic agent in lung cancer, but direct evidence is still lacking. The study aimed to determine the regulatory impact of a major H. cordata constituent derivative (sodium new houttuyfonate [SNH]) on lncRNA networks in non-small cell lung cancer (NSCLC) to identify new potential therapeutic targets. After exposing NSCLC cells to SNH, we analysed the following: cell death (via flow cytometry, TUNEL and ASC speck formation assays), immune factors (via ELISA), gene transcription (via RT-qPCR), subcellular localisation (via FISH), gene-gene and gene-protein interactions (via dual-luciferase reporter and RNA immunoprecipitation assays, respectively) and protein expression and distribution (via western blotting and immunocytochemistry or immunohistochemistry). In addition, statistical analysis (via one-way ANOVA or unpaired t-tests) was performed. Exposure to SNH promoted NSCLC cell pyroptosis, concomitant with significant up-regulation of TCONS-14036, a novel lncRNA. Mechanistic research demonstrated that TCONS-14036 functions as a competing endogenous (ce)RNA by sequestering microRNA (miR)-1228-5p, thereby up-regulating PRKCDBP-encoding transcript levels. Indeed, PRKCDBP promoted pyroptosis by activating the NLRP3 inflammasome, resulting in CASP1, IL-1ß and GSDMD cleavage. Our findings elucidate the potential molecular mechanisms underlying the ability of SNH to suppress NSCLC growth through activation of pyroptosis via the TCONS-14036/miR-1228-5p/PRKCDBP pathway. Thus, we identify a new potential therapeutic targets for NSCLC.

3.
Eur J Psychiatry ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36643859

RESUMO

Background and Objectives: Individuals with specific psychological weaknesses are prone to mental problems during the coronavirus pandemic. This self-rating study assessed the combined effects of infection-related stress, resilience, worry, and loneliness on the likelihood of depression and anxiety among infected and non-infected individuals during the Tianjin Pandemic in 2022. Methods: Individuals infected with Omicron (n = 249) and health residents (n = 415) were recruited from two hospitals and communities in Tianjin. Each respondent completed the following on-site assessment: Self-developed Scale of Demographics, Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), the Connor-Davidson Resilience Scale (CD-RISC), De Jong Gierveld Scale (DJGLS), and the Penn State Worry Questionnaire (PSWQ). The respondents were categorized into depression or non-depression group by SDS scores, and anxiety or non-anxiety group by SAS scores. Results: The overall scores of CD-RISC, DJGJLS, and PSWQ were significantly different both between the depression group and non-depression groups and between the anxiety group and non-anxiety groups. The greater likelihood of depression was associated with lower overall scores of CD-RISC and higher scores of PSWQ; the greater likelihood of anxiety was associated with higher scores of PSWQ. The likelihood of depression was also positively associated with having infection-related stress and three demographics. Conclusions: This on-site study demonstrates the importance of specific traits in a small-scale pandemic: the worse resilience and the greater worry propensity related to the higher probability of depression, and the greater propensity of worry related to the higher probability of anxiety. Moreover, those experiencing infection-related stress, being male, living alone, and being unemployed are more likely to have depressive problems.

4.
Anal Chem ; 95(2): 638-649, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36599407

RESUMO

Data-dependent acquisition (DDA) mode in ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) can provide massive amounts of MS1 and MS/MS information of compounds in untargeted metabolomics and can thus facilitate compound identification greatly. In this work, we developed a new platform called AntDAS-DDA for the automatic processing of UHPLC-HRMS data sets acquired under the DDA mode. Several algorithms, including extracted ion chromatogram extraction, feature extraction, MS/MS spectrum construction, fragment ion identification, and MS1 spectrum construction, were developed within the platform. The performance of AntDAS-DDA was investigated comprehensively with a mixture of standard and complex plant data sets. Results suggested that features in complex sample matrices can be extracted effectively, and the constructed MS1 and MS/MS spectra can benefit in compound identification greatly. The efficiency of compound identification can be improved by about 20%. AntDAS-DDA can take full advantage of MS/MS information in multiple sample analyses and provide more MS/MS spectra than single sample analysis. A comparison with advanced data analysis tools indicated that AntDAS-DDA may be used as an alternative for routine UHPLC-HRMS-based untargeted metabolomics. AntDAS-DDA is freely available at http://www.pmdb.org.cn/antdasdda.


Assuntos
Metabolômica , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Metabolômica/métodos , Cromatografia Líquida de Alta Pressão/métodos , Íons , Análise de Dados
5.
Theranostics ; 13(1): 59-76, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593959

RESUMO

Rationale: Cells migrating through interstitial matrix enables stiffening of the tumor micro-environment. To overcome the stiff resistance of extracellular matrix, aggressive cells require the extracellular mechanosensory activation and intracellular tension response. Mechanotransduction linker srGAP2 can synergistically control the mechanical-biochemical process of malignant cell migration. Methods: To mimic the tumor micro-environment containing abundant collagen fibers and moving durotaxis of triple-negative breast cancer cells, the stiff-directed matrix was established. The newly designed srGAP2 tension probe was used to real-time supervise srGAP2 tension in living cells. The phosphorylation sites responsible for srGAP2 tension were identified by phosphorylated mutagenesis. Transwell assays and Xenograft mouse model were performed to evaluate TNBC cells invasiveness in vitro and in vivo. Fluorescence staining and membrane protein isolation were used to detect protein localization. Results: The present study shows srGAP2 serves as a linker to transmit the mechanical signals among cytoskeleton and membrane. SrGAP2 exhibits tension gradients among different parts in the stiff-directionally migrating triple-negative breast cancer cells. Cells showing the polarized tension that increased in the leading edge move faster, particularly guided by the stiff interstitial matrix. The srGAP2 tension-directed cell migration results from the upstream events of PKCα-mediated phosphorylation at Ser206 in the F-bar domain of srGAP2. In addition, Syndecan-4 (SDC4), a transmembrane mechanoreceptor protein, drives PKCα regional recruit on the area of membrane trending deformation, which requires the distinct extent of extracellular mechanics. Conclusion: SDC4-PKCα polarized distribution leads to the intracellular tension gradient of srGAP2, presenting the extra- and intracellular physiochemical integration and essential for persistent cell migration in stiff matrix and caner progression. Targeting the srGAP2-related physicochemical signaling could be developed into the therapeutic strategies of inhibiting breast cancer cell invasion and durotaxis.


Assuntos
Proteína Quinase C-alfa , Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Neoplasias de Mama Triplo Negativas/metabolismo , Mecanotransdução Celular , Movimento Celular/fisiologia , Citoesqueleto/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral , Proteínas Ativadoras de GTPase/metabolismo
6.
iScience ; 26(1): 105095, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36713263

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the world. Mitochondrial fission regulator 2 (MTFR2) is involved in the development of various cancers. However, the roles of MTFR2 in HCC remain unknown. In this study, we conducted a comprehensive analysis of MTFR2 in HCC, which was generated from integrative MTFR2 analyses of eight HCC cell lines, and three datasets (public dataset, real-world dataset, and immunotherapy dataset) derived from bulk HCC tissues, survival, and immunotherapy data. We demonstrated that the expression level of MTFR2 is upregulated in HCC, leading to poor prognosis. MTFR2 is positively correlated with the level of immune cell infiltration, multiple immune checkpoints and immunotherapy response prediction pathways, and acts as an important role in cancer-immunity cycle. In conclusion, our work indicates that MTFR2 can shape a barrier of immune microenvironment and result in poor prognosis in hepatocellular carcinoma, but the immune barrier may be broken by immunotherapy.

7.
World Neurosurg ; 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36632895

RESUMO

OBJECTIVE: Schizencephaly is a congenital cerebral malformation characterized by clefts in the hemispheres of the brain, where variations in semiology often make it difficult to localize epileptogenic focus. Here, we report on a series of patients who underwent stereo-encephalography (SEEG) for epileptogenic focus localization and subsequent SEEG-guided surgical intervention. METHODS: Four patients (27, 33, 27, 25 year-old) with a mean seizure history of 16 years (range 8-22 years) were analyzed. Data pertaining to semiology, video-EEG, MRI, PET, and invasive EEG studies, surgical intervention and post-surgery outcome were collected and analyzed. RESULTS: All seizure onset zones were within the extent of schizencephaly; however, the limbic system (including the hippocampus, amygdala, cingulate gyrus or insula) was involved in early spreading. Two patients underwent SEEG-guided radiofrequency thermo-ablation (RFTA) in the seizure onset zone, one patient underwent lesionectomy via craniotomy, and the other one underwent neither RFTA nor lesionectomy. At 2 years post-surgery, the outcomes were as follows: Engel grade Ia (n = 2), Ib (n = 1), and III (n = 1). DISCUSSION: This paper reports on a precise approach to treating with schizencephaly dependent of seizure onset zone and functional cortex mapping. Subsequent SEEG-guided surgical interventions (radiofrequency thermo-ablation and lesionectomy) were shown to reduce seizure frequency, while preserving the neurological functions in drug-resistant epilepsy patients with schizencephaly.

8.
ACS Cent Sci ; 9(1): 27-35, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36712491

RESUMO

Metal-organic frameworks (MOFs) with Brønsted acidity are an alternative solid acid catalyst for many important chemical and fuel processes. However, the nature of the Brønsted acidity on the MOF's metal cluster or center is underexplored. To design and optimize the acid strength and density in these MOFs, it is important to understand the origin of their acidity at the molecular level. In the present work, isoreticular MOFs, ZrNDI and HfNDI (NDI = N,N'-bis(5-isophthalate)naphthalenediimide), were prepared as a prototypical system to unravel and compare their Brønsted and Lewis acid sites through an array of spectroscopic, computational, and catalytic characterization techniques. With the aid of solid-state nuclear magnetic resonance and density functional calculations, Hf6 oxo-clusters on HfNDI are quantitatively proved to possess a higher density Brønsted acid site, while ZrNDI-based MOFs display stronger and higher-population Lewis acidity. HfNDI-based MOFs exhibit a superior catalytic performance in activating dihydroxyacetone (DHA) and converting DHA to ethyl lactate, with 71.1% selectivity at 54.7% conversion after 6 h. The turnover frequency of BAS-dominated Hf-MOF in DHA conversion is over 50 times higher than that of ZSM-5, a strong BAS-based zeolite. It is worth noting that HfNDI is reported for the first time in the literature, which is an alternative platform catalyst for biorefining and green chemistry. The present study furthermore highlights the uniqueness of Hf-based MOFs in this important biomass-to-chemical transformation.

9.
Heliyon ; 9(1): e12715, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36685431

RESUMO

Background: The activation of HIF-1α/CXCR4 pathway in liver sinusoidal endothelial cells (LSECs) could downregulate CXCR7, leading to the capillarization of LSECs to promote hepatic fibrosis. However, the mechanism between CXCR4 and CXCR7 is still undefined. The aim is to investigate the role of PDGF-BB in the dedifferentiation of LSECs and hepatic stellate cells (HSCs) activation. Methods: The activation of HIF-1α/CXCR4 pathway in two kinds of liver fibrosis models were observed. The effects of HIF-1α, CXCR4, PDGF-BB on the dedifferentiation of LSECs were investigated by using the inhibitors of HIF-1α, CXCR4 or PDGFR-ß separately or transfecting with a CXCR4 knockdown lentiviral vector. In addition, the relationship between LSECs and HSCs was demonstrated by co-culture of LSECs and HSCs using the transwell chamber. Results: CXCR4 upregulation and CXCR7 downregulation were accompanied by LSECs capillarization and HSCs activation both in CCl4-induced and BDL-induced fibrotic liver. In vitro, downregulation of HIF-1α significantly descreased CXCR4 and CD31 expression, and enhanced the expressions of CXCR7, CD44 and LYVE1. Downregulation of CXCR4 in LSECs significantly downregulated PDGF-BB, PDGFR-ß and CD31, and enhanced CXCR7, CD44 and LYVE1 expression, while the expression of HIF-1α did not change significantly. STI571, a PDGF receptor inhibitor, could significantly downregulate PDGFR-ß and increase the expression of CXCR7 to inhibit the dedifferentiation of LSECs. In addition, alleviateion the dedifferentiation of LSECs could decrease the expression of PDGFR-ß of HSCs, then inhibiting the activation of HSCs. Conclusions: This study revealed that HIF-1α/CXCR4/PDGF-BB/CXCR7 axis promoted the dedifferentiation of LSECs, consequently triggering HSCs activation and liver fibrosis.

10.
World J Clin Cases ; 11(2): 456-463, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36686350

RESUMO

BACKGROUND: Multicentric reticulohistiocytosis (MRH)/systemic lupus erythematosus (SLE) overlap syndrome is an uncommon disease in the clinic and is diagnosed through characteristic clinical manifestations, histopathology, and immunopathology. Here, we report the case of a 30-year-old woman with SLE who developed MRH. CASE SUMMARY: A 30-year-old woman with a history of polyarthritis for the past 12 years had multiple skin nodules on her body for 10 years, including the sacrococcygeal area, dorsum of the hands, interphalangeal joint of the feet and sternoclavicular joint. The histopathology of a biopsy of the distal interphalangeal joint of the hands revealed granulomatous inflammation, fibrous hyperplasia with ground-glass degeneration, inflammatory cell exudation and focal necrosis. The immunohistochemical stains showed positive staining for CD68 and negative staining for S100 and acid-fast staining. The patient was diagnosed with SLE with MRH. Her symptoms were improved after a combined treatment of prednisone, hydroxychloroquine and cyclophosphamide. CONCLUSION: MRH/SLE overlap syndrome is difficult to diagnose and treat. Cyclophosphamide may be an alternative choice for the treatment of MRH.

11.
Reprod Sci ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690916

RESUMO

The present study aimed to determine the clinical predictive significance of HIF-1α in follicular development and assisted reproductive technology (ART). We collected follicular fluid (FF) and granulosa cells (GCs) from PCOS (polycystic ovary syndrome) patients (experimental group) and other patients who were infertile due to tubal factors or male factors (control group) with IVF/ICSI-ET. The localization and expression of HIF-1α in GCs were determined by immunofluorescence staining. HIF-1α protein and mRNA expression were detected by enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. To clarify the regulation of HIF-1α by TGF-ß1, we added the HIF-1α-specific blocker YC-1 to GCs. The serum AMH, LH, LH/FSH, testosterone, BMI and the number of oocytes retrieved in the PCOS group were significantly higher, while the cleavage rate was significantly lower, than those in the control group. HIF-1α protein was expressed in the cytoplasm of GCs. The expression of HIF-1α protein in the FF of the PCOS group was significantly lower than that in the control group. However, the expression of HIF-1α protein in GCs between the two groups was not significantly different. HIF-1α protein was highly expressed in large FF (follicular diameter ≥ 14 mm). Compared with the control group, the expression of HIF-1α mRNA in GCs of the PCOS group was significantly lower. The results showed a significant positive correlation between HIF-1α and TGF-ß1 expression. We found that both HIF-1α and TGF-ß1 were involved in the development of PCOS follicular development. The mutual regulation of HIF-1α and TGF-ß1 may be one of the important mechanisms of the occurrence and development of PCOS.

12.
Int J Biol Macromol ; 230: 123252, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36639082

RESUMO

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by inflammation and hepatic steatosis that may coincide with fibrotic activity. To date, no pharmacological agents have been approved for NASH treatment. Here, a homogeneous (1,3),(1,6)-ß-D-glucan (PUP-W-1, Mw: 41.07 kDa) was successfully purified from Polyporus umbellatus (Pers.) Fries sclerotia and characterized. The analysis showed that the PUP-W-1 backbone consisted of a repeating chain of eight →3)-ß-D-Glcp-(1 â†’ units, with branched chains of four ß-D-Glcp residues, joined by repeating 1,6-linkage units at the O-6 position of the backbone. The pharmacological effects of PUP-W-1 treatment in the context of NASH pathogenesis were explored using a methionine choline-deficient (MCD) diet-induced murine steatohepatitis model. The MCD model mice exhibited pronounced steatohepatitis, inflammatory activity, steatosis, stellate cell activation, and mild fibrotic activity. Treatment of the mice for three weeks with PUP-W-1 prevented the development of NASH due to the suppression of inflammation, lipid accumulation, and fibrosis. As suggested by these findings, PUP-W-1 may hold promise as a natural drug candidate or precursor for the treatment of NASH.

13.
Virol J ; 20(1): 8, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647143

RESUMO

Herpes simplex virus type 1 (HSV-1) is a widely disseminated virus that establishes latency in the brain and causes occasional but fatal herpes simplex encephalitis. Currently, acyclovir (ACV) is the main clinical drug used in the treatment of HSV-1 infection, and the failure of therapy in immunocompromised patients caused by ACV-resistant HSV-1 strains necessitates the requirement to develop novel anti-HSV-1 drugs. Artemisia argyi, a Traditional Chinese Medicine, has been historically used to treat inflammation, bacterial infection, and cancer. In this study, we demonstrated the antiviral effect and mechanism of ethanol extract of A. argyi leaves (hereafter referred to as 'AEE'). We showed that AEE at 10 µg/ml exhibits potent antiviral effects on both normal and ACV-resistant HSV-1 strains. AEE also inhibited the infection of HSV-2, rotavirus, and influenza virus. Transmission electron microscopy revealed that AEE destroys the membrane integrity of HSV-1 viral particles, resulting in impaired viral attachment and penetration. Furthermore, mass spectrometry assay identified 12 major components of AEE, among which two new flavones, deoxysappanone B 7,3'-dimethyl ether, and 3,7-dihydroxy-3',4'-dimethoxyflavone, exhibited the highest binding affinity to HSV-1 glycoprotein gB at the surface site critical for gB-gH-gL interaction and gB-mediated membrane fusion, suggesting their involvement in inactivating virions. Therefore, A. argyi is an important source of antiviral drugs, and the AEE may be a potential novel antiviral agent against HSV-1 infection.


Assuntos
Antivirais , Artemisia , Herpesvirus Humano 1 , Extratos Vegetais , Aciclovir/farmacologia , Antivirais/química , Antivirais/farmacologia , Etanol , Herpesvirus Humano 1/efeitos dos fármacos , Envelope Viral , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Artemisia/química , Folhas de Planta/química
14.
Artigo em Inglês | MEDLINE | ID: mdl-36648175

RESUMO

Although numerous approaches were proposed for the nucleic acid (NA)-based SARS-CoV-2 detection, the nonideal NA desorption efficiency of conventional magnetic beads (MBs) limits their widespread application. In this study, we developed solvent-responsive MBs (called responsive MBs), which, in the presence of buffers, modulated the absorption and desorption capacities of NA by flipping the surface -COO-. Relative to other commercial MBs, responsive MBs exhibited similar absorption profiles and markedly enhanced desorption profiles. When applied for NA detection of complex samples, responsive MBs exhibited better performance of RNA detection than DNA, with obvious advantages in sensitivity. Specifically, the RNA and DNA desorption rates of commercial MBs were ∼85 and 82.5%, while those of responsive MBs were nearly 94 and 93.5%, respectively. Furthermore, responsive MBs exhibited remarkable extraction ability in a wide range of tissues and better performance of RNA extraction than DNA. When applied for SARS-CoV-2 detection, the responsive MBs along with the simulated digital RT-LAMP (a previously established apparatus) further improved detection efficiency, yielding a precise quantitative detection as low as 25 copies and an ultimate sensibility detection of 5 copies/mL. It was also successfully employed in numerous NA-based technologies such as polymerase chain reaction (PCR), sequencing, and so on.

15.
J Hepatol ; 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36669703

RESUMO

BACKGROUND & AIMS: Capsaicin receptor, also known as transient receptor potential vanilloid 1 (TRPV1), is involved in pain physiology and neurogenic inflammation. Herein, we discovered the presence of TRPV1 in hepatic stellate cells (HSCs) and aimed to delineate its function in this cell type and liver fibrosis. METHODS: TRPV1 expression was examined in liver biopsies from patients with liver fibrosis using quantitative real-time PCR (qPCR) and immunostaining. Its contribution to liver fibrosis was examined in Trpv1-/- mice, upon lentiviral delivery of the TRPV1 gene, and in human and mouse primary HSC, using patch clamp, intracellular Ca2+ mobilization determination, FACS analyses and gain/loss of function experiments. Binding of sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) to TRPV1 was determined using mass spectrometry, co-immunoprecipitation, surface plasmon resonance (SPR), bioluminescence resonance energy transfer (BRET), and NanoBiT. RESULTS: TRPV1 mRNA levels are significantly down-regulated in patients and mouse models with liver fibrosis, showing a negative correlation with F stage and α-smooth muscle actin (α-SMA) expression, a marker of HSC activation. TRPV1 expression and function decrease during HSC activation in fibrotic liver in vivo or during culture. Genetic and pharmacological inhibition of TRPV1 in quiescent HSC leads to NF-κB activation and pro-inflammatory cytokine production. TRPV1 requires binding with its N-terminal ankyrin repeat domain (ARD) to the TIR-His583 (Toll/interleukin-1 receptor) domain of SARM1 to prevent HSC from pro-inflammatory activation. Trpv1-/- mice display increased HSC activation and more severe liver fibrosis, whereas TRPV1 overexpression acts antifibrotic in various disease models. CONCLUSION: Antifibrotic properties of TRPV1 are attributed to the prevention of HSC activation via the recruitment of SARM1, promisingly providing an attractive therapeutic strategy against liver fibrosis. IMPACT AND IMPLICATIONS: We identified the neuronal channel protein TRPV1 as gatekeeper of quiescence in HSC, one driver cell of liver fibrogenesis and chronic liver disease. Physiologically expressed in healthy liver and consistently downregulated during liver fibrosis development, its therapeutic reexpression is expected to have few side effects, making it an attractive target diagnostic tool and drug candidate for industry and clinicians.

16.
Adv Mater ; : e2210047, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36637449

RESUMO

Intestinal milieu disorders are strongly related to the occurrence of inflammatory bowel diseases (IBDs), which results from mucosa destruction, epithelium disruption and tight junction (TJ) proteins loss. Excess of H2 S in the intestinal milieu produced by sulfate-reducing bacteria metabolism contributes to IBDs development via epithelial barrier breakdown. Conventional interventions, such as surgery and anti-inflammatory medications, are considered not completely effective because of frequent recurrence and other complications. Herein, a novel oral delivery system, a hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based polymer-coated Zr-based metal-organic framework (UiO-66) with a Cux -rhodamine B (CR) probe (hereinafter referred to as HUR), was produced via co-flow microfluidic assistance with ability to reduce H2 S levels, thus restoring the intestinal lumen milieu. HPMCAS serves as an enteric coating that exposes UiO-66@CR at the pH of the intestine but not the acidic pH of the stomach. The synthesized HUR exhibits notable therapeutic efficacy, including mucosa recovery, epithelium integrity restoration and TJ proteins up-regulation via H2 S scavenging to protect against intestinal barrier damage and microbiome dysbiosis. Thus, HUR has been verified to be a promising theranostic platform able to decrease the H2 S content for intestinal milieu disorder treatment. The presented study therefore opens the door for further exploitation for IBDs therapy. This article is protected by copyright. All rights reserved.

17.
Acta Biomater ; 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36623783

RESUMO

Photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT) can cause cancer cell death through an immunogenic process. However, the study of second near-infrared window (NIR-II)-triggered PTT and PDT combined with CDT to induce an immune response has not been recently reported. Here, we integrated gold nanobipyramids and copper sulfide in a core/shell architecture (AuNBP@CuS). The material displays both photodynamic and photothermal properties under irradiation with a NIR-II laser. The released Cu2+ from CuS under an acidic tumor microenvironment can be converted to Cu+ by glutathione following a Fenton-like reaction with hydrogen peroxide to generate highly toxic hydroxyl radicals in the tumor region. Both in vitro and in vivo results demonstrated that such multifunctional nanoplatforms could achieve enhanced efficiency for image-guided tumor suppression based on the NIR-II photo/chemodynamic therapy. We found that damage-associated molecular pattern molecules such as adenosine triphosphate, pre-apoptotic calreticulin, and high mobility group box-1 in dying cells induced by the NIR-II photo/chemodynamic therapy could simultaneously trigger adaptive immune responses. This is the first report revealing that NIR-II photo/chemodynamic therapy based on AuNBP@CuS had promising performance on tumor suppressor with an effective immunogenic cell death process. STATEMENT OF SIGNIFICANCE: 1. AuNBP@CuS displays both NIR-II photodynamic and photothermal properties. 2. Cu+ following a Fenton-like reaction to generate highly toxic hydroxyl radicals. 3. The NIR-II photo/chemodynamic therapy can trigger adaptive immune responses. 4. Such multifunctional nanoplatforms could achieve enhanced efficiency for tumor suppression.

18.
J Exp Med ; 220(3)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36520461

RESUMO

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.


Assuntos
Fígado Gorduroso , Doenças Metabólicas , Neoplasias , Camundongos , Animais , Ácidos Graxos/metabolismo , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Antidepressivos Tricíclicos/metabolismo , Nortriptilina/metabolismo , Nortriptilina/uso terapêutico , Reposicionamento de Medicamentos , Fígado Gorduroso/patologia , Doenças Metabólicas/metabolismo , Neoplasias/patologia , Fígado/metabolismo
19.
Brain Res ; 1802: 148226, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36586663

RESUMO

Glycogen synthase kinase-3 (GSK-3), a key role in the pathogenesis of Alzheimer's disease (AD), has been linked with the formation of ß-amyloid (Aß), tubulin-associated unit (tau) protein phosphorylation and apoptosis. Moreover, the excessive presence of elements such as copper (Cu) can promote Aß aggregation and increase the risk of AD. Combined with the role of GSK-3 and metal elements in AD, a metal-chelating imine GSK-3 inhibitor N-(4-{[(2-amino-5-phenylpyridin-3-ylidene)imino]methyl}pyridin-2-yl)cyclopropanecarboxamide (PIMPC) was designed and synthesized. In our study, Aß/Cu2+-induced AD rat model was established and treated with PIMPC. The results indicated that PIMPC can not only down-regulate the high expression levels of Aß, tau and p-tau proteins of the AD rats, but also chelate Cu and aluminum (Al) elements in the brain. In addition, PIMPC may play an anti-apoptotic effect by down-regulating the high expression of cleaved Caspase-3 protein, and it can modulate ATPase and nitric oxide synthase (NOS) levels, oxidative stress and neurotransmitter disturbance. In summary, PIMPC acts on multiple targets to relieve the learning and memory impairment of AD rats induced by Aß/Cu2+.


Assuntos
Doença de Alzheimer , Animais , Ratos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fosforilação , Proteínas tau/metabolismo , Cobre/farmacologia
20.
Ecotoxicol Environ Saf ; 249: 114355, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36508822

RESUMO

The plasticizer di- (2-ethylhexyl) phthalate (DEHP) is considered a risk factor for allergic diseases and has attracted public attention for its adverse effects on health. However, respiratory adverse effects after DEHP exposure in food allergies have rarely been reported. MiRNAs are considered to be key regulators in the complex interrelationships between the host and microbiome and may be a potential factor involved in DEHP-induced pulmonary toxicity. To investigate the adverse effects of DEHP on the lung during sensitization, we established an ovalbumin (OVA)-sensitized mouse model exposed to DEHP and performed 16S rDNA gene sequencing, miRNA sequencing, and correlation analysis. Our results showed that DEHP aggravated the immune disorder in OVA-sensitized mice, which was mainly characterized by an increase in the proportion of Th2 lymphocytes, and further enhanced OVA-induced airway inflammation without promoting pulmonary fibrosis. Compared with the OVA group, DEHP interfered with the lung microbial community, making Proteobacteria the dominant phylum, while Bacteroidetes were significantly reduced. Differentially expressed miRNAs were enriched in the PI3K/AKT pathway, which was closely related to immune function and airway inflammation. The expression of miR-146b-5p was elevated in the DEHP group, which was positively correlated with the proportion of Th2 cells and significantly negatively correlated with the abundance of Bacteroidetes. The results indicate that DEHP may interfere with the expression of miR-146b-5p, affect the composition of the lung microbiota, induce an imbalance in T cells, and lead to immune disorders and airway inflammation. The current study uses multi-omics to reveal the potential link between the plasticizer DEHP and allergic diseases and provides new insights into the ecotoxicology of environmental exposures to DEHP.


Assuntos
Dietilexilftalato , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipersensibilidade , MicroRNAs , Camundongos , Animais , Ovalbumina , Plastificantes/toxicidade , Plastificantes/metabolismo , Dietilexilftalato/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pulmão , Inflamação/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos Endogâmicos BALB C
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