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1.
Cancer Lett ; 524: 161-171, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34687791

RESUMO

Sorafenib and its derivative regorafenib are the first- and second-line targeted drugs for advanced HCC, respectively. Although both drugs improve overall survival, drug resistance remains the major barrier to their full efficacy. Thus, strategies to enhance sorafenib and regorafenib efficacy against HCC are solely needed. Interleukin-6 receptor alpha (IL-6Rα) is the receptor of IL-6, a multi-functional cytokine, which plays key roles in liver-regeneration, inflammation and development of hepatocellular carcinoma (HCC). Here we show the expression of IL-6Rα was induced in response to sorafenib. Depletion of IL-6Rα abolished IL-6 induced STAT3 phosphorylation at 705th tyrosine and tumor growth of HCC cells under sorafenib treatment. Mechanistically, activating transcription factor 3 (ATF3) was induced in response to sorafenib and subsequently bound to the promoter of IL-6Rα, leading to its transcriptional activation. Depletion of ATF3 or its upstream transcription factor, ATF4, attenuated IL-6Rα induction and IL-6 mediated sorafenib resistance. The ATF4-ATF3-IL-6Rα cascade is also activated by regorafenib. Furthermore, blockade of IL-6Rα with the FDA approved IL-6Rα antibody drug, Sarilumab, drastically attenuated both sorafenib and regorafenib resistance in patient-derived xenograft (PDX) tumors, where human IL-6 could be detected by a novel in situ hybridization technique, named RNAscope. Together, our data reveal that ATF3-mediated IL-6Rα up-regulation promotes both sorafenib and regorafenib resistance in HCC, and targeting IL-6Rα represents a novel therapeutic strategy to enhance sorafenib/regorafenib efficacy for advanced HCC treatment.

2.
Int J Biol Sci ; 17(15): 4108-4121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803486

RESUMO

Laron syndrome (LS) is an autosomal recessive genetic disease mainly caused by mutations in the human growth hormone receptor (GHR) gene. Previous studies have focused on Ghr mutant mice, but compared with LS patients, Ghr knockout (KO) mice exhibit differential lipid metabolism. To elucidate the relationship between GHR mutation and lipid metabolism, the role of GHR in lipid metabolism was examined in GHR KO pigs and hepatocytes transfected with siGHR. We observed high levels of free fatty acids and hepatic steatosis in GHR KO pigs, which recapitulates the abnormal lipid metabolism in LS patients. RNAseq analysis revealed that genes related to the fatty acid oxidation pathway were significantly altered in GHR KO pigs. AHR, a transcription factor related to lipid metabolism, was significantly downregulated in GHR KO pigs and siGHR-treated human hepatocytes. We found that AHR directly regulated fatty acid oxidation by directly binding to the promoters of ACOX1 and CPT1A and activating their expression. These data indicate that loss of GHR disturbs the ERK-AHR-ACOX1/CPT1A pathway and consequently leads to hepatic steatosis. Our results established AHR as a modulator of hepatic steatosis, thereby providing a therapeutic target for lipid metabolism disorder.

3.
J Nanobiotechnology ; 19(1): 379, 2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34802438

RESUMO

Matrix metalloproteinase (MMP) 2 and 9 are the family members of proteases normally up-regulated in tumor to enhance the invasion and metastatic of tumor cells, and are associated with poor outcome of head and neck squamous cell carcinomas (HNSCCs). In the present work, MMPs-degradable gelatin nanoparticles (GNPs) are simultaneously loaded with photosensitizer indocyanine green (ICG) along with signal transducer activator of transcription 3 (STAT3) inhibitor NSC74859 (NSC, N) for efficient photothermal therapy (PTT) and immunotherapy of HNSCCs. In the tumor tissue, Gel-N-ICG nanoparticle was degraded and encapsulated ICG and NSC were effectively released. Under near-infrared (NIR) irradiation, the released ICG nanoparticles enabled effective photothermal destruction of tumors, and the STAT3 inhibitor NSC elicited potent antitumor immunity for enhanced cancer therapy. Based on two HNSCC mouse models, we demonstrated that Gel-N-ICG significantly delayed tumor growth without any appreciable body weight loss. Taken together, the strategy reported here may contribute that the stimuli-responsive proteases triggered nanoplatform could reduce tumor size more effectively in complex tumor microenvironment (TME) through combination of PTT and immunotherapy.

4.
Front Cell Infect Microbiol ; 11: 739429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722335

RESUMO

Background: The severities of human adenovirus (HAdV) infection are diverse in different areas of Tibet, China, where a large altitude span emerges. Serious consequences may be caused by medical staff if the clinical stages and immunological conditions of patients in high-altitude areas are misjudged. However, the clinical symptoms, immunological characteristics, and environmental factors of HAdV infection patients at different altitude areas have not been well described. Methods: In this retrospective, multicenter cohort study, we analyzed the data of patients who were confirmed HAdV infection by PCR tests in the General Hospital of Tibet Military Command or CDC (the Center for Disease Control and Prevention) of Tibet Military Command from January 1, 2019, to December 31, 2020. Demographic, clinical, laboratory, radiological, and epidemiological data were collected from medical records system and compared among different altitude areas. The inflammatory cytokines as well as the subsets of monocytes and regulatory T cells of patients were also obtained and analyzed in this study. Results: Six hundred eighty-six patients had been identified by laboratory-confirmed HAdV infection, including the low-altitude group (n = 62), medium-altitude group (n = 206), high-altitude group (n = 230), and ultra-high-altitude group (n = 188). Referring to the environmental factors regression analysis, altitude and relative humidity were tightly associated with the number of infected patients (P < 0.01). A higher incidence rate of general pneumonia (45.7%) or severe pneumonia (8.0%) occurred in the ultra-high-altitude group (P < 0.05). The incubation period, serial interval, course of the disease, and PCR-positive duration were prolonged to various extents compared with the low-altitude group (P < 0.05). Different from those in low-altitude areas, the levels of IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, TNF-α, TNF-ß, and VEGF in the plasma of the ultra-high-altitude group were increased (P < 0.05), while the proportion of non-classical monocytes and regulatory T cells was decreased (P < 0.05). Conclusions: The findings of this research indicated that patients with HAdV infection in high-altitude areas had severe clinical symptoms and a prolonged course of disease. During clinical works, much more attention should be paid to observe the changes in their immunological conditions. Quarantine of patients in high-altitude areas should be appropriately extended to block virus shedding.


Assuntos
Infecções por Adenoviridae , Adenovírus Humanos , Adenovírus Humanos/genética , Altitude , China/epidemiologia , Estudos de Coortes , Humanos , Estudos Retrospectivos , Tibet
5.
J Colloid Interface Sci ; 608(Pt 2): 1173-1190, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34735853

RESUMO

Ionic liquids (ILs) have been used in solvents for proteins in many applications, including biotechnology, pharmaceutics, and medicine due to their tunable physicochemical and biological properties. Protein aggregation is often undesirable, and predominantly occurs during bioprocesses, while the aggregation process can be reversible or irreversible and the aggregates formed can be native/non-native and soluble/insoluble. Recent studies have clearly identified key properties of ILs and IL-water mixtures related to protein performance, suggesting the use of the tailorable properties of ILs to inhibit protein aggregation, to promote protein crystallization, and to control protein aggregation pathways. This review discusses the critical properties of IL and IL-water mixtures and presents the latest understanding of the protein aggregation pathways and the development of IL systems that affect or control the protein aggregation process. Through this feature article, we hope to inspire further advances in understanding and new approaches to controlling protein behavior to optimize bioprocesses.

6.
Front Microbiol ; 12: 742300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34759900

RESUMO

ß-Galactosidase plays an important role in medicine and dairy industry. In this study, a new glycoside hydrolase family 42 (GH42) ß-galactosidase-encoding gene, gal42, was cloned from a newly isolated marine bacterium Bacillus sp. BY02 and expressed in Escherichia coli. Structural characterization indicated that the encoding ß-galactosidase, Gal42, is a homotrimer in solution, and homology modeling indicated that it retains the zinc binding sites of the Cys cluster. The reaction activity of Gal42 was significantly increased by Zn2+ (229.6%) and other divalent metal ions (Mn2+, Mg2+, and Co2+), while its activity was inhibited by EDTA (53.9%). Meanwhile, the thermo-stability of the Gal42 was also significantly enhanced by 5 and 10 mM of zinc ion supplement, which suggested that the "Cys-Zn" motif played important roles in both structural stability and catalytic function. Furthermore, Gal42 showed effective lactose hydrolysis activity, which makes the enzyme hydrolyze the lactose in milk effectively. These properties make Gal42 a potential candidate in food technology.

7.
Chem Sci ; 12(41): 13737-13743, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34760158

RESUMO

Catalytic asymmetric variants for functional group transformations based on carbon-carbon bond activation still remain elusive. Herein we present an unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C(sp2)-C(sp2) σ bond activation and click desymmetrization to form synthetically versatile and value-added oxaspiro products. The operationally straightforward and enantioselective palladium-catalyzed atom-economic annulation process exploits a TADDOL-derived bulky P-ligand bearing a large cavity to control enantioselective spiro-annulation that converts cyclopropenones and cyclic 1,3-diketones into chiral oxaspiro cyclopentenone-lactone scaffolds with good diastereo- and enantio-selectivity. The click-like reaction is a successful methodology with a facile construction of two vicinal carbon quaternary stereocenters and can be used to deliver additional stereocenters during late-state functionalization for the synthesis of highly functionalized or more complex molecules.

8.
Arch Anim Breed ; 64(2): 457-466, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746369

RESUMO

The circadian rhythm is a biological rhythm that is closely related to the rhythmic expression of a series of clock genes. Results from several studies have indicated that clock genes are associated with the estrous cycle in female animals. Until now, the relationship between estrus cycle transition and clock gene expression in reproductive-axis-related tissues has remained unknown in Small-tailed Han (STH) sheep. This study was conducted to analyze the expression patterns of six canonical clock genes (Clock, BMAL1, Per1, Per2, Cry1, and Cry2) in the follicle phase and luteal phase of STH sheep. We found that all six genes were expressed in the brain, cerebellum, hypothalamus, pituitary, ovary, uterus, and oviduct in follicle and luteal phases. The results indicated that Clock expression was significantly higher in the cerebellum, hypothalamus, and uterus of the luteal phase than that of the follicle phase, whereas BMAL1 expression was significantly higher in the hypothalamus of the luteal phase than that of the follicle phase. Per1 expression was significantly higher in the brain, cerebellum, hypothalamus, and pituitary of the luteal phase than that of the follicle phase, and Per2 expression was significantly higher in the hypothalamus, pituitary, and uterus of the luteal phase than that of the follicle phase. Cry1 expression was significantly higher in the brain, cerebellum, and hypothalamus of the luteal phase than that of the follicle phase, whereas Cry2 expression was significantly higher in the pituitary of the luteal phase than that of the follicle phase. The clock gene expression in all tissues was different between follicle and luteal phases, but all clock gene mRNA levels were found to exhibit higher expression among seven tissues in the luteal phase. Our results suggest that estrous cycles may be associated with clock gene expression in the STH sheep. This is the first study to systematically analyze the expression patterns of clock genes of different estrous cycle in ewes, which could form a basis for further studies to develop the relationship between clock genes and the estrous cycle.

9.
Front Mol Biosci ; 8: 756075, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616774

RESUMO

We propose a method based on neural networks to accurately predict hydration sites in proteins. In our approach, high-quality data of protein structures are used to parametrize our neural network model, which is a differentiable score function that can evaluate an arbitrary position in 3D structures on proteins and predict the nearest water molecule that is not present. The score function is further integrated into our water placement algorithm to generate explicit hydration sites. In experiments on the OppA protein dataset used in previous studies and our selection of protein structures, our method achieves the highest model quality in terms of F1 score, compared to several previous studies.

10.
Front Neurosci ; 15: 745227, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557073

RESUMO

Aging, an irreversible and unavoidable physiological process in all organisms, is often accompanied by obesity, diabetes, cardiovascular diseases, sleep disorders, and fatigue. Thus, older adults are more likely to experience metabolic symptoms and sleep disturbances than are younger adults. Restricted feeding (RF) is a dietary regimen aimed at improving metabolic health and extending longevity, as well as reorganizing sleep-wake cycles. However, the potential of RF to improve metabolic health and sleep quality in older adults who are known to show a tendency toward increased weight gain and decreased sleep is unknown. To elucidate this issue, aged mice were assigned to an RF protocol during the active phase for 2 h per day for 2 weeks. Sleep-wake cycles were recorded during the RF regime in RF group and control mice. At the end of this period, body weight and blood biochemistry profiles, including blood glucose, cholesterol, and enzyme activity, in addition to dopamine concentrations in the brain, were measured in the RF group and age-matched controls. RF for 2 weeks improved the metabolic health of aged mice by reducing their body weights and blood glucose and cholesterol levels. At the beginning of the RF regime, sleep decreased in the dark period but not in the light period. After stable food entrainment was achieved (7 days post-RF commencement), the amount of time spent in wakefulness during the light period dramatically increased for 2 h before food availability, thereby increasing the mean duration of awake episodes and decreasing the number of wakefulness episodes. There was no significant difference in the sleep-wake time during the dark period in the RF group, with similar total amounts of wakefulness and sleep in a 24-h period to those of the controls. During the RF regime, dopamine levels in the midbrain increased in the RF group, pointing to its potential as the mechanism mediating metabolic symptoms and sleep-wake regulation during RF. In conclusion, our study suggested that RF during aging might prohibit or delay the onset of age-related diseases by improving metabolic health, without having a severe deleterious effect on sleep.

11.
Environ Sci Technol ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559504

RESUMO

Aggregation significantly influences the transport, transformation, and bioavailability of engineered nanomaterials. Two-dimensional MoS2 nanosheets are one of the most well-studied transition-metal dichalcogenide nanomaterials. Nonetheless, the aggregation behavior of this material under environmental conditions is not well understood. Here, we investigated the aggregation of single-layer MoS2 (SL-MoS2) nanosheets under a variety of conditions. Trends in the aggregation of SL-MoS2 are consistent with classical Derjaguin-Landau-Verwey-Overbeek (DLVO) colloidal theory, and the critical coagulation concentrations of cations follow the order of trivalent (Cr3+) < divalent (Ca2+, Mg2+, Cd2+) < monovalent cations (Na+, K+). Notably, Pb2+ and Ag+ destabilize MoS2 nanosheet suspensions much more strongly than do their divalent and monovalent counterparts. This effect is attributable to Lewis soft acid-base interactions of cations with MoS2. Visible light irradiation synergistically promotes the aggregation of SL-MoS2 nanosheets in the presence of cations, which was evident even in the presence of natural organic matter. The light-accelerated aggregation was ascribed to dipole-dipole interactions due to transient surface plasmon oscillation of electrons in the metallic 1T phase, which decrease the aggregation energy barrier. These results reveal the phase-dependent aggregation behaviors of engineered MoS2 nanosheets with important implications for environmental fate and risk.

12.
Comput Struct Biotechnol J ; 19: 4941-4953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527198

RESUMO

MicroRNA (miRNA) deregulation plays a critical role in the heterogeneous development of prostate cancer (PCa) by tuning mRNA levels. Herein, we aimed to characterize the molecular features of PCa by clustering the miRNA-regulated transcriptome with non-negative matrix factorization. Using 478 PCa samples from The Cancer Genome Atlas, four molecular subtypes (S-I, S-II, S-III, and S-IV) were identified and validated in two merged microarray and RNAseq datasets with 656 and 252 samples, respectively. Interestingly, the four subtypes showed distinct clinical and biological features after comprehensive analyses of clinical features, multiomic profiles, immune infiltration, and drug sensitivity. S-I is basal/stem/mesenchymal-like and immune-excluded with marked transforming growth factor ß, epithelial-mesenchymal transition and hypoxia signals, increased sensitivity to olaparib, and intermediate prognosis. S-II is luminal/metabolism-active and responsive to androgen deprivation therapy with frequent TMPRSS2-ERG fusion and a good prognosis. S-III is characterized by moderate proliferative and metabolic activity, sensitivity to taxane-based chemotherapy, and intermediate prognosis. S-IV is highly proliferative with moderate EMT and stemness, frequent deletions of TP53, PTEN and RB, and the poorest prognosis; it is also immune-inflamed and sensitive to anti-PD-L1 therapy. Overall, based on miRNA-regulated gene profiles, this study identified four distinct PCa subtypes that could improve risk stratification at diagnosis and provide therapeutic guidance.

13.
Front Physiol ; 12: 703593, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512380

RESUMO

Introduction: This work aimed to reveal the crucial role of Nell-1 in the angiogenic differentiation of human dental pulp stem cells (DPSCs) alone or co-cultured with human umbilical vein endothelial cell (HUVECs) in vitro and whether this molecule is involved in the pulp exposure model in vivo. Methods: Immunofluorescence was conducted to ascertain the location of Nell-1 on DPSCs, HUVECs, and normal rat dental tissues. RT-PCR, Western blot, and ELISA were performed to observe the expression levels of angiogenic markers and determine the angiogenic differentiation of Nell-1 on DPSCs alone or co-cultured with HUVECs, as well as in vitro tube formation assay. Blood vessel number for all groups was observed and compared using immunohistochemistry by establishing a rat pulp exposure model. Results: Nell-1 is highly expressed in the nucleus of DPSCs and HUVECs and is co-expressed with angiogenic markers in normal rat pulp tissues. Hence, Nell-1 can promote the angiogenic marker expression in DPSCs alone and co-cultured with other cells and can enhance angiogenesis in vitro as well as in the pulp exposure model. Conclusion: Nell-1 may play a positive role in the angiogenic differentiation of DPSCs.

14.
ACS Appl Mater Interfaces ; 13(36): 43115-43122, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34473473

RESUMO

Transition-metal dichalcogenides (TMDs) have attracted intense research interest for a broad range of device applications. Atomic layer deposition (ALD), a CMOS compatible technique, can enable the preparation of high-quality TMD films on 8 to 12 in. wafers for large-scale circuit integration. However, the ALD growth mechanisms are still not fully understood. In this work, we systematically investigated the growth mechanisms for WS2 and found them to be strongly affected by nucleation density and film thickness. Transmission electron microscope imaging reveals the coexistence and competition of lateral and vertical growth mechanisms at different growth stages, and the critical thicknesses for each mechanism are obtained. The in-plane lateral growth mode dominates when the film thickness remains less than 5.6 nm (8 layers), while the vertical growth mode dominates when the thickness is greater than 20 nm. From the resulting understanding of these growth mechanisms, the conditions for film deposition were optimized and a maximum grain size of 108 nm was achieved. WS2-based field-effect transistors were fabricated with electron mobility and on/off current ratio up to 3.21 cm2 V-1 s-1 and 105, respectively. Particularly, this work proves the capability of synthesis of TMD films in a wafer scale with excellent controllability of thickness and morphology, enabling many potential applications other than transistors, such as nanowire- or nanosheet-based supercapacitors, batteries, sensors, and catalysis.

15.
Front Cell Infect Microbiol ; 11: 728933, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485181

RESUMO

Introduction: The oral squamous cell carcinoma (OSCC) is detrimental to patients' physical and mental health. The prognosis of OSCC depends on the early diagnosis of OSCC in large populations. Objectives: Here, the present study aimed to develop an early diagnostic model based on the relationship between OSCC and oral microbiota. Methods: Overall, 164 samples were collected from 47 OSCC patients and 48 healthy individuals as controls, including saliva, subgingival plaque, the tumor surface, the control side (healthy mucosa), and tumor tissue. Based on 16S rDNA sequencing, data from all the five sites, and salivary samples only, two machine learning models were developed to diagnose OSCC. Results: The average diagnostic accuracy rates of five sites and saliva were 98.17% and 95.70%, respectively. Cross-validations showed estimated external prediction accuracies of 96.67% and 93.58%, respectively. The false-negative rate was 0%. Besides, it was shown that OSCC could be diagnosed on any one of the five sites. In this model, Actinobacteria, Fusobacterium, Moraxella, Bacillus, and Veillonella species exhibited strong correlations with OSCC. Conclusion: This study provided a noninvasive and inexpensive way to diagnose malignancy based on oral microbiota without radiation. Applying machine learning methods in microbiota data to diagnose OSCC constitutes an example of a microbial assistant diagnostic model for other malignancies.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Microbiota , Neoplasias Bucais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Humanos , Neoplasias Bucais/diagnóstico , Saliva , Carcinoma de Células Escamosas de Cabeça e Pescoço
16.
Stem Cells Int ; 2021: 8124444, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349803

RESUMO

The surface topographies of artificial implants including surface roughness, surface groove size and orientation, and surface pore size and distribution have a great influence on the adhesion, migration, proliferation, and differentiation of nerve cells in the nerve regeneration process. Optimizing the surface topographies of biomaterials can be a key strategy for achieving excellent cell performance in various applications such as nerve tissue engineering. In this review, we offer a comprehensive summary of the surface topographies of nerve implants and their effects on nerve cell behavior. This review also emphasizes the latest work progress of the layered structure of the natural extracellular matrix that can be imitated by the material surface topology. Finally, the future development of surface topographies on nerve regeneration was prospectively remarked.

17.
Pathogens ; 10(7)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34358006

RESUMO

Human noroviruses (huNoVs) cause epidemic acute gastroenteritis with significant mortality and morbidity worldwide. However, there are no commercial vaccines or antivirals against these important pathogens so far. In this study, we found that bovine colostrum (bCM) inhibited huNoV VLPs and their capsid-protruding (P) domains binding to histo-blood group antigens (HBGAs) that are huNoV receptor or attachment factors for infection, suggesting that bCM may function as a natural antiviral against huNoVs. We then characterized the bCM for the functional inhibition components by sequentially separating bCM into multiple fractions through various chromatography approaches, followed by determining their inhibitory abilities against huNoV receptor-binding P protein interacting with HBGAs. The protein components of bCM functional fractions were examined by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Our data suggested that some milk proteins, likely in the form of glycoproteins, contribute to the observed blocking effects of bCM. Our findings lay an important foundation to further develop bCM into a potential natural antiviral against huNoVs.

18.
Planta Med ; 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359084

RESUMO

The root Rhynchosia volubilis was widely used for contraception in folk medicine, although its molecular mechanism on antifertility has not yet been revealed. In human sperm, it was reported that the cation channel of sperm, an indispensable cation channel for the fertilization process, could be regulated by various steroid-like compounds in plants. Interestingly, these nonphysiological ligands would also disturb the activation of the cation channel of sperm induced by progesterone. Therefore, this study aimed to explore whether the compounds in R. volubilis affect the physiological regulation of the cation channel of sperm. The bioguided isolation of the whole herb of R. volubilis has resulted in the novel discovery of five new prenylated isoflavonoids, rhynchones A - E (1:  - 5: ), a new natural product, 5'-O-methylphaseolinisoflavan (6: ) (1H and 13C NMR data, Supporting Information), together with twelve known compounds (7:  - 18: ). Their structures were established by extensive spectroscopic analyses and drawing a comparison with literature data, while their absolute configurations were determined by electronic circular dichroism calculations. The experiments of intracellular Ca2+ signals and patch clamping recordings showed that rhynchone A (1: ) significantly reduced cation channel of sperm activation by competing with progesterone. In conclusion, our findings indicat that rhynchone A might act as a contraceptive compound by impairing the activation of the cation channel of sperm and thus prevent fertilization.

19.
Curr Med Sci ; 41(4): 680-686, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34403092

RESUMO

OBJECTIVE: Age-related hearing loss (AHL), characterized by degeneration of cochlea structures, is the most common sensory disorder among the elderly worldwide. The calcium channel is considered to contribute to normal hearing. However, the role of the T-type voltage-activated calcium channel, Cav3.1, remains unclear in AHL. Here, we investigate the age-related change of Cav3.1 expression in the cochlea and D-gal-induced senescent HEI-OC1 cells. METHODS: Cochleae from C57BL/6 mice at 2 months and 12 months of age were assessed. Senescence in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells was induced by D-gal treatment. The immunofluorescence technique was employed to investigate the distribution of Cav3.1 in vivo and in vitro. Quantitative assessment was achieved by Western blotting and real-time PCR. RESULTS: In comparison with 2-month-old animals, 12-month old C57BL/6 mice exhibited great loss of hair cells and elevated auditory brainstem threshold. The Cav3.1 was located in hair cells, spiral ganglion cells, lateral walls, and the expression of Cav3.1 protein and mRNA decreased in the aged cochleae. D-gal-induced senescence assay confirmed the down-regulation of Cav3.1 expression in senescent HEI-OC1 cells. CONCLUSION: Our results show that age-related down-regulated expression of Cav3.1 in the cochleae is associated with AHL and may contribute to the pathogenesis of AHL.

20.
Toxicology ; 461: 152910, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34453960

RESUMO

Autism is thought to be associated with both environmental and genetic factors. Phenanthrene (Phe) makes up a relatively high proportion of the low-ring polycyclic aromatic hydrocarbons. However, the association between exposure to Phe and Autism remain unclear. In this study, the effect and mechanisms of phenanthrene exposure on autistic behavior were investigated. Three-week-old male Kunming mice were exposed to doses of 5, 50, or 500 µg/kg/d Phe for 22 days. Exposure to phenanthrene induced a marked decrease in the activity of the mice in the central area in the open field test, and caused a significant decrease in communication with unfamiliar mice in the three-chambered social test. The hippocampus of the mice exposed to high concentrations of Phe showed pathological changes. Exposure to phenanthrene induced an increase in the levels of ROS and a decrease in levels of glutathione, and caused a significant decrease in the expression of Shank3 and Beclin1. This also led to an increase in the phosphorylation levels of Akt and mTOR. However, administering Rapamycin or vitamin E, inhibited the oxidative stress and activation of the mTOR pathway induced by Phe exposure, effectively alleviating the above-mentioned autistic-like anxious social behaviors. These results indicate that exposure to phenanthrene will lead to autism-like behavior. The underlying mechanism involves oxidative stress and the mTOR pathway.

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