Female reproductive health is noticeably compromised by obesity. The underlying mechanisms remain to be elucidated. Accumulating evidence indicates that the expression level of ovarian Kiss1 peaks in ...the afternoon during prooestrus, suggesting local regulatory roles for Kiss1 in the ovulatory process. We used a diet-induced model of obesity to evaluate whether the ovarian Kiss1 system is affected by obesity, and, to investigate the association of the Kiss1 system with ovulatory disorders in female rats.
Post-weaning, female, Sprague-Dawley rats were randomly fed either a high-fat diet (HFD) or a normal chow diet (NCD) until they reached postnatal day 30 (PND 30), PND 42, or PND 70. The timing of vaginal opening was recorded, and oestrous cyclicity was monitored for 2 consecutive weeks immediately post puberty and again at 8-9 weeks of age. Tissues from the left ovary were collected for determination of the levels of Kiss1 and G protein-coupled receptor 54 (GPR54) mRNA, and tissues from the right ovary were collected for assessment of the immunoreactivity (IR) of the corresponding protein products, kisspeptin and GPR54.
The high-fat diet resulted in a significantly higher body weight and an earlier puberty onset. Oestrous cyclicity was disrupted by the HFD with significant reductions in the expression of ovulation-related genes. A marked suppression of ovarian Kiss1 mRNA levels was observed during prooestrus and oestrus at PND 42, and, during prooestrus, oestrus, and metoestrus at PND 70 in the HFD rats compared with the NCD controls. In the HFD group, the immunoreactivity of kisspeptin was significantly lower in theca cells from antral follicles during prooestrus and oestrus at PND 42, and, during prooestrus, oestrus at PND 70. At the prooestrus stage, in the HFD group the immunoreactivity of kisspeptin was also lower in the theca cells of preovulatory follicles at both PND 42 and PND 70.
Exposure of female rats to an post-weaning, high-fat diet has long-term deleterious effects on ovulation, that may involve down-regulation of ovarian Kiss1 mRNA and kisspeptin.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Leiomyosarcoma (LMS) is an uncommon and aggressive form of cancer that originates in the smooth muscles. It possesses the capacity for rapid growth and often manifests with general, nonspecific ...symptoms arising from the displacement of nearby structures rather than direct invasion. In this particular instance, an 81-year-old woman presented with right lower abdominal pain, leading to the discovery of a mass adjacent to the right external iliac artery. In this case, the patient was misdiagnosed initially because of her nonspecific and poorly distinguished clinical symptoms. The laboratory results were within normal ranges. A well-defined tumor was detected through laparoscopic operation and subsequently surgically excised. The histopathological analysis of the tumor revealed the presence of malignant spindle cells, nuclear pleomorphism, and tumor giant cells. Immunohistochemistry tests indicated positive results for CD34 and Desmin, while CD117 and DOG1 showed adverse effects. It is worth noting that LMS of the right external iliac artery is an infrequent occurrence, potentially resulting in delayed diagnosis and misidentification. To enhance our comprehension of this uncommon cancer, more cases with detailed information are essential.
Accumulating evidence demonstrates that the expression levels of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are regulated at the various levels, including ...transcription, post-transcriptional modification and post-translational modifications (PTMs). The PTMs of PD-1/PD-L1 contain phosphorylation, ubiquitination, methylation, glycosylation and palmitoylation. Recently, PD-L1 was reported to be acetylated at Lys263 site by p300 and was deacetylated by histone deacetylase 2 (HDAC2). Acetylation of PD-L1 prevented its translocation to the nucleus and led to a reduction of the nuclear portion of PD-L1, resulting in evading immune surveillance of tumor cells. In this review article, we briefly describe the PTMs of PD-1/PD-L1 and mainly summarize the novel findings of PD-L1 acetylation in tumor cells. Moreover, we discuss the associations of PD-L1 acetylation and ubiquitination, phosphorylation and methylation. Furthermore, we highlight that targeting acetylation of PD-L1 by HDAC inhibitors might be useful for enhancing tumor immunotherapy.
CNOT7 plays an important role in many biological processes, providing attractive opportunities for the treatment of malignant tumors. However, the functions and mechanism of CNOT7 in ovarian cancer ...(OC) have not been elucidated. The purpose of this study was to assess the role of CNOT7 in OC.
SKOV3 and A2780 cells were chosen as the cell lines for the experiments of this manuscript via the analysis of the expression of CNOT7 protein and the mRNA level in ovarian surface epithelium (OSE) cells, SKOV3, HO8910 and A2780 cells. The expression of CNOT7 was detected by western blot assays and RT-PCR in A2780 and SKOV3 cells. The MTT assays, colony formation assays and EdU assays were used to measure cell proliferation when CNOT7 was knocked down or overexpressed in A2780 and SKOV3 cells. Furthermore, cell migration and invasion ability were achieved from transwell assays. Cell cycle and apoptosis rate after small interference RNA-CNOT7 (siRNA-CNOT7) were detected by flow cytometry assays. Finally, the cell proliferation, migration and invasion ability were detected when A2780 and SKOV3 cells with CNOT7 overexpression were treated with LY294002.
The expression of CNOT7 protein in OC cells, including SKOV3, HO8910 and A2780 cells were significantly higher than that in OSE cells (P < 0.05). The mRNA level of CNOT7 in HO8910 and A2780 cells were significantly higher than that in OSE cells (P < 0.01). However, the mRNA level of CNOT7 in SKOV3 cells was no significant difference compared with OSE cells (P > 0.05). The results suggested that knockdown of CNOT7 could inhibit the cell proliferation, migration and invasion ability in A2780 and SKOV3 cells, and increase cell apoptosis and autophagy. The expression of apoptosis-related molecules (PARP, Caspase3 and Caspase9) and autophagy-related protein (LC3B) were up-regulated after CNOT7 knockdown, while the expression of cycle-related protein (CDK6) and the anti-apoptotic gene (Bcl2) were downregulated. Meanwhile, the opposite results were observed when CNOT7 was overexpressed in A2780 and SKOV3 cells. It is worth noting that the effect of CNOT7 overexpression in A2780 and SKOV3 cells could be partially or completely eliminated by treatment with AKT inhibitor LY294002.
CNOT7 has a carcinogenic effect in OC, and the carcinogenic effect may be achieved via the AKT signaling pathway.
Endometriosis is a benign disease but manifests with malignant features and limited treatment options. Women with endometriosis should not be ignored or patronized by the medical profession and ...society. In this regard, a major cultural change and searching for the optimum therapeutic regimen from multiple perspectives is needed in China even in the whole world. Long non-coding RNAs are crucial for various human diseases while its potential functions and mechanisms are largely unknown in endometriosis. LINC00261 was significantly downregulated in endometriosis tissues and our study indicated that it suppresses proliferation and invasion of endometriosis cells functionally
. Insights of the mechanism of competitive endogenous RNAs were obtained from bioinformatic analysis, RIP, RNA pull-down and luciferase assays, which further confirmed that LINC00261 functions as a molecular sponge to regulate BCL2L11 expression by binding to miR-132-3p directly. These data defined LINC00261/miR-132-3p/BCL2L11 regulatory networks may be a novel therapeutic target for endometriosis.
Leiomyosarcoma (LMS) is an uncommon and aggressive form of cancer that originates in the smooth muscles. It possesses the capacity for rapid growth and often manifests with general, nonspecific ...symptoms arising from the displacement of nearby structures rather than direct invasion. In this particular instance, an 81-year-old woman presented with right lower abdominal pain, leading to the discovery of a mass adjacent to the right external iliac artery. In this case, the patient was misdiagnosed initially because of her nonspecific and poorly distinguished clinical symptoms. The laboratory results were within normal ranges. A well-defined tumor was detected through laparoscopic operation and subsequently surgically excised. The histopathological analysis of the tumor revealed the presence of malignant spindle cells, nuclear pleomorphism, and tumor giant cells. Immunohistochemistry tests indicated positive results for CD34 and Desmin, while CD117 and DOG1 showed adverse effects. It is worth noting that LMS of the right external iliac artery is an infrequent occurrence, potentially resulting in delayed diagnosis and misidentification. To enhance our comprehension of this uncommon cancer, more cases with detailed information are essential.
In natural rock masses, joints or flaws usually occur in sets that are more or less parallel and regularly spaced. Many problems occurred in tunnel engineering mainly result from the failure of ...joints or faults because they are weaker compared with the rock matrix. Therefore, it is important to study the interaction of joints with the tunnel, as well as the interactions between themselves. In this research, rock-like specimens of non-persistent jointed rock masses containing a circular hole are prepared and tested under uniaxial compression. The test results show that the peak strength and elastic modulus of the non-persistent jointed rock specimens display a “U” type variation with respect to the joint inclination. The multiple joints can be simplified and regarded as a combination of three types of two-joints relative location, and the crack coalescence types and failure modes are in accordance with the classic crack coalescence types of the two joints. The crack coalescence between the joints and a circular hole can be categorized into three modes with respect to the joint inclination. The Discrete Element Method (DEM) model of the jointed rock specimen that contains a circular hole is established in particle flow code 2D (PFC2D). The simulation results show a good agreement with the experiment results. Furthermore, the displacement fields at the crack zones reveal that the coalescence of joints is mainly caused by tensile cracks and that shear slipping cracks easily occur at the sidewalls of the circular hole. By comparing the parallel-bond force fields in jointed models containing a circular hole with no a circular hole, it is shown that the circular hole can change the stress state at the top and bottom. The joints at a joint inclination of 90° have the smallest effect on the mechanical behavior of the rock specimen.
The study aimed to investigate the safety, pharmacokinetics (PK), and efficacy of YJ001 spray, a candidate drug for diabetic neuropathic pain (DNP) therapy.
Forty-two healthy subjects received one of ...four single doses (240, 480, 720, 960 mg) of YJ001 spray or placebo, and 20 patients with DNP received repeated doses (240 and 480 mg) of YJ001 spray or placebo via topical route of administration to the local skin of both feet. Safety, and efficacy assessments were performed, and blood samples were collected for PK analyses.
The pharmacokinetic results revealed that the concentrations of YJ001 and its metabolites were low, and most of them were lower than the lower limit of quantitation. In patients with DNP, treatment with a 480 mg YJ001 spray dose significantly reduced pain and improved sleep quality compared with placebo. No serious adverse events (SAEs) or clinically significant findings of the safety parameters were observed.
Systemic exposure to YJ001 and its metabolites is low after YJ001 spray is applied locally to the skin, which will reduce systemic toxicity and adverse reactions. YJ001 appears to be well tolerated and potentially effective in the management of DNP and is a promising new remedy for DNP.
The novel Bi3+/Ln3+:LuVO4 (Ln = Eu, Sm, Dy, Ho) nanocrystals are successfully fabricated by a facile and mixed hydrothermal method. With 10mol% Bi3+ doping into the LuVO4 nanocrystal, the Ln3+ ...excitation band could be diverted from 293nm to 346nm, attributing to the dominant of Bi3+ - V5+ metal–metal charge transfer instead of O2- to V5+ within VO4 group before doping. Under 346nm excitation, the as-prepared nanophosphors yield intense multicolor emissions. The emission color of Bi3+/Ln3+:LuVO4 nanophosphors can be tuned through adjusting the doping Ln3+ ions. They may find potential applications as white light-emitting diode materials in color display field.
SHR-1222 is a humanized monoclonal antibody targeting sclerostin and has the potential to promote bone formation and reduce bone resorption. This study was aimed to assess the safety, tolerability, ...pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1222 in healthy men and postmenopausal women with low bone mass (BMD). It was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Subjects received SHR-1222 at 50, 100, 200, 300, and 400 mg sequentially or matching placebo subcutaneously. Totally, 50 subjects with low BMD were enrolled and randomly assigned; 10 received placebo and 40 received SHR-1222 (50 mg, n = 4; 100, 200, 300, or 400 mg, n = 9). The most common adverse events that occurred at least 10% higher in subjects with SHR-1222 treatment than those with placebo were decreased blood calcium, blood urine present, increased blood cholesterol, electrocardiogram T wave abnormal, urinary tract infection, increased blood pressure diastolic, and positive bacterial test. All the above adverse events were mild in severity and well resolved except one of increased blood cholesterol in a subject lost to follow-up. The serum SHR-1222 concentration increased in a dose-dependent manner. Administration of SHR-1222 upregulated the bone-formation markers N-terminal propeptide of type 1 procollagen, osteocalcin, and bone-specific alkaline phosphatase, while downregulated the bone-resorption marker β-C-telopeptide. The BMD at the lumbar spine notably rose after a single dose of SHR-1222. The largest increase occurred in the 400 mg cohort (3.8, 6.7, and 6.1% on day 29, 57, and 85, respectively; compared with 1.4, 0.8, and 1.0% in the placebo group). Although 10.0% of subjects receiving SHR-1222 tested positive for anti–SHR-1222 antibodies, no obvious effects of antibody formation were found on pharmacokinetics. Overall, SHR-1222 was well tolerated at doses from 50 to 400 mg and is a promising new remedy for osteoporosis.
Clinical Trial Registration:
http://www.clinicaltrials.gov
, NCT03870100.
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