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Cachexia, a complex disorder that results in depletion of adipose tissue and skeletal muscle, is driven by anorexia, metabolic abnormalities and inflammation. There are limited therapeutic options for this syndrome. Previous evidence has demonstrated that increasing adipose tissue may improve quality of life and survival outcomes in cachexia. Cisplatin, as a chemotherapy drug, also causes cachexia during antitumor therapy due to its adverse effects. To establish a rat model of cachexia, the animals were intraperitoneally treated with cisplatin at doses of 1, 2 and 3 mg/kg, and the rats that responded to cisplatin at the optimal dose were used to test the effect of nomegestrol acetate (NOMAc). Rats that were assessed to be sensitive to cisplatin were randomly grouped and intragastrically administered vehicle, 5 or 10 mg/kg megestrol acetate (MA) or 2.5, 5 or 10 mg/kg NOMAc. The body weights and food consumption of the rats were assessed. Serum IL-6 and TNF-α levels were assessed using ELISA. The protein expression levels of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), peroxisome proliferator activated receptor γ (PPARγ), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1) from inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) were evaluated using western blotting. The optimal way to establish a chemotherapy-induced rat model of cachexia demonstrated in the present study was to intraperitoneally administer the rats with 2 mg/kg cisplatin for 3 consecutive days. NOMAc (2.5, 5 mg/kg) and MA (10 mg/kg) were able to significantly ameliorate the loss of body weight in the cisplatin-induced cachectic rats. NOMAc significantly reduced the serum levels of TNF-α at 10 mg/kg. Morphologically, iWAT atrophy, with a remarkable reduction in adipocyte volume, was observed in the cisplatin-induced cachectic rats, but the effects were reversed by administering 5, 10 mg/kg NOMAc or 10 mg/kg MA. Furthermore, 2.5 mg/kg NOMAc markedly reduced the protein expression levels of the lipolysis genes HSL and ATGL, and 5 mg/kg NOMAc markedly enhanced the protein expression levels of adipogenesis genes, including FASN, SREBP-1 and PPARγ in iWAT but not in eWAT. NOMAc was demonstrated to improve cachexia at lower doses compared with MA. Overall, NOMAc is likely to be a promising candidate drug for ameliorating cancer cachexia induced by cisplatin.

In this paper, a new fourth-order compact difference scheme based on the reduction order method is proposed for solving the regularized long wave (RLW) equation. The compact finite difference scheme is three-level and linear. The discrete mass and discrete energy, boundedness and uniqueness of the present compact scheme are proved. Convergence and stability of the compact scheme are also analyzed by using the discrete energy method. Our compact scheme has the rates of convergence of second-order in temporal direction and fourth-order in spatial direction, respectively. Numerical examples are carried out to verify the reliability of the theory analysis.

Background HIV-infected patients are easy to combine with various opportunistic infections due to their low immunity. Improving microbiological diagnosis in these patients is of paramount clinical importance.Methods Thirty-six HIV-infected patients with suspected infection were retrospectively reviewed from April 2018 to December 2019. The diagnostic performance of pathogens was compared between traditional microbiological methodology and mNGS.Results The sensitivity of mNGS for diagnosing infectious disease was outperformed of culture, especially for virus (mNGS only; P Conclusions mNGS was more sensitive and comprehensive for pathogen identification therefore a promising method for microbiological diagnosis in AIDS patients with infection.

This study investigated the effect of a novel progestin and its combination with metformin on the growth of endometrial cancer (EC) cells. Inhibitory effects of four progestins, including nomegestrol acetate (NOMAC), medroxyprogesterone acetate, levonorgestrel, and cyproterone acetate, were evaluated in RL95-2, HEC-1A, and KLE cells using cell counting kit-8 assay. Flow cytometry was performed to detect cell cycle and apoptosis. The activity of Akt (protein kinase B), mTOR (mammalian target of rapamycin) and its downstream substrates 4EBP1 (4E-binding protein 1) and eIF4G (Eukaryotic translation initiation factor 4G) were assayed by Western blotting. Nude mice were used to assess antitumor effects in vivo. NOMAC inhibited the growth of RL95-2 and HEC-1A cells, accompanied by arresting the cell cycle at G0/G1 phase, inducing apoptosis, and markedly down-regulating the level of phosphorylated mTOR/4EBP1/eIF4G in both cell lines (p &lt, 0.05). Metformin significantly increased the inhibitory effect of and apoptosis induced by NOMAC and strengthened the depressive effect of NOMAC on activity of mTOR and its downstream substrates, compared to their treatment alone (p &lt, 0.05). In xenograft tumor tissues, metformin (100 mg/kg) enhanced the suppressive effect of NOMAC (100 mg/kg) on mTOR signaling and increased the average concentration of NOMAC by nearly 1.6 times compared to NOMAC treatment alone. Taken together, NOMAC suppressing the growth of EC cells likely correlates to down-regulating the activity of the mTOR pathway and metformin could strengthen this effect. Our findings open a new window for the selection of progestins in hormone therapy of EC.

We evaluated the effectiveness of Kuntai Capsule (KTC) for treating endometriosis using rat model and investigated its preliminary mechanism of action involved. SD rats were implanted with endometrial tissues and treated with KTC for three weeks. Then, laparotomy was performed to examine volume changes of the autografts. The serum levels of TNF-α, IL-6, COX-2, E2, and P4 were measured through ELISA. TUNEL was performed to analyze the apoptosis on ectopic endometrium. Protein levels of caspases 8, 9, and 3 and cytochrome c in the ectopic and eutopic endometrium were measured by western blotting. Results showed that KTC significantly decreased the volumes of ectopic endometrium. The level of TNF-αincreased and E2decreased in the KTC treatment groups. TUNEL and western blot assay showed that KTC could induce apoptosis of endometriotic tissues, accompanied with the increased protein expression of caspases 8 and 9, activated caspase-3, and cytochrome c in a dose-dependent manner. However, these protein expression profiles were not affected in eutopic endometrium. Our findings suggest that KTC could inhibit the growth of ectopic endometrial tissue through upregulating the level of TNF-αand its downstream signaling, including caspases and cytochrome c.

Panax ginseng is widely used as a functional food in Asia because of its bioactivities. Here, we report that ginsenoside Rh2, an extract of red Panax ginseng, suppressed growth of uterine leiomyomas (ULs) in a rat model and decreased serum hormone levels in a dose-dependent manner. Rh2 also inhibited the growth of cultured human UL cells in vitro. After Rh2 treatment, cells showed morphological changes that were consistent with apoptosis. Using ELISA, real-time RT-PCR, and Western blot methods, we found that Rh2 significantly reduced the activity of oestrogen receptor alpha (ERα) and c-Src, increased p38 MAPK activity, and reversed ERα activity mediated by PP2 and SB203580, specific inhibitors of c-Src and p38 MAPK, respectively, in UL cells. These findings provide a novel mechanism for the anti-proliferative efficacy of Rh2 that likely involves regulating ERα/Src/p38 MAPK activity.

This study aimed to investigate the antifertility effect of Juniperus sabina fruit on male rats and its possible mechanism, and hence it might be developed as a potential nonhormonal male contraceptive. Male rats were intragastrically fed for consecutive 8-week and 4-week recovery with the fruit of J. Sabina, and sperm maturation, serum testosterone level, and histopathology were analyzed. Epididymal epithelial cell culture was prepared for detection of podophyllotoxin activities. Furthermore, cell proliferation, transmission electron microscopy, Annexin V/Propidium iodide, TUNEL, RT-PCR, ELISA, and western blotting were examined. The results showed that rat sperm motility and fertility were remarkably declined after feeding the fruit. Moreover, the fruit targeted the epididymis rather than the testis. After 4-week recovery, more than half of the male rats resumed normal fertility. It was found that podophyllotoxin significantly inhibited epididymal epithelial cell proliferation, promoted cell apoptosis, and increased the mRNA and protein levels of TNF-α and the expression levels of cytochrome c, caspase-8, caspase-9, and caspase-3. Our findings suggest that the fruit of J. sabina could inhibit male rat sperm maturation and fertility. The potential mechanism might be related to podophyllotoxin, inducing epididymal epithelial cell apoptosis through TNF-α and caspase signaling pathway.

This study aimed to investigate the antifertility effect of Juniperus sabina fruit on male rats and its possible mechanism, and hence it might be developed as a potential nonhormonal male contraceptive. Male rats were intragastrically fed for consecutive 8-week and 4-week recovery with the fruit of J. Sabina, and sperm maturation, serum testosterone level, and histopathology were analyzed. Epididymal epithelial cell culture was prepared for detection of podophyllotoxin activities. Furthermore, cell proliferation, transmission electron microscopy, Annexin V/Propidium iodide, TUNEL, RT-PCR, ELISA, and western blotting were examined. The results showed that rat sperm motility and fertility were remarkably declined after feeding the fruit. Moreover, the fruit targeted the epididymis rather than the testis. After 4-week recovery, more than half of the male rats resumed normal fertility. It was found that podophyllotoxin significantly inhibited epididymal epithelial cell proliferation, promoted cell apoptosis, and increased the mRNA and protein levels of TNF-α and the expression levels of cytochrome c, caspase-8, caspase-9, and caspase-3. Our findings suggest that the fruit of J. sabina could inhibit male rat sperm maturation and fertility. The potential mechanism might be related to podophyllotoxin, inducing epididymal epithelial cell apoptosis through TNF-α and caspase signaling pathway.

Antimitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cholangitis (PBC), while data regarding the profile of AMA during ursodeoxycholic acid (UDCA) treatment are scarce. Here, we assessed the influence of UDCA treatment on titers of AMA and factors relevant to its production.Serum IgA-AMA, IgM-AMA, IgG-AMA, B cell-activating factor of the tumor necrosis factor family (BAFF), and the frequency of circulating plasmablasts were detected in PBC patients, including those who received UDCA therapy for 24 weeks, healthy controls, chronic hepatitis B patients, and autoimmune hepatitis patients. Consecutive liver sections from controls and PBC patients were stained by immunohistochemistry for detection of intrahepatic CD38Significant decrease in titers of IgG-AMA was found only confined to PBC patients with biochemical response to UDCA treatment (P = 0.005), and similar pattern was also observed at week 24 in quantifying circulating plasmablasts (P = 0.025) and serum BAFF (P = 0.013). Notably, positive correlation between serum BAFF levels and titers of IgG-AMA, and the frequency of circulating plasmablasts were observed in PBC patients (r = 0.464, P = 0.034 and r = 0.700, P 0.001, respectively). Additionally, in situ staining revealed significant accumulation of CD38Decreased titers of serum IgG-AMA are associated with biochemical response to UDCA treatment, implicating the potentiality of this hallmark in therapeutic response evaluation and the beneficial effect of UDCA on humoral immunity in PBC patients.

Objective This study aimed to investigate the link between the inhibitory effect of ginsenoside Rg3 on the ectopic endometrium growth and the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, a mechanism known to inhibit angiogenesis and induce ectopic endometrial cell apoptosis. Materials and methods A model of endometriosis was established by allotransplantation in rats. The rats were randomly divided into 5 groups: the ginsenoside Rg3 low-dose group (group A,5mg/kgBW/d of ginsenoside Rg3), the ginsenoside Rg3 high-dose group (group B, 10mg/kgBW/d of ginsenoside Rg3), the gestrinone group (group C, 0.5mg/kgBW/d of gestrinone), the control group (groupD, 10ml/kg BW/d of 0.5%CMC-Na) and the ovariectomized group (group E, 10ml/kgBW/d of 0.5%CMC-Na). Rats were executed after 21 days of continuous administration. The ectopic endometrium volume was measured and the inhibitory rate was calculated. The levels of serum estradiol (E2) and progesterone (P) were detected by Electro-Chemiluminescence Immunoassay (ECLI). The protein expressionof VEGF, VEGFR-2, p-Akt, and p-mTOR inthe ectopic endometrium wastested by immunohistochemistry(IHC) and Western Blotting. The mRNA expression levels of VEGF, VEGFR-2, Akt, and mTOR were tested by Real-Time Polymerase Chain Reaction (PCR). The apoptosis rate of the ectopic endometrial cells was detected by Terminal Deoxynucleotidyl Transferase-mediated Digoxigenin-dUTP Nick-End Labeling Assay(TUNEL). Main results Tissue measurements revealed a dose-dependent inhibition effect of ginsenoside Rg3 on the growth of the ectopic endometrium in treated rats compared to controls. Immunohistochemical and Western Blotting assays confirmed that the expression of VEGF, p-Akt, and p-mTOR was down-regulated in ginsenoside Rg3 -treated lesions. Real-time PCR results also showed that the mRNA expression levels of VEGF, Akt, and mTOR in the ectopic endometrium were reduced. Conclusions The present study demonstrates, for the first time, that ginsenoside Rg3 suppresses angiogenesis in developing endometrial lesions. The ginsenoside Rg3 inhibitory effect on the growth of the ectopic endometrium in EMs rats might occur through the blocking of the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, thus halting angiogenesis and promoting the apoptosis of ectopic endometrial cells.

Background: Spermatozoa become mature and acquire fertilizing capacity during their passage through the epididymal lumen. In this study, we identified new epididymal luminal fluid proteins involved in sperm maturation in infertile rats by dutasteride, a dual 5α-reductase inhibitor, in order to provide potential epididymal targets for new contraceptives and infertility treatment. Methods: Male rats were treated with dutasteride for 28 consecutive days. We observed the protein expression profiles in the epididymal luminal fluids in infertile and normal rats using isobaric tags for relative and absolute quantitation (iTRAQ) technique. The confidence of proteome data was validated by enzyme-linked immunosorbent assays. Results: 1045 proteins were tested, and 23 of them presented different expression profiling in the infertile and normal rats. The seven proteins were down-regulated, and 16 proteins were up-regulated. Among the seven proteins which were significantly down-regulated by dutasteride in the epididymal luminal fluids, there were three β-defensins (Defb2, Defb18 and Defb39), which maybe the key proteins involved in epididymal sperm maturation and male fertility. Conclusions: We report for the first time that dutasteride influences the protein expression profiling in the epididymal luminal fluids of rats, and this result provides some new epididymal targets for male contraception and infertility therapy.