Antimicrobial peptides act on the rumen the performance of castrated bulls

Background Many countries have already banned the use of antibiotics in animal husbandry,making it extremely difficult to maintain animal health in livestock breeding.In the livestock industry,there is an urgent need to develop alternatives to antibiotics which will not lead to drug resistance on prolonged use.In this study,eighteen castrated bulls were randomly divided into two groups.The control group(CK)was fed the basal diet,while the antimicrobial peptide group(AP)was fed the basal diet supplemented with 8 g of antimicrobial peptides in the basal diet for the experimental period of 270 d.They were then slaughtered to measure production performance,and the ruminal contents were isolated for metagenomic and metabolome sequencing analysis.Result The results showed that antimicrobial peptides could improve the daily weight,carcass weight,and net meat weight of the experimental animals.Additionally,the rumen papillae diameter and the micropapillary density in the AP were significantly greater than those in the CK.Furthermore,the determination of digestive enzymes and fermentation parameters showed that the contents of protease,xylanase,andβ-glucoside in the AP were greater than those in the CK.However,lipase content in the CK was greater than that in the AP.Moreover,the content of acetate,propionate,butyrate,and valerate was found to be greater in AP than those in CK.The metagenomic analysis annotated 1993 differential microorganisms at the species level.The KEGG enrichment of these microorganisms revealed that the enrichment of drug resistance-related pathways was dramatically decreased in the AP,whereas the enrichment of immune-related pathways was significantly increased.There was also a significant reduction in the types of viruses in the AP.187 probiotics with significant differences were found,135 of which were higher in AP than in CK.It was also found that the antimicrobial mechanism of the antimicrobial peptides was quite specific.Seven low-abundance microorganisms(Acinetobactersp.Ac1271,Aequorivita soesokkakensis,Bacillus lacisalsi,Haloferax larsenii,Lysinibacillussp.3DF0063,Parabacteroidessp.217,Streptomycessp.So13.3)were found to regulate growth performance of the bull negatively.Metabolome analysis identified 45 differentially differential metabolites that significantly different between the CK and the AP groups.Seven upregulated metabolites(4-pyridoxic acid,Ala-Phe,3-ureidopropionate,hippuric acid,terephthalic acid,L-alanine,uridine 5-monophosphate)improve the growth performance of the experimental animals.To detect the interactions between the rumen microbiome and metabolism,we associated the rumen microbiome with the metabolome and found that negative regulation between the above 7 microorganisms and 7 metabolites.Conclusions This study shows that antimicrobial peptides can improve the growth performance of animals while resisting viruses and harmful bacteria and are expected to become healthy alternatives to antibiotics.We demonstrated a new antimicrobial peptides pharmacological model.We demonstrated low-abundance microorganisms may play a role by regulating the content of metabolites.

Effects of Buddlejae Flos Granules on Inflammatory Factors TGF-β1,NF-κB,IL-10 and IL-12 in Lacrimal Gland Cells of Castrated Male Rabbits

Objective To observe the effects of Buddlejae Flos (Mi Meng Hua,密蒙花) granules on the expression of TGF-β1, NF-κB, IL-10 and IL-12 in lacrimal gland cells in castrated male rabbits. Methods A total of 30 New Zealand male white rabbits were randomly divided into 5 groups. Group A: blank group;group B: model group;group C: Buddlejae Flos (Mi Meng Hua,密蒙花) granules group;group D: placebo group;group E: testosterone group. Except for the group A, all rabbits were treated with bilateral testicular and epididymis resection before intervention. Rabbits in group C were administered with Buddlejae Flos (Mi Meng Hua,密蒙花) granules (100 mg/kg), 3 times per day;Rabbits in group D were administered with normal saline, 3 times per day. Rabbits in group E were injected with testosterone propionate (0.5 mL/kg) in the thigh muscle, every 3 days. Schirmer I test (SIT) and break-up time (BUT) were measured on 1st day before modeling and 30th day after modeling. After 30 days of intervention, all rabbits were sacrificed. The removal lacrimal gland was stained in immunohistochemica staining. The expression of TGF-β1, NF-κB, IL-10 and IL-12 in lacrimal gland tissue of each group was detected, and the structure of lacrimal gland was observed. Results The results of SIT and BUT showed that there was significant difference between group B and D compared with group A (P < 0.05). There were no significant differences between group C and E (P > 0.05). There were no significant differences in the comparison of inflammatory factors TGF-β1, NF-κB, IL-10 and IL-12 between group B and D (P > 0.05). There were significant differences between group B and D compared with other groups (P < 0.01). There was no significant difference between group A, C and E (P > 0.05). Conclusions Buddlejae Flos (Mi Meng Hua,密蒙花) granules have an inhibitory effect on the expression of TGF-β1, NF-κB, IL-10 and IL-12 in castrated male rabbit lacrimal gland cells, and alleviate the inflammation of lacrimal gland tissue by inhibiting the expression of TGF-β1, NF-κB, IL-10 and IL-12 in lacrimal gland tissue, so as to treat dry eye.

Effect of Flos Buddlejae Granules on Apoptosis Factors Bax,Bcl-2,Fas and FasL in Lacrimal Gland Cells of Castrated Male Rabbits

Objective To observe the effect of different concentration Flos Buddlejae(Mi Meng Hua,密蒙花)granules on apoptosis factors of lacrimal gland cells of castrated male rabbits,and study the treatment effects of Flos Buddlejae(Mi Meng Hua,密蒙花)granules in the dry eye model of castrated male rabbits.Methods Flos Buddlejae(Mi Meng Hua,密蒙花)raw material was made into granules.Thirty healthy adult New Zealand rabbits were randomly divided into five groups,six rabbits in each group.Group A:blank group,Group B:model group,Group C:Flos Buddlejae(Mi Meng Hua,密蒙花)granule group,Group D:placebo group,Group E:testosterone group.Except for group A,all rabbits underwent removal of bilateral testis and epididymis.Rabbits in group C were administered Flos Buddlejae(Mi Meng Hua,密蒙花)granules(100 mg/kg),three times per day;rabbits in group D were administered normal saline,three times per day.Rabbits in group E were injected with testosterone propionate(0.5 mL/kg)in the thigh muscle,every 3 days.All rabbits were tested by Schirmer I test(SIT)and tear film break-up time(BUT)before operation and 4 weeks after operation.After 4 weeks,all rabbits were sacrificed by air embolism and clipping of the lacrimal gland.Apoptosis factors,including Bax,Bcl-2,Fas and FasL of lacrimal gland cells were characterized by immunohistochemistry,and resulting data were statistically analyzed.Results(1)Comparison of SIT and BUT before and after operation:There were statistically significant differences between groups B and D(P<0.01),but not among other groups(P>0.05).(2)Comparison of apoptosis factors Bax,Bcl-2 Fas and FasL:In a comparison of groups B and D,there was no statistically significant difference after operation(P>0.05).In a comparison of the other groups,there were statistically significant differences(P<0.01).In comparisons among A,C and E groups,there were no statistically significant differences(P>0.05).Conclusion Compared with androgen,Flos Buddlejae(Mi Meng Hua,密蒙花)granules caused similar but slightly weaker depression of Bax,Fas and FasL,and increased expression of Bcl-2.

Chemical Composition of Meat in Castrated Male Brahman Cattle in Venezuela

Chemical composition of Brahman cattle was studied and determined in this study. Fifty males had been castrated at birth, farmed semi-intensively on the Venezuelan plain and then slaughtered at the age of 31 months with an approximate weight of 500 kilograms. The average pH value of beef was 5,84 after obtained for 24 hours after staughtering, which matches the ~atue found in similar studies made on the same breed in Venezuela （5.8）. The moisture, crude protein and ash contents correspond to the expected values of cattle, while the intramuscular fat values are slightly higher than those of the different breeds ofBos indicus. The total collagen values found in this study are either similar or lower than those found by other researches from the different breeds ofBos indicus and their crossbreeds, while the collagen solubility value （39%） was higher than the one found in other studies on the Brahman breed.

Proliferation and phenotypic changes of stromal cells in response to varying estrogen/androgen levels in castrated rats

It is known that human benign prostatic hyperplasia might arise from an estrogen/androgen （E/T） imbalance. We studied the response of castrated rat prostate to different ratios of circulating E/T. The castrated male Wistar rats were randomly injected with E/T at different ratios for 4 weeks. The prostates of E/T （1：100） group showed a distinct prostatic hyperplasia response by prostatic index, hematoxylin and eosin staining, and quantitative immunohistochemical analysis of a-smooth muscle actin （SMA）. In this group, cells positive for Vimentin, non-muscle myosin heavy chain （NMMHC） and proliferating cell nuclear antigen （PCNA） increased in the stroma and epithelium. Furthermore, the mRNA levels of smooth muscle myosin heavy chain （SMMHC） and NMMHC increased. So E/T at a ratio of 1：100 can induce a stromal hyperplastic response in the prostate of castrated rats. The main change observed was an increase of smooth muscle cells, whereas some epithelial changes were also seen in the rat prostates.

Protein profiles in various epididymal segments of normal and castrated rats

Aim: Epididymal proteins are known to play an important role in the maturation of spermatozoa, we ougnt to deter-mine if there are regional differences in androgen-dependent epididymal proteins. Methods: A group of adult rats wascastrated and epididymides were removed three days following castration. The epididymides were dissected into caput,corpus and cauda segments, homogenized, and proteins were fractionated by anion exchange HPLC. Proteins in select-ed fractions were resolved by SDS-PAGE and visualized by silver staining. Results: It was observed that the levels ofmultiple proteins drastically reduced in the various regions of epididymis of the orchiectomized rats. Conclusion: Theepididymal proteins appear to be useful markers to study androgenic action in the epididymis.

Expression of type-Ⅰ collagen and matrix metalloproteinase-9 mRNA in bone of castrated adult female rats:effects of estrogen

Abstract Objectives To elucidate the molecular changes of bone collagen during the development of postmenopausal osteoporosis and to investigate the molecular effects of estrogen replacement. Methods An adult ovariotomy rat model was used. Type Ⅰ collagen and matrix metalloproteinase 9 (MMP 9) expressions in bone tissues of rats treated by sham surgery (SH), bilateral ovariotomy (OVX) and OVX with estradiol (OVX E2) were analysed at mRNA level by using dot blot technique. The distribution of mRNA of these two genes in bone tissues was studied by in situ hybridization. Results The expression levels of both type Ⅰ collagen and MMP 9 in bone tissues of OVX rats were higher than those of SH group, while treated with estradiol, the expression of both genes declined to some degree. In situ hybridization showed that type Ⅰ collagen mRNA located in osteoblasts, whereas MMP 9 was mainly expressed in osteoclasts, some lining cells on bone surface, and some mononuclear cells in bone marrow. Conclusions The reduction of high bone turnover in osteoporotic bone tissues induced by estrogen replacement may result from alterations in gene expression related to bone formation and bone resorption. These alterations are consistent with the changes observed previously by histomorphometry and biochemical markers of bone metabolism on OVX animals and postmenopausal osteoporosis.

Analysis of risk factors leading to anxiety and depression in patients with prostate cancer after castration and the construction of a risk prediction model

BACKGROUND Cancer patients often suffer from severe stress reactions psychologically,such as anxiety and depression.Prostate cancer(PC)is one of the common cancer types,with most patients diagnosed at advanced stages that cannot be treated by radical surgery and which are accompanied by complications such as bodily pain and bone metastasis.Therefore,attention should be given to the mental health status of PC patients as well as physical adverse events in the course of clinical treatment.AIM To analyze the risk factors leading to anxiety and depression in PC patients after castration and build a risk prediction model.METHODS A retrospective analysis was performed on the data of 120 PC cases treated in Xi'an People's Hospital between January 2019 and January 2022.The patient cohort was divided into a training group(n=84)and a validation group(n=36)at a ratio of 7:3.The patients’anxiety symptoms and depression levels were assessed 2 wk after surgery with the Self-Rating Anxiety Scale(SAS)and the Selfrating Depression Scale(SDS),respectively.Logistic regression was used to analyze the risk factors affecting negative mood,and a risk prediction model was constructed.RESULTS In the training group,35 patients and 37 patients had an SAS score and an SDS score greater than or equal to 50,respectively.Based on the scores,we further subclassified patients into two groups:a bad mood group(n=35)and an emotional stability group(n=49).Multivariate logistic regression analysis showed that marital status,castration scheme,and postoperative Visual Analogue Scale(VAS)score were independent risk factors affecting a patient's bad mood(P<0.05).In the training and validation groups,patients with adverse emotions exhibited significantly higher risk scores than emotionally stable patients(P<0.0001).The area under the curve(AUC)of the risk prediction model for predicting bad mood in the training group was 0.743,the specificity was 70.96%,and the sensitivity was 66.03%,while in the validation group,the AUC,specificity,and sensitivity were 0.755,66.67%,and 76.19%,respectively.The Hosmer-Lemeshow test showed aχ^(2) of 4.2856,a P value of 0.830,and a C-index of 0.773(0.692-0.854).The calibration curve revealed that the predicted curve was basically consistent with the actual curve,and the calibration curve showed that the prediction model had good discrimination and accuracy.Decision curve analysis showed that the model had a high net profit.CONCLUSION In PC patients,marital status,castration scheme,and postoperative pain(VAS)score are important factors affecting postoperative anxiety and depression.The logistic regression model can be used to successfully predict the risk of adverse psychological emotions.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

Composition and Physico-Chemical Properties of Meat from Capons Fed Cereals

Chemical composition, physico-chemical properties and fatty acid composition of breast and drumstick meat from capons （castrated male cockerels） fed cereals were studied. Three groups of capons were reared. One group was fed ad libitum the same commercial diet until the 4th mon of life. The last month of its life, the capons of this group were fed corn. The second and third group of capons were fed the same diet from caponization. The second group was fed mixture of corn （50%） and wheat （50%）. The third group of capons was fed 2/3 corn and 1/3 mixture of corn （50%） and barley （50%）. Capons were reared under free-range conditions and slaughtered at 150 d of age. Caponization was performed at 48 d. No signiifcant effects of feeding in chemical composition, pH, water holding capacity, drip and cooking losses and texture of the meat were observed. The meat of the third group （capons fed 83%corn） was more yellow and showed higher content of C18：2 than that of the other capons.

Effect of Castration on Sensorial and Instrumental Characteristics of Longissimus Dorsi Muscle （LDM） of Brahman Cattle

This study aimed to investigate the effect of castration on the sensory and instrumental qualities of the longisssimus dorsi muscle of Brahman. Fifty animals （25 Brahman castrated and 25 uncastrated） were fed with forage and finished with forage and a commercial feed. The sensory analysis was performed by a seven-member sensory panel that had been trained. The panel evaluated the juiciness, myofibril tenderness, overall tenderness, connective tissue amount and flavor intensity of each sample according to an 8-point scale. The steaks that were to be used in the instrumental analysis were frozen, thawed, and cooked just like those used in the sensory analysis test. In order to assess shear force, the steaks were cooled 2 h at room temperature. Each strip was sheared once with a Warner-Bratzler ceil, and an average shear force value was calculated and recorded for each steak. Water retention capacity was measured as weight loss during cooking. Steaks used for shear force analysis were weighted before and after cooking. Significant differences were observed （P 〈 0.05） among sensory attributes, shear force, and cooking loss values in the beef of castrated and uncastrated. Both the panel and the consumers were able to detect differences in sensory characteristics between castrated and uncastrated, with the ratings favoring the castrated. The Warner-Bratzler device was also able to detect differences in tenderness between both groups, with steer beef having lower shear force and cooking loss values.

Elucidation of the Probable Ovarian-Dependent Mechanism of the Estrogenic Effects of Buccholzia coriacea and Progesterone Effects of Cogniauxia pololeana in the Rat

The present study was carried out with the objective of evaluating, in castrated rats, the utero trophic, hormonal and biochemical activities of aqueous extracts of Buchholzia coriacea (BC) and Cogniauxia podolaena (CP) leaves. Each extract administered at the dose of 600 mg/Kg in castrated rats did not cause a significant change in the fresh weight/dry weight ratio of the uterus compared to castrated rats given distilled water. However, those receiving 17-β-estradiol as a reference product showed a significant (p < 0.5) increase in this ratio. These results indicate the absence of uterotrophic effects of both extracts in the ovariectomized rat compared with the effects of 17-β estradiol. In addition, the extracts did not cause significant changes in estrogen or progesterone levels in treated rats, as observed with 17-β-estradiol. In addition, the determination of protein and total cholesterol in the uterus of castrated rats treated with each extract did not show significant variation from controls. At the time, castrated rats treated with 17-β-estradiol showed a significant increase (p < 0.5) in uterine protein level and a significant decrease (p < 0.5) in total cholesterol level. Only the blood protein level was significantly increased in the castrated rats that received the extracts. These results suggest that the respective estrogenic and progesterone effects of the extracts of the two plants may be ovarian-dependent, these plants would not contain phytohormones.

Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 50α-reductase inhibitor

Aim： To investigate the relationship between low androgen level and ultrastructure of vascular endothelium. Methods： Forty-eight male Sprague-Dawley rats were randomly divided into four groups： group A, normal rats with sham castration; group B, castrated rats; group C, castrated rats given testosterone （T） undecanoate; and group D, intact rats treated with 5α-reductase inhibitor. After 10 weeks of treatment or castration, rats in different groups were killed and serum T, free T （FT） and dihydrotestosterone （DHT） were measured. The aortic endothelia were scanned under electron microcopy and the Vascular Endothelium Structure Score （VESS） was computed. Results： Serum T and FT concentrations of rats in group B were significantly lower than those of the other three groups （P 〈 0.01）; DHT concentrations of group D rats were significantly decreased （P 〈 0.01 ） when compared with those of groups A and C. Rats in groups B and D rats （with low androgen levels） had obvious damage to their endothelial surfaces, which appeared crimpled, rough, adhesive and ruptured, and had high destruction of VESS. Conclusion： These results suggest that low concentrations of T and DHT are associated with ultrastructural damage of the aortic endothelia in male rats.

Androgen and prostatic stroma

<abstract>Aim: To investigate the effect of androgen on the proliferation, differentiation and regression of canine prostatic stromal cells in vivo and human stromal cells in vitro. Methods: Twenty-two dogs, including 15 normal prostate dogs and 7 prostatic hyperplasia dogs, had their serum concentration of testosterone and estrodiol determined by radioimmunoassay before and after castration. The expression of androgen receptor (AR) and estrogen receptor (ER) in the prostate were analysed by immunohistochemistry and semi-quantitative RT-PCR before and after castration. Light microscopy, transmission electron microscopy and TUNEL assay were carried out successively before and after castration to evaluate the prostatic histomorphology. In vitro serum-free cell cultures from human prostatic stroma were established and exposed to dihydrotestosterone (DHT). The proliferation of the cell culture was detected by MTT assay. The expression of TGFβ, bFGF, AR, and smooth muscle cell (SMC) specific proteins (myosin and/or smoothelin) were detected using immunohistochemistry and RT-PCR. The differentiation from fibroblasts to smooth muscle cells was deduced by measuring the expression of SMC specific proteins. Results: Before castration, the serum concentrations of testosterone and estrodiol were not statistically different between normal and hyperplasia groups. Following castration, the serum concentration of testosterone decreased rapidly in 2 days, and the concentration of estrodiol had no significant change compared with the pre-castration data. In the prostate, AR was presented in both the epithelial and stromal cells and the AR mRNA level was higher in hyperplasia than in normal prostate tissues (P<0.05). While ER predominantly existed in the prostate stromal cells and the ER mRNA had no difference between the hyperplasia and the normal group. Within the early phase of castration (<d7), the expression of AR was increased rapidly. Then it gradually dropped to a lower level than that of the pre-castration by the end of d90. The expression of ER remained unchanged in the whole course. The prostatic stromal cells, including SMCs and fibroblasts, diminished and underwent serial pathological changes of atrophy and apoptosis after castration. The atrophic cells were filled with huge intracellular lipofuscin. The expression of SMC myosin declined after castration, coincident with the increase in TGFβ mRNA level and decline in bFGF mRNA level. In vitro, DHT caused a weak increase in the proliferation and expression of SMC-specific proteins (P<0.05). However, DHT and bFGF together stimulated the proliferation of stromal cells significantly more than either agent alone (P<0.01). The combination of DHT and TGFβ greatly enhanced the expression of SMC-specific proteins (P<0.01) more strongly than either alone (P<0.01). Conclusions: The whole prostate gland is an androgen-sensitive organ with both the epithelium and stroma under the control of androgen. Androgen may direct the proliferation, differentiation and regression of stromal cells by regulating the expression of TGFβ, bFGF, AR and smooth muscle cell specific proteins.

Efficacy of maximal androgen blockade versus castration alone in the treatment of advanced prostate cancer： a retrospective clinical experience from a Chinese medical centre

In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.

IL-6/IL-6R as a potential key signaling pathway in prostate cancer development

Interleukin-6(IL-6)is a pleiotropic cytokine involved in prostate regulation and in prostate cancer(PC)development/progression.IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells.The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression.Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients.In PC treatment,patients diagnosed with advanced stages are frequently submitted to hormonal castration,although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer(CRPC).Therefore,it is important to understand the mechanisms involved in CRPC.Several pathways have been proposed to be involved in CRPC development,and their understanding will improve the way to more effective therapies.In fact,the prostate is known to be dependent,not exclusively,on androgens,but also on growth factors and cytokines.The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression,under androgen deprivation conditions.The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway.Furthermore,we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions.The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.

Ailanthone:a new potential drug for castration-resistant prostate cancer

Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castrationresistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens [3]. Mechanisms of CRPC progression include AR amplification and overexpression [4], AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (ARVs) [4], and induction of intracrine androgen metabolic enzymes [3]. Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD [5]. These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis [6].

Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics

This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on our recent progress in the understanding of:1)The plasticity and dynamics of tumorestroma interaction;2)The significance of epigenetic reprogramming in conferring cancer growth,invasion and metastasis;3)New insights on altered junctional communication affecting PCa bone and brain metastases;4)Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy;5)Geneticbased therapy to co-target tumor and bone stroma;6)PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis;7)The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis;and 8)Characterization of imprinting cluster of microRNA,in tumorestroma interaction.This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation.This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications.We dedicate this article in our fond memory of Dr.Donald S.Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.

Effects of castration and testosterone replacement on veno-occlusion during penile erection in the rat

Aim: To determine if androgens directly regulate veno-occlusion or if androgens act indirectly to maintain the penilestructures which control outflow. Methods: Using CASTRATE and TESTO rats, measurement was made of meanarterial pressure (MAP), intracavernosal pressure (CCP), and intracavernosal flow (CCF) during erection resultingfrom stimulation of the autonomic innervation of the penis. CCP and CCF were also measured during saline infusioninto the cavernosal sinuses before and after treatment with sodium nitroprusside (SNP, a nitric oxide donor drag) tofully relax cavernosal smooth muscle. Penile tissue was also collected to measure the content of α actin and proline andhydroxyproline to determine if brief withdrawal of androgenic support led to changes in the number of smooth musclecells or the collagen content of the tissue. Results: Infusion of saline into the cavernosal sinuses demonstrated thatveno-occlusion was defective in CASTRATE rats while reno-occlusion was fully functional in TESTO animals.Furthermore, veno-occlusion could be induced in CASTRATE rats if they were first treated with SNP. Thisobservation suggests that failure of veno-occlusion in the CASTRATE rats is due to a deficiency in the production of NOresulting in a reduction in the degree of relaxation of the penile smooth muscle. The measurements of smooth muscleα actin and proline and hydroxyproline content of collagen showed that both were unaffected by castration and that thebasic structure of the penis did not degenerate after one week without androgenic support. Conclusion: Theseresults can be interpreted to mean that androgens control the veno-occlusive mechanism indirectly via a NO dependentmechanism and not by maintaining the structures of the penis which are essential to reno-occlusion.

Testosterone deficiency：a historical perspective

The biological effects of the testes and testosterone are known since antiquity. Aristotle knew the effects of castration and his hypothesis on fertilization is one of the first scientific encounters in reproductive biology. Over centuries, castration has been performed as punishment and to produce obedient slaves, but also to preserve the soprano voices of prepubertal boys. The Chinese imperial （and other oriental） courts employed castrates as overseers in harems who often obtained high-ranking political positions. The era of testis transplantation and organotherapy was initiated by John Hunter in London who transplanted testes into capons in 1786. The intention of his experiments was to prove the ＇vital principle＇ as the basis for modern transplantation medicine, but Hunter did not consider endocrine aspects. Arnold Adolph Berthold postulated internal secretion from his testicular transplantation experiments in 1849 in Gottingen and is thus considered the father of endocrinology. Following his observations, testicular preparations were used for therapy, popularized by self-experiments by Charles-Edouard Brown-Sequard in Paris （1889）, which can at best have placebo effects. In the 1920s Sergio Voronoff transplanted testes from animals to men, but their effectiveness was disproved. Today testicular transplantation is being refined by stem cell research and germ cell transplantation. Modern androgen therapy started in 1935 when Enrest Lacquer isolated testosterone from bull testes in Amsterdam. In the same year testosterone was chemically synthesized independently by Adolf Butenandt in G6ttingen and Leopold Ruzicka in Basel. Since testosterone was ineffective orally it was either compressed into subcutaneous pellets or was used orally as 17α-methyl testosterone, now obsolete because of liver toxicity. The early phases of testosterone treatment coincide with the first description of the most prominent syndromes of hypogonadism by Klinefelter, by Kallmann, DelCastillo and Pasqualini. In the 1950s longer-acting injectable testosterone enanthate became the preferred therapeutic modality. In the 1950s and 1960s, research concentrated on the chemical modification of androgens in order to emphasize their anabolic effects. Although anabolic steroids have largely disappeared from clinical medicine, they continue to live an illegal life for doping in athletics. In the 1970s the orally effective testosterone undecanoate was added to the spectrum of preparations. Recent transdermal gels and long-acting injectable preparations provide options for physiological testosterone substitution therapy.