Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation.

Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/ß-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/ß-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.

[on oligozoospermia and asthenospermia].

OBJECTIVE: To observe the clinical effect of Yihechun Capsules (YHC) on oligozoospermia and asthenospermia. METHODS: A total of 181 male patients with infertility were randomly divided into a YHC+Levocarnitine (LC) group (n = 93, including 42 cases of oligozoospermia, 20 cases of asthenospermia and 31 cases of oligoasthenospermia) and an LC control group (n = 88, including 39 cases of oligozoospermia, 22 cases of asthenospermia and 27 cases of oligoasthenospermia), the former treated with YHC (ï¼»0.3 g per capsuleï¼½, once 4 capsules, bid, 30 minutes after meal) combined with LC oral liquid (2－3 g/d, tid, at mealtime) and the latter with LC oral liquid only (2－3 g/d, tid, at mealtime). After 3 months of treatment, comparisons were made between the two groups of patients in sperm concentration, the percentages of grade a and grade a+b sperm, and the rate of pregnancy. RESULTS: Of the 181 patients, 5 in the YHC+LC group and 2 in the LC control group failed to complete the course of treatment. There were no statistically significant differences between the two groups of patients in the baseline sperm concentration and the percentages of grade a and grade a+b sperm (P > 0.05), wich were all markedly increased in both the YHC+LC and the LC control groups (P < 0.05) after 3 months of treatment. And the patients of the YHC+LC group, compared with the controls, showed even more significant increases, as the oligozoospermia patients in sperm concentration (ï¼»21.07 ± 6.98ï¼½ vs ï¼»16.56 ± 1.82ï¼½ ×106/ml, P < 0.05) and the percentages of grade a sperm (ï¼»27.53 ± 3.34ï¼½% vs ï¼»26.88 ± 1.35ï¼½%, P < 0.05) and grade a+b sperm (ï¼»53.32 ± 3.16ï¼½% vs ï¼»52.63 ± 2.48ï¼½%, P < 0.05), the asthenospermia patients in sperm concentration (ï¼»26.36 ± 3.37ï¼½ vs ï¼»24.42 ± 2.21ï¼½ ×106/ml, P < 0.05) and the percentages of grade a sperm (ï¼»25.28 ± 4.64ï¼½% vs ï¼»21.32 ± 3.28ï¼½%, P < 0.05) and grade a+b sperm (ï¼»49.19 ± 2.87ï¼½% vs ï¼»45.64 ± 1.78ï¼½%, P < 0.05), and the oligoasthenospermia patients in sperm concentration (ï¼»19.38 ± 3.39ï¼½ vs ï¼»18.75 ± 1.35ï¼½ ×106/ml, P < 0.05) and the percentages of grade a sperm (ï¼»22.65 ± 4.81ï¼½% vs ï¼»21.31 ± 2.42ï¼½%, P < 0.05) and grade a+b sperm (ï¼»48.74 ± 5.61ï¼½% vs ï¼»44.36 ± 1.32ï¼½%, P < 0.05). The pregnancy rate was dramatically higher in the YHC+LC than in the LC control group (36.4% ï¼»32/88ï¼½ vs 15.1% ï¼»13/86ï¼½, P < 0.01). CONCLUSIONS: Yihechun Capsules combined with Levocarnitine oral liquid is evidently effective for the treatment of oligozoospermia and asthenospermia.

Review of the Correlation of LAT1 With Diseases: Mechanism and Treatment.

LAT1 is a member of the system L transporter family. The main role of the LAT1 is to transport specific amino acids through cell membranes to provide nutrients to cells and participate in several metabolic pathways. It also contributes to the transport of hormones and some drugs, which are essential for the development and treatment of some diseases. In recent years, many studies have shown that LAT1 is related to cancer, obesity, diabetes, and other diseases. However, the specific mechanism underlying the influence of LAT1 on such conditions remains unclear. Through the increasing number of studies on LAT1, we have obtained a preliminary understanding on the function of LAT1 in diseases. These studies also provide a theoretical basis for finding treatments for LAT1-related diseases, such as cancer. This review summarizes the function and mechanism of LAT1 in different diseases and the treatment of LAT1-related diseases. It also provides support for the development of novel and reliable disease treatments.

Polycystic ovary syndrome and mitochondrial dysfunction.

Polycystic ovary syndrome (PCOS) is a prevalent hormonal disorder of premenopausal women worldwide and is characterized by reproductive, endocrine, and metabolic abnormalities. The clinical manifestations of PCOS include oligomenorrhea or amenorrhea, hyperandrogenism, ovarian polycystic changes, and infertility. Women with PCOS are at an increased risk of suffering from type 2 diabetes; me\tabolic syndrome; cardiovascular events, such as hypertension, dyslipidemia; gynecological diseases, including infertility, endometrial dysplasia, endometrial cancer, and ovarian malignant tumors; pregnancy complications, such as premature birth, low birthweight, and eclampsia; and emotional and mental disorders in the future. Although numerous studies have focused on PCOS, the underlying pathophysiological mechanisms of this disease remain unclear. Mitochondria play a key role in energy production, and mitochondrial dysfunction at the cellular level can affect systemic metabolic balance. The recent wide acceptance of functional mitochondrial disorders as a correlated factor of numerous diseases has led to the presupposition that abnormal mitochondrial metabolic markers are associated with PCOS. Studies conducted in the past few years have confirmed that increased oxidative stress is associated with the progression and related complications of PCOS and have proven the relationship between other mitochondrial dysfunctions and PCOS. Thus, this review aims to summarize and discuss previous and recent findings concerning the relationship between mitochondrial dysfunction and PCOS.

[Compound Amino Acid Capsules combined with clomiphene for severe oligospermia].

OBJECTIVE: To study the effect of Compound Amino Acid Capsules (CAAC) combined with clomiphene in the treatment of severe oligospermia. METHODS: A total of 104 patients with severe oligospermia admitted to our Center of Reproductive Medicine from January to September 2018 were randomly assigned to a trial (n = 60) and a control group (n = 44), the former treated by oral administration of CAAC combined with clomiphene and the latter with clomiphene only, both for 12 weeks. Comparisons were made between the two groups of patients in the sperm concentration, and the percentages of progressively motile sperm (PMS) and total motile sperm (TMS) before and after 4, 8 and 12 weeks of medication as well as the pregnancy rate during the treatment. RESULTS: Compared with the baseline, the trial group showed significant elevation at 4, 8 and 12 weeks in sperm concentration (ï¼»3.13 ± 1.29ï¼½ vs ï¼»12.06 ± 2.24ï¼½, ï¼»22.10 ± 2.65ï¼½ and ï¼»28.13 ± 3.59ï¼½ ×106/ml, P < 0.01), PMS (ï¼»14.03 ± 2.49ï¼½% vs ï¼»21.05 ± 3.14ï¼½%, ï¼»29.08 ± 4.70ï¼½% and ï¼»35.08 ± 3.70ï¼½%, P < 0.01) and TMS (ï¼»20.10 ± 4.05ï¼½% vs ï¼»27.10 + 4.87ï¼½%, ï¼»36.09 ± 5.64ï¼½% and ï¼»45.04 ± 6.69ï¼½%, P < 0.01), and so did the control group in sperm concentration (ï¼»3.27 ± 1.46ï¼½ vs ï¼»10.21 ± 2.35ï¼½, ï¼»19.89 ± 2.74ï¼½ and ï¼»25.23 ± 3.69ï¼½ ×106/ml, P < 0.01), PMS (ï¼»13.32 ± 3.12ï¼½% vs ï¼»17.02 ± 3.26ï¼½%, ï¼»22.13 ± 3.70ï¼½% and ï¼»27.18 ± 2.54ï¼½%, P < 0.01) and TMS (ï¼»21.30 ± 4.87ï¼½% vs ï¼»24.22 ± 5.07ï¼½%, ï¼»30.03 ± 5.33ï¼½% and ï¼»35.05 ± 5.69ï¼½%, P < 0.01), even more significant in the trial than in the control group at the three time points after medication (P < 0.01). The pregnancy rate was markedly higher in the former than in the latter group at 4 (1.72% vs 0.53%, P < 0.01), 8 (4.21% vs 2.87%, P < 0.01) and 12 weeks (8.32% vs 6.32%, P < 0.01). No adverse reactions were observed in neither of the two groups during the treatment. CONCLUSIONS: CAAC combined with clomiphene can significantly improve the semen parameters of the patients with severe oligospermia, with no obvious adverse events.