Deubiquitination complex platform: A plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes

Deubiquitinating enzymes (DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin‒proteasome degradation and are critical for regulating protein expression levels in vivo. Therefore, dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways. To data, extensive studies on the ubiquitin chain specificity of DUBs have been reported, but substrate protein recognition is still not clearly understood. As a breakthrough, the scaffolding role may be significant to substrate protein selectivity. From this perspective, we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity. Furthermore, we proposed a deubiquitination complex platform (DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples, which might fill the gaps in the understanding of DUB substrate specificity.

A Clinical Study to Evaluate Efficacy of KVGAP’S Femicare Syrup on Raktapradara w.s.r to Dysfunctional Uterine Bleeding

Dysfunctional uterine bleeding (Raktapradara) is the commonest gynaecological disorder affecting the quality women’s life of reproductive age group. A clinical study was conducted with KVGAP’S Femicare Syrup on 28 patients of DUB. KVGAP’S Femicare syrup is a polyherbal Ayurvedic formulation prepared from ingredients like Ashoka, Ashwagandha, Gokshura, Guduchi, Shatavari, Manjhistha, Usheera, Kumari, Sariva, Pippali, and Shilajathu. The parameters assessed were number of bleeding episodes, excessive bleeding, investigators global assessment scale, VAS for pain, participants overall assessment scale, clot and interval (number of days of the cycle). Patients were assessed at the beginning of the trail, after 1 month and after 2 months. 56.52%, 73.08%, 77.6%, 85%, 81.93%, 100% improvement were observed in the clinical parameters assessed (number of bleeding episodes, excessive bleeding, investigators global assessment scale, VAS for pain, participants overall assessment scale, clot) respectively. Results were statistically significant. Interval didn’t show any changes. Out of 28 patients in this study, 1 patient shown mild improvement, 11 patients (39%) were shown moderate improvement and 16 patients (57%) had marked improvement. Overall effect of the treatment was 77.31%. This study showed that KVGAP’S Femicare syrup showed promising results in treating DUB. Hence it can be concluded that KVGAP’S Femicare Syrup is effective and safe in the management of dysfunctional uterine bleeding.

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it, while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing

Deubiquitylases in Tumors / 中国生物化学与分子生物学报

Dynamic ubiquitination in eukaryotes either enters proteins into the 26S proteasome degradation pathway or functions in signal transduction, and therefore regulates protein stability, localization and activity, thus participates in transcription, cell cycle, inflammation, tumor, immunity and other functions.Ubiquitination modification is a reversible process, which is regulated by ubiquitin ligases (E3s) and deubiquitylases (I)lJBs).DUBs mediate the deubiquitination of substrate proteins, regulate protein functions, and participate in various cellular processes.The protein abundance, localization and catalytic activity of deubiquitylases are strictly regulated.During the occurrence and development of tumors, many important tumor-related proteins are regulated by deubiquitylases, and dysfunction of deubiquitylases also affect DNA damage repair, apoptosis, autophagy, molecular signaling pathways and chromatin remodeling, which modulate the process of cell growth, invasion and metastasis in tumors.Therefore, DUB is an important protein family involved in tumorigenesis, and is potential drug targets.Many small molecule inhibitors have been used in the research of anti-tumor treatments.This article mainly summarizes the regulation mechanism of ubiquitin molecules, ubiquitin chain specificity, and deubiquitinating enzyme system in tumors, and provides basis for the design of clinical drug targets and diagnostic indicators.

Evaluation of post partum intrauterine contraceptive device versus interval intrauterine contraceptive device insertion

Background: Family planning is important not only for population stabilization, but it has been increasingly recognized as central tool to improve maternal and neonatal health. Aim of current study was to compare interval and post partum intrauterine contraceptive device (IUCD) insertion in terms of effectiveness and safety.Methods: This was a prospective observational cohort study, done in the department of Obstetrics and Gynecology, GMERS Medical College, Sola, Ahmedabad, from August 2015 to April 2017 was taken for evaluation. 80 women in each group who were inserted IUCD after delivery and in the interval period were studied. Outcome was measured by expulsion rate, continuation rate, and incidence of dysfunctional uterine bleeding (DUB), Pelvic inflammatory disease (PID), failure rate and effect on puerperium.Results: Expulsion rate in PPIUCD group was 8.75% while in interval IUCD group it was 1.25%. Continuation rate following Postpartum intrauterine contraceptive device (PPIUCD) and interval IUCD insertion was 86.25% and 95% respectively. Incidence of bleeding per vaginum (menorrhagia) was 7.5% in PPIUCD group while 8.75% in interval IUCD group. There was one case 1.25% of PID in interval IUCD group while no case in PPIUCD was noted. Failure rate was nil in both the group. There was no effect on puerperium following PPIUCD insertion group during present study.Conclusions: PPIUCD is an effective and safe spacing method of contraception as compared to interval IUCD insertion. There is no statistically significant change in incidence of expulsion rate, continuation rate and other complications in both the group.

Histopathological Study Of Endometrial Lesions In Patients In A Tertiary Care Hospital In North Telangana

Introduction:Abnormal uterine bleeding (AUB) is considered one of the most common and challenging problems presenting to the gynecologist. Histopathological examination of endometrial biopsy is gold standard diagnostic tool in evaluation of AUB. Our study is aimed at determining the spectrum of endometrial pathologies in different age group patients presenting with AUB at our hospital which caters largely to women living in rural area. Materials & Methods : The present study is a retrospective and prospective study done for a period of one year in department of Pathology. All hysterectomy cases and endometrial biopsy cases were considered in the present study. Complete patient history, clinical and radiological findings were considered. Results: A total of 100 cases were included in our study and out of them the most common lesion was proliferative phase constituting upto 33 cases followed by secretory phase.The most common age group was in between 31-40 years. The most common complaint was abnormal uterine bleeding. Conclusion: Histopathological examination of endometrium is gold standard diagnostic tool in evaluation of AUB and there is an age specific association of endometrial lesions.

A comparative study on the effectiveness of ormeloxifene versus norethisterone in the management of perimenopausal dysfunctional uterine bleeding.

Background: Menstrual disorders are the second most common gynecological condition resulting in hospital referrals. Dysfunctional Uterine Bleeding is defined as abnormal uterine bleeding in the absence of organic disease. Menorrhagia (menstrual blood loss >80 ml per cycle) affects 10-33% of women at some stage in their lives. Approximately 90% of dysfunctional uterine bleeding result from anovulation and 10% occur with ovulatory cycles. Only half of women complaining of heavy menstrual bleeding fit the clinical criteria of more than 80 ml blood loss per cycle. Among women aged 30-49, one in 20 consults her general practitioner each year with menorrhagia . it can be managed both medically and surgically. Material and methods: Thirty women presenting with DUB were randomly allocated to 2 equal groups, Group-A, which received 60 mg ormeloxifene twice a week for 12 weeks and Group-B, which received 5 mg norethisteron twice daily for 21 days for 3 months. The primary outcome measures were reduction in menstrual blood loss which was measured by fall in PBAC (Pictorial Blood loss Assessment Chart) score, rise in hemoglobin level and reduction in endometrial thickness Results: The reduction in mean PBAC score with ormeloxifene (277.33 to 70.11) was significantly more than that seen with norethisterone (246 to 108.5) after 3 months of therapy (p<0.05). The increase in hemoglobin level and reduction in endometrial thickness were also found to be significantly more with ormeloxifene than norethisterone (9.68 g %to 11.07 g% vs. 10.17 g% to 10.58 g%, p<0.05, and 7.8 mm vs. 6.7 mm to 5.9 mm, p<0.05, respectively). No major side effects were reported in any group. Conclusion: Ormeloxifene was found to be more effective than norethisterone in reducing blood loss and reducing endometrial thickness

Experience With Uterine Balloon Therapy For Dysfunctional Uterine Bleeding.

Uterine balloon therapy is a minimally invasive technique for dysfunctional uterine bleeding done on day care basis. It can be offered as a treatment of option to women who have completed their family and have a diagnosis of dysfunctional uterine bleeding. The study was undertaken to analyse the success rate, complications of UBT and incidence of patients requiring alternative methods of treatment for DUB. Twenty four patients were treated with UBT (Thermachoice) for DUB. Efficacy of the procedure was analyzed at follow up periods of one, 3, 6 and 12 months. After undergoing UBT, at twelve months follow up, amenorrhea was achieved in 29.17% of patients, 33.33% were having oligomennorhea, 33.33% were eumenorrehic and no response was seen in 4.17% of patients. Our overall treatment success and patient satisfaction rate was 95.83%.Uterine balloon therapy is a safe, minimally invasive day care procedure requiring no extra expertise for the treatment of DUB in patients who want to save uterus with instant results. Post procedure there is improved patient well being and high treatment satisfaction.

Vaginal Removal of Non Prolapsed Uterus with Benign Pathology.

Vaginal hysterectomy was the first minimally invasive surgical approach for benign gynecologic conditions, a number of other approaches for hysterectomy have been introduced, yet when compared with vaginal hysterectomy these approaches do not offer significant benefits for similar indications. Objectives : (1) To know the benign gynecological conditions that can be treated by vaginal hysterectomy. (2) To find out the operative difficulties of vaginal hysterectomy done in non-prolapsed uterus. (3) To know the morbidity and mortality of vaginal hysterectomy. Methodology : This is a prospective study conducted at our Hospital from 1st December 2010 to 30th Nov. 2011. Hundred consecutive cases of non-descent vaginal hysterectomy for benign pathology of uterus were studied. Results : In our study maximum hysterectomies were done in the age group 41-50 (49%) followed by 31- 40 (40%) least were in age more than 50 years. Mean parity of the cases undergoing hysterectomy were 2.47. In 77% patients, complaints were menorrhagia. The maximum hysterectomies, 41% for fibroid uterus were done, followed by 39% for DUB. One patient had intraoperative bladder injury. Mean operating time for the hysterectomies was 53.21 minutes. No mortality was seen, 12% post-operative complications were present. The mean post-operative stay in the hospital was 5.95 days. Conclusion : Vaginal hysterectomy is both feasible and optimal for many patients who long have been considered inappropriate candidates for vaginal hysterectomy. Many more hysterectomies should be carried out vaginally without resorting to abdominal or laparoscopic approach for benign conditions of the uterus.

The Key and Analyzing of DUB by Traditional and Western Medicine / 中国中医药信息杂志

Objective To explore the key way of DUB (dysfunctional uterine bleeding) by traditional and western medicine. Method Analyse the traditional medicine's unique understanding of DUB, the symptoms of DUB and the function of Chinese traditional medicine on DUB. And sum up the modern molecular pathology of DUB. Result Chinese traditional medicine has some regulations in curing DUB. And given the modern molecular biology technique, it maybe play an important part in researching the essential of the syndrome of DUB and the function regulation of Chinese traditional medicine. Conclusion DUB, which is an important disease that is in the person of “menstruation adjustment”, “blooding disease”in traditional Chinese gynecology, must be studied systematically first, so as to improve the combination of traditional medicine and western medicine in gynecology.

A Clinical and Pathological Study of Dysfunctional Uterine Bleeding / 대한산부인과학회잡지

OBJECTIVES: Dysfunctional uterine bleeding(DUB) is defined as abnormal bleeding from the uterine endometrium unrelated to anatomic lesions of the uterus, and its incidence is 10-15% among gynecologic diseases. We conducted this study for understanding correlation between clinical aspecets and pathological findings of DUB. Methods: We conducted a retrospective review of 599 women with DUB who underwent endometrial biopsy with special regard to the relation between pathologic findings and presenting symtoms or complaints from Jan. 1988 to Dec. 1997. RESULTS: Age distribution of DUB was mainly 5th decade, mean age was 44.1years, among various bleeding patterns, intermenstrual bleeding was the most common pattern(31.6%) and the next was menorrhagia(25.0%). Histologic findings of endometrium were proliferative phase, 327 cases(54.6%), hyperplasia, 139 cases(23.2%), secretory phase, 74 cases(12.4%) in order of frequency, and there was no difference in distribution of histologic findings among various bleeding patterns. CONCLUSION: Compared to other previoius studies, our study showed more incidence of endometrial hyperplasia, especially at age group of 40 or more. So patients aged more than this age with abnormal uterine bleeding must undergo emdometrial biopsy for pathologic diagnosis. Patients who are diagnosed endometrial hyperplasia must be carefully followed up because there are possibilities of progression to endometrial carcinoma.