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The antiapoptotic BAG3 protein plays a crucial role in cellular proteostasis and it is involved in several signalling pathways governing cell proliferation and survival. Owing to its multimodular structure, it possesses an extensive interactome including the molecular chaperone HSP70 and other specific cellular partners, which make it an eminent factor in several pathologies, particularly in cancer. Despite its potential as a therapeutic target, very few BAG3 modulators have been disclosed so far. Here we describe the identification of a promising BAG3 modulator able to bind the BAG domain of the protein featuring an imidazopyridine scaffold and obtained through the application of the Groebke-Blackburn-Bienaymé chemical synthesis procedure. The disclosed compound 10 showed a relevant cytotoxic activity, and in line with the biological profile of BAG3 disruption, it induced the activation of caspase 3 and 9.

Objective: This study aimed to evaluate the efficacy of a new biomarker, termed SIR-En, in identifying patients at risk of endometrial carcinoma among those presenting with abnormal uterine bleeding during menopause., Material and Methods: A retrospective case-control analysis was conducted on 242 women with menopausal abnormal uterine bleeding and endometrial thickness ≥ 4 mm. Peripheral blood samples were collected within 7 days before histological diagnosis. systemic inflammatory reaction (SIR) indices were calculated, including NLR, MLR, PLR, and SII. SIR-En was derived by multiplying SII and endometrial thickness. Statistical analyses, including multivariate linear regression and ROC curve analysis, were performed to assess the diagnostic capability of SIR-En., Results: Patients were categorized into endometrial hyperplasia (50 patients) and endometrial cancer (192 patients) groups. The SIR-En index was significantly higher in the carcinoma group (8710 vs. 6420; p = 0.003). The ROC curve for SIR-En had an AUC of 0.6351 (95% CI: 0.5579-0.7121). Using Youden's method, the optimal SIR-En cutoff was 13,806, showing a specificity of 0.940 and a positive predictive value of 0.957., Conclusions: Combining systemic inflammatory indices with endometrial thickness, the SIR-En index can effectively distinguish between endometrial hyperplasia and carcinoma in menopausal women with abnormal uterine bleeding. Despite the retrospective design, the identified cutoff's high specificity and positive predictive value support its potential utility in clinical practice. Further prospective studies are required to validate these findings and optimize clinical application.

The common bean ( Phaseolus vulgaris L.) is one of the oldest food crops in the world. In this study, the ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-MS/MS) technique was used to characterize the polar lipid composition and polyphenolic fraction of five bean varieties commonly consumed in Italy: Cannellino (PVCA), Controne (PVCO), Borlotti (PVBO), Stregoni (PVST), and Vellutina (PVVE). Lipid content represents a minor fraction of the whole metabolome in dry beans, and little is known about their polar lipids, which could be potentially bioactive components. Thirty-three compounds were detected through UHPLC-MS/MS, including oxylipins, phospholipids, N-acyl glycerolipids, and several fatty acids. The dichloromethane extracts were subjected to principal component analysis (PCA), with the results showing greater differentiation for the Borlotti variety. Moreover, 27 components belonging to different polyphenol classes, such as phenolic acids, flavonoids, catechins, anthocyanins and their glycosides, and some saponins, were identified in the hydroalcoholic seed extracts. In addition, the mineral content of the beans was determined. Considering the high number of compounds in the five apolar seed extracts, all samples were examined to determine their in vitro inhibitory activity against the enzyme cyclooxygenase-2 (COX-2), which is inducible in inflammatory cells and mediates inflammatory responses. Only PVCO showed the best inhibition of the COX-2 enzyme with an IC 50 = 31.15 ± 2.16 µg/mL. In light of these results, the potential anti-inflammatory properties of PVCO were evaluated in the LPS-stimulated murine macrophage cell line J774A.1. Herein, we demonstrate, for the first time, that PVCO at 30 µg/mL can significantly reduce the release of TNF-α, with a less significant anti-inflammatory effect being observed in terms of IL-6 release.

A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays. Compounds 2 , 5 , and 6 showed high affinity for BRD4, with IC 50 values of 0.60 ± 0.25 µM, 3.46 ± 1.22 µM, and 4.66 ± 0.52 µM, respectively. Additionally, these compounds were tested against two other bromodomains, BRD3 and BRD9, and two of them showed high selectivity for BRD4. The reported 3D structure-based pharmacophore model proves to be a straightforward and useful tool for selecting novel BRD4 ligands.

This research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of Myrianthus arboreus and from Oenothera maritima Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid. This result, confirmed by comparison with the natural ursolic acid, was thoroughly investigated and validated in silico by molecular docking, which gave a precise picture of the interactions in the MA/FAS complex. Moreover, biological assays showcased the inhibitory activity of myrianthic acid against the FAS enzyme, most likely related to its antiproliferative activity towards tumor cells. Given the significance of FAS in specific pathologies, especially cancer, the myrianthic acid structural moieties could serve as a promising reference point to start the potential development of innovative approaches in therapy.

Vulvar carcinoma is a rare cancer affecting the genital tract, constituting 4% of gynecological tumors. Vulvar squamous cell carcinoma (VSCC) is the most common type. Diagnosis relies on biopsy during vulvoscopy, plus imaging such as ultrasonography (USG), magnetic resonance imaging (MRI) and positron emission tomography (PET). This review aims to lay out a thorough overview as to the current preoperative management of VSCC, both in case of vulvar and lymph node involvement. The data research was conducted using the following databases: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library from 2010 to 2024. The selection criteria included only original articles. Seventeen studies were assessed for eligibility. A concordance rate of 62.3% for vHSIL and 65.2% for carcinoma at vulvoscopy, with a sensitivity of 98%, specificity of 40%, PPV (Positive Predictive Value) of 37% and NPV (Negative Predictive Value) of 98% in identifying malignant lesions was found. Regarding the reliability of PET for staging and assessing lymph node involvement, a mean SUV (Standardized Uptake Value) for malignant vulvar lesions of 8.4 (range 2.5-14.7) was reported. In the case of MRI, useful for the evaluation of loco-regional infiltration and lymph node involvement, the ratio of the short-to-long-axis diameter and the reader's diagnostic confidence for the presence of lymph node metastasis yielded accuracy of 84.8% and 86.9%, sensitivity of 86.7% and 87.5%, specificity of 81.3% and 86.2%, PPV of 89.7% and 87.5% and NPV of 76.5% and 86.2%, respectively. A long lymph node axis >10 mm and a short diameter >5.8 mm were found to be predictors of malignancy. At USG, instead, the two main characteristics of potentially malignant lymph nodes are cortical thickness and short axis length; the combination of these ultrasound parameters yielded the highest accuracy in distinguishing between negative and positive lymph nodes. Despite the heterogeneity of the included studies and the lack of randomized clinical trials, this review provides a broad overview of the three imaging tools used for the presurgical management of VSCC. Nowadays, although MRI and PET represent the gold standard, ultrasound evaluation is taking on a growing role, as long as it is carried out by expert sonographer. The management of this rare disease should be always performed by a multidisciplinary team in order to precisely stage the tumor and determine the most suitable treatment approach.

The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure-activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs) are rare uterine mesenchymal neoplasms with uncertain biological potential. These tumors, which affect both premenopausal and postmenopausal women, usually have a benign clinical course. Nevertheless, local recurrences and distant metastases have been described. By analyzing 511 cases retrieved from individual reports and cases series, we provide here the most comprehensive overview of UTROSCT cases available in the literature, supplemented by two new cases of UTROSCTs. Case 1 was an asymptomatic 31-year-old woman who underwent a laparoscopic resection of a presumed leiomyoma. Case 2 was a 58-year-old postmenopausal woman with abnormal vaginal bleeding who underwent an outpatient hysteroscopic biopsy of a suspicious endometrial area. In both cases, immunohistochemical positivity for Calretinin and Inhibin was noted, typical for a sex cord differentiation. In both cases, total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed. In light of the available literature, no pathognomonic clinical or imaging finding can be attributed to UTROSCT. Patients usually present with abnormal uterine bleeding or pelvic discomfort, but 20% of them are asymptomatic. In most cases, a simple hysterectomy appears to be the appropriate treatment, but for women who wish to become pregnant, uterus-preserving approaches should be discussed after excluding risk factors. Age, tumor size, lymphovascular space invasion, nuclear atypia, and cervical involvement are not reliable prognostic factors in UTROSCT. The current research suggests that aggressive cases (with extrauterine spread or recurrence) can be identified based on a distinct genetic and immunohistochemical phenotype. For instance, UTROSCTs characterized by GREB1::NCOA1-3 fusions and PD-L1 molecule expression appear to be predisposed to more aggressive behaviors and recurrence, with GREB1::NCOA2 being the most common gene fusion in recurrent tumors. Hence, redefining the criteria for UTROSCTs may allow a better selection of women suitable for fertility-sparing treatments or requiring more aggressive treatments in the future.

Mass spectrometry-based chemical proteomic approaches using limited proteolysis have become a powerful tool for the identification and analysis of the interactions between a small molecule (SM) and its protein target(s). Gracilioether A (GeA) is a polyketide isolated from a marine sponge, for which we aimed to trace the interactome using this strategy. DARTS (Drug Affinity Responsive Target Stability) and t-LiP-MS (targeted-Limited Proteolysis-Mass Spectrometry) represented the main techniques used in this study. DARTS was applied on HeLa cell lysate for the identification of the GeA target proteins, and t-LiP-MS was employed to investigate the protein's regions involved in the binding with GeA. The results were complemented through the use of binding studies using Surface Plasmon Resonance (SPR) and in silico molecular docking experiments. Ubiquitin carboxyl-terminal hydrolase 5 (USP5) was identified as a promising target of GeA, and the interaction profile of the USP5-GeA complex was explained. USP5 is an enzyme involved in the pathway of protein metabolism through the disassembly of the polyubiquitin chains on degraded proteins into ubiquitin monomers. This activity is connected to different cellular functions concerning the maintenance of chromatin structure and receptors and the degradation of abnormal proteins and cancerogenic progression. On this basis, this structural information opens the way to following studies focused on the definition of the biological potential of Gracilioether A and the rational development of novel USP5 inhibitors based on a new structural skeleton., Competing Interests: The authors declare no conflicts of interest.

Ferroptosis, an iron-dependent form of cell death, and dysregulated microRNA (miRNA) expression correlate with colorectal cancer (CRC) development and progression. The tumor suppressor ability of miR-148a-3p has been reported for several cancers. Nevertheless, the role of miR-148a-3p in CRC remains largely undetermined. Here, we aim at investigating the molecular mechanisms and regulatory targets of miR-148a-3p in the CRC cell death mechanism(s). To this end, miR-148a-3p expression was evaluated in SW480 and SW620 cells and normal colon epithelial CCD 841 CoN cells with quantitative real-time polymerase chain reaction (qRT-PCR). Data reported a reduction of miR-148a-3p expression in SW480 and SW620 cells compared to non-tumor cells ( p < 0.05). Overexpression of miR-148a selectively inhibited CRC cell viability ( p < 0.001), while weakly affecting normal CCD 841 CoN cell survival ( p < 0.05). At the cellular level, miR-148a-3p mimics promoted apoptotic cell death via caspase-3 activation ( p < 0.001), accumulation of mitochondrial reactive oxygen species (ROS) ( p < 0.001), and membrane depolarization ( p < 0.001). Moreover, miR-148a-3p overexpression induced lipid peroxidation ( p < 0.01), GPX4 downregulation ( p < 0.01), and ferroptosis ( p < 0.01), as revealed by intracellular and mitochondrial iron accumulation and ACSL4/TFRC/Ferritin modulation. In addition, levels of SLC7A11 mRNA and protein, the cellular targets of miR-148a-3p predicted by bioinformatic tools, were suppressed by miR-148a-3p's overexpression. On the contrary, the downregulation of miR-148a-3p boosted SLC7A11 gene expression and suppressed ferroptosis. Together, these in vitro findings reveal that miR-148a-3p can function as a tumor suppressor in CRC by targeting SLC7A11 and activating ferroptosis, opening new perspectives for the rationale of therapeutic strategies through targeting the miR-148a-3p/SLC7A11 pathway.

Canine mammary tumours (CMTs) are the most common cancer in intact female dogs. In addition to surgery, additional targeted and non-targeted therapies may offer survival benefits to these patients. Therefore, exploring new treatments for CMT is a promising area in veterinary oncology. CMT cells have an altered lipid metabolism and use the oxidation of fatty acids for their energy needs. Here we investigated the tumoricidal effects of teglicar, a reversible inhibitor of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid import into mitochondria, on two CMT cells, P114 and CMT-U229. Viability and apoptosis were examined in CMT cells using the crystal violet assay, trypan blue assay, and flow cytometry analysis. The expression of mediators of apoptosis signalling (e.g., caspase-9, caspase-8, and caspase-3) was assessed by quantitative real-time polymerase chain reaction and western blot analyses. Teglicar was able to decrease cell viability and induce apoptosis in P114 and CMT-U229 cells. At the molecular level, the effect of teglicar was associated with an upregulation of the mRNA expression levels of caspase-9 , caspase-8, and caspase-3 and an increase in their protein levels. In summary, our results show that teglicar has a potential effect against CMTs through the induction of apoptotic cell death, making it a promising therapeutic agent against CMTs.

Testicular ultrasonography and steroid concentrations (cortisol, dehydroepiandrosterone sulfate (DHEA-S), cortisol/DHEA-S ratio, testosterone) in hair were examined for their utility in the bull breeding soundness evaluation (BBSE). Beef and dairy bulls ( n = 16; 2.7 ± 0.4 years old; body condition score 3.2 ± 0.1) of five breeds were maintained under the same conditions at an accredited semen collection center. Bulls underwent routine semen collection twice weekly for 12 weeks and semen was processed and cryopreserved. Ultrasonography and hair sampling were undertaken at the last semen collection. Bulls with homogeneous testicular parenchyma ( n = 8) had a higher ( p < 0.05) percentage of motile sperm post-thawing compared with bulls with heterogeneous parenchyma ( n = 8). There were no differences ( p > 0.05) in the hair concentrations of cortisol, DHEA-S, and testosterone between bulls with homogeneous and heterogeneous parenchyma. In bulls with homogeneous parenchyma, hair DHEA-S concentration was positively correlated with percentage motile sperm (R 2 = 0.76), progressively motile sperm (R 2 = 0.70), and motility yield (R 2 = 0.71). The findings indicate that the integration of testicular ultrasonography and hair DHEA-S status in the BBSE could provide a more comprehensive assessment of indicative fertility in bulls. Additionally, ultrasonography can be used in the BBSE when the evaluation of semen parameters is not available.

Hereditary women's syndromes due to inherited mutations result in an elevated risk of developing gynecological cancers over the lifetime of affected carriers. The BRCA 1 and 2 mutations, Lynch syndrome (LS), and mutations in rare hereditary syndromes increase this risk and require more effective management of these patients based on surveillance and prophylactic surgery. Patients need counseling regarding risk-reducing surgery (RRS) and the time required to perform it, considering the adverse effects of premenopausal surgery and the hormonal effect on quality of life, bone density, sexual activity, and cardiological and vascular diseases. Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard for BRCA-mutated patients. An open question is that of endometrial cancer (EC) risk in patients with BRCA1/2 mutation to justify prophylactic hysterectomy during RRSO surgical procedures. RRS provides a 90-95% risk reduction for ovarian and breast cancer in women who are mutation carriers, but the role of prophylactic hysterectomy is underinvestigated in this setting of patients. In this review, we evaluate the management of the most common hereditary syndromes and the benefits of risk-reducing surgery, particularly exploring the role of prophylactic hysterectomy., Competing Interests: The authors declare no conflicts of interest.

Despite wide screening campaigns and early detection, cervical cancer remains the fourth most common cancer among women. Radical hysterectomy, whether by open, laparoscopic or by robotic-assisted techniques, is the mainstay treatment. However, for adequate surgical results and good oncological prognosis, a gynecological surgeon should be trained to perform those procedures. The learning curve of radical hysterectomy, especially by laparoscopy, is influenced by several factors. The LACC trial, the decrease in cervical cancer incidence and radical hysterectomy procedures have widely reduced the learning curve for surgeons. This article mainly discusses the learning curve of laparoscopic radical hysterectomy for cervical cancers, and how several factors are influencing it negatively, with the need to have medical authorities reset specific surgical training programs and allocate them to special oncological centers.

Background and Objectives: The standard treatment approach in locally advanced cervical cancer (LACC) is exclusive concurrent chemoradiation therapy (RTCT). The risk of local residual disease after six months from RTCT is about 20-30%. It is directly related to relapse risk and poor survival, such as in patients with recurrent cervical cancer. This systematic review aims to describe studies investigating salvage surgery's role in persistent/recurrent disease in LACC patients who underwent definitive RTCT. Materials and Methods: Studies were eligible for inclusion when patients had LACC with radiologically suspected or histologically confirmed residual disease after definitive RTCT, diagnosed with post-treatment radiological workup or biopsy. Information on complications after salvage surgery and survival outcomes had to be reported. The methodological quality of the articles was independently assessed by two researchers with the Newcastle-Ottawa scale. Following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we systematically searched the PubMed, Scopus, Cochrane, Medline, and Medscape databases in May 2022. We applied no language or geographical restrictions but considered only English studies. We included studies containing data about postoperative complications and survival outcomes. Results: Eleven studies fulfilled the inclusion criteria and all were retrospective observational studies. A total of 601 patients were analyzed concerning the salvage surgery in LACC patients for persistent/recurrent disease after RTCT treatment. Overall, 369 (61.4%) and 232 (38.6%) patients underwent a salvage hysterectomy (extrafascial or radical) and pelvic exenteration (anterior, posterior, or total), respectively. Four hundred and thirty-nine (73%) patients had histologically confirmed the residual disease in the salvage surgical specimen, and 109 patients had positive margins (overall range 0-43% of the patients). The risk of severe (grade ≥ 3) postoperative complications after salvage surgery is 29.8% (range 5-57.5%). After a median follow-up of 38 months, the overall RR was about 32% with an overall death rate of 40% after hysterectomy or pelvic exenteration with or without lymphadenectomy. Conclusions: There is heterogeneity between the studies both in their design and results, therefore the effect of salvage surgery on survival and recurrence cannot be adequately estimated. Future homogeneous studies with an appropriately selected population are needed to analyze the safety and efficacy of salvage hysterectomy or pelvic exenteration in patients with residual tumors after definitive RTCT.

Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor ( 8 ), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC 50 from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC 50 from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC 50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments.

Primiparous buffaloes were tested in two periods of the year characterized, by either low or high reproductive efficiency. They were subjected to two protocols for synchronization of ovulation: (i) Ovsynch (OV) and (ii) progesterone based (P 4 ) treatment. After calving, the animals underwent a series of four cycles of re-synchronization protocols. The season did not affect pregnancy rates when the results of the two treatments were pooled together with regard to the first synchronization protocol, followed by AI. Pregnancy rates were similar during the low breeding season (50.3% vs. 57.4% in OV and P 4 , respectively), but different during the high breeding season (50.4% vs. 67.7% in OV and P 4 , respectively; p = 0.000). Logistic regression confirmed a significant effect of treatment and season interaction on pregnancy ( p = 0.003). Following re-synchronization, a treatment by season interaction was detected during the low breeding season (odds ratio = 2.233), in favor of P 4 . Finally, a survival analysis showed a better response of animals subjected to P 4 treatment from the second AI onward. In conclusion, the pooled data of pregnancy rates from both treatments between seasons are not different following AIs. Better results, though, were obtained from the implementation of P 4 treatment, and are recorded in a season-fashioned mode when the comparison is made following first or cumulative AIs.

In the present study, we aimed at assessing the influence of breed and feeding system on the bovine milk profile of betaines and carnitines and milk capacity in counteracting the inflammatory endothelial cell (EC) damage induced by interleukin (IL)-6. In the first experimental design, two breeds were chosen (Holstein vs. Modicana) to investigate the biomolecule content and antioxidant capacity in milk and dairy products. In the second experimental design, two feeding systems (pasture vs. total mixed ratio) were tested only in Holstein to evaluate the possible effect on the functional profile of milk and dairy products. Finally, the bulk milk from the two experimental designs was used to evaluate the efficacy of preventing IL-6-induced endothelial inflammatory damage. Results showed that Modicana milk and whey had higher biomolecule content and antioxidant activity compared to Holstein milk (p < 0.01). Milk from Holstein fed TMR showed higher concentration of γ-butyrobetaine, δ-valerobetaine (p < 0.01), and l-carnitine (p < 0.05). Similarly, whey from Holstein fed TMR also showed higher content of δ-valerobetaine, glycine betaine, l-carnitine, and acetyl-l-carnitine (p < 0.01) compared to the Holstein fed pasture. Conversely, the antioxidant activity of milk and dairy products was not affected by the feeding system. In ECs, all milk samples reduced the IL-6-induced cytokine release, as well as the accumulation of reactive oxygen species (ROS) and the induction of cell death, with the most robust effect elicited by Modicana milk (p < 0.01). Overall, Modicana milk showed a higher content of biomolecules and antioxidant activity compared to Holstein, suggesting that the breed, more than the feeding system, can positively affect the health-promoting profile of dairy cattle milk.

Background and Objectives: Uterine sarcomas represents only 3% of all the female genital tract ones. The tumoral stage is the most significant prognostic factor. The role of the bilateral salpingo-oophorectomy (BSO) in the surgical management of FIGO stage IA and IB appears still controversial. This review aims to investigate the impact of bilateral adnexectomy in the treatment of uterine sarcoma. Methods: Following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we systematically searched the PubMed, Scopus, Cochrane, Medline, and Medscape databases in February 2022. We applied no language or geographical restrictions, but we considered only English studies. We included the studies containing data about Recurrence Rate (RR), Disease-free Survival (DFS), and Overall Survival (OS). We used comparative studies for meta-analysis. Results: Seventeen studies fulfilled the inclusion criteria; 2 retrospective observational studies, and 15 retrospective comparative studies, And 14 out of the 15 comparative studies were enrolled in meta-analysis. A total of 3743 patients were analyzed concerning the use of adnexectomy with hysterectomy in patients with uterine sarcoma and compared with those who did not. Meta-analysis highlighted a non-significant worsening of the OS in the BSO group compared to the OP group and showed that adnexectomy does not improve the DFS (BSO OR 1.23 (95% CI 0.81-1.85) p = 0.34; I 2 = 24% p = 0.22). Conclusions: Most studies selected for our review showed that adnexectomy does not significantly affect the RR, OS, and PFS in treating FIGO stage I uterine sarcomas. Therefore, even if there is a unanimous consensus about bilateral adnexectomy in menopausal patients, preservation of ovarian tissue may be considered in premenopausal women. Nonetheless, there are not enough cases in the literature to recommend this procedure.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The complex metabolic dysregulation at the base of this syndrome often renders infertility management challenging. Many pharmacological strategies have been applied for the induction of ovulation with a non-negligible rate of severe complications such as ovarian hyperstimulation syndrome and multiple pregnancies. Ovarian drilling (OD) is currently being adopted as a second-line treatment, to be performed in case of medical therapy. Laparoscopic ovarian drilling (LOD), the contemporary version of ovarian wedge resection, is considered effective for gonadotropins in terms of live birth rates, but without the risks of iatrogenic complications in gonadotropin therapy. Its endocrinal effects are longer lasting and, after the accomplishment of this procedure, ovarian responsiveness to successive ovulation induction agents is enhanced. Traditional LOD, however, is burdened by the potential risks of iatrogenic adhesions and decreased ovarian reserve and, therefore, should only be considered in selected cases. To overcome these limits, novel tailored and mini-invasive approaches, which are still waiting for wide acceptance, have been introduced, although their role is still not well-clarified and none of them have provided enough evidence in terms of efficacy and safety.

The development of new bioactive compounds represents one of the main purposes of the drug discovery process. Various tools can be employed to identify new drug candidates against pharmacologically relevant biological targets, and the search for new approaches and methodologies often represents a critical issue. In this context, in silico drug repositioning procedures are required even more in order to re-evaluate compounds that already showed poor biological results against a specific biological target. 3D structure-based pharmacophoric models, usually built for specific targets to accelerate the identification of new promising compounds, can be employed for drug repositioning campaigns as well. In this work, an in-house library of 190 synthesized compounds was re-evaluated using a 3D structure-based pharmacophoric model developed on soluble epoxide hydrolase (sEH). Among the analyzed compounds, a small set of quinazolinedione-based molecules, originally selected from a virtual combinatorial library and showing poor results when preliminarily investigated against heat shock protein 90 (Hsp90), was successfully repositioned against sEH, accounting the related built 3D structure-based pharmacophoric model. The promising results here obtained highlight the reliability of this computational workflow for accelerating the drug discovery/repositioning processes.

The multidomain BAG3 protein is a member of the BAG (Bcl-2-associated athanogene) family of co-chaperones, involved in a wide range of protein-protein interactions crucial for many key cellular pathways, including autophagy, cytoskeletal dynamics, and apoptosis. Basal expression of BAG3 is elevated in several tumor cell lines, where it promotes cell survival signaling and apoptosis resistance through the interaction with many protein partners. In addition, its role as a key player of several hallmarks of cancer, such as metastasis, angiogenesis, autophagy activation, and apoptosis inhibition, has been established. Due to its involvement in malignant transformation, BAG3 has emerged as a potential and effective biological target to control multiple cancer-related signaling pathways. Recently, by using a multidisciplinary approach we reported the first synthetic BAG3 modulator interfering with its BAG domain (BD), based on a 2,4-thiazolidinedione scaffold and endowed with significant anti-proliferative activity. Here, a further in silico-driven selection of a 2,4-thiazolidinedione-based compound was performed. Thanks to a straightforward synthesis, relevant binding affinity for the BAG3BD domain, and attractive biological activities, this novel generation of compounds is of great interest for the development of further BAG3 binders, as well as for the elucidation of the biological roles of this protein in tumors. Specifically, we found compound 6 as a new BAG3 modulator with a relevant antiproliferative effect on two different cancer cell lines (IC 50 : A375 = 19.36 μM; HeLa = 18.67 μM).

Tanshinone IIA (TIIA) and cryptotanshinone (CRY) from Salvia miltiorrhiza Bunge were investigated for their inhibitory activity against the cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1)/endothelial prostaglandin 3 (EP3) pathway using in silico, in vitro, in vivo, and ex vivo assays. From the analysis of the docking poses, both diterpenoids were able to interact significantly with COX-2, 5-lipoxygenase (5-LO), platelet-activating factor receptor (PAFR), and mPGES-1. This evidence was further corroborated by data obtained from a cell-free assay, where CRY displayed a significant inhibitory potency against mPGES-1 (IC 50 = 1.9 ± 0.4 µM) and 5-LO (IC 50 = 7.1 µM), while TIIA showed no relevant inhibition of these targets. This was consistent with their activity to increase mice bleeding time (CRY: 2.44 ± 0.13 min, p ≤ 0.001; TIIA: 2.07 ± 0.17 min p ≤ 0.01) and with the capability to modulate mouse clot retraction (CRY: 0.048 ± 0.011 g, p ≤ 0.01; TIIA: 0.068 ± 0.009 g, p ≤ 0.05). For the first time, our results show that TIIA and, in particular, CRY are able to interact significantly with the key proteins involved not only in the onset of inflammation but also in platelet activity (and hyper-reactivity). Future preclinical and clinical investigations, together with this evidence, could provide the scientific basis to consider these compounds as an alternative therapeutic approach for thrombotic- and thromboembolic-based diseases.

The estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics-driven exhaustive analysis to guide the identification of potential novel ligands. Starting from eight crystal structures of this protein co-complexed with known binders and one apo form, we conducted an exhaustive molecular docking/molecular dynamics (MD) investigation. To balance accuracy and an affordable calculation time, the systems were simulated for 100 ns in explicit solvent. Moreover, one complex was simulated for 1 µs to assess the influence of simulation time on the results. A set of MD-derived parameters was computed and compared with molecular docking-derived and experimental data. MM-GBSA and the per-residue interaction energy emerged as the main indicators for the good interaction between the specific binder and the protein counterpart. To assess the performance of the proposed analysis workflow, we tested six molecules featuring different binding affinities for BRD9, obtaining promising outcomes. Further insights were reported to highlight the influence of the starting structure on the molecular dynamics simulations evolution. The data confirmed that a ranking of BRD9 binders using key parameters arising from molecular dynamics is advisable to discard poor ligands before moving on with the synthesis and the biological tests.

Natural products have been the main source of bioactive molecules for centuries. We tested the biological profile of two metabolites extracted from Gentiana lutea L. by means of computational techniques and in vitro assays. The two molecules (loganic acid and gentiopicroside) were tested in silico using an innovative technique, named Inverse Virtual Screening (IVS), to highlight putative partners among a panel of proteins involved in inflammation and cancer events. A positive binding with cyclooxygenase-2 (COX-2), alpha-1-antichymotrypsin, and alpha-1-acid glycoprotein emerged from the computational experiments and the outcomes from the promising interaction with COX-2 were confirmed by Western blot, highlighting the reliability of IVS in the field of the natural products.

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (M pro ), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds M pro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid.

Endometriosis is a chronic, inflammatory disease affecting more than 170 million women worldwide and up to 10% of women of reproductive age. As a consequence of inflammatory reaction and infiltration of anatomic structures, endometriosis can cause "pain symptoms" including dysmenorrhea, dyspareunia, dyschezia, dysuria, and chronic pelvic pain. In this review, we summarized the impact of endometriosis on quality of life in all its aspects including sexual life, work, and social relationships. The data research was conducted using web-based search engines and/or various electronic research databases querying for all articles related to endometriosis and quality of life from the inception of the database up to February 2020. Endometriosis has not only physical but also psychological effects, causing depression, anxiety, and compromising social relationships. Furthermore, endometriosis negatively impacts sexual life and social relationships. At last, the economic burden of endometriosis should not be underestimated, both individually and for the community, as this pathology leads to a loss of productivity at work and large use of health resources. Thus, endometriosis-related symptoms control women's lives compromising the quality of life in all aspects. In this review, we summarized the impact of endometriosis on various aspects of women's lives., Competing Interests: The authors declare no conflict of interest.

The object of the study was to estimate the long-lasting effects induced by ammonium glycyrrhizinate (AG) after a single administration in mice using animal models of pain and inflammation together with biochemical and docking studies. A single intraperitoneal injection of AG was able to produce anti-inflammatory effects in zymosan-induced paw edema and peritonitis. Moreover, in several animal models of pain, such as the writhing test, the formalin test, and hyperalgesia induced by zymosan, AG administered 24 h before the tests was able to induce a strong antinociceptive effect. Molecular docking studies revealed that AG possesses higher affinity for microsomal prostaglandin E synthase type-2 compared to type-1, whereas it seems to locate better in the binding pocket of cyclooxygenase (COX)-2 compared to COX-1. These results demonstrated that AG induced anti-inflammatory and antinociceptive effects until 24-48 h after a single administration thanks to its ability to bind the COX/mPGEs pathway. Taken together, all these findings highlight the potential use of AG for clinical treatment of pain and/or inflammatory-related diseases.

Simplextone E ( 1 ), a new metabolite of polyketide origin, was isolated with eight known analogues ( 2 - 9 ) from the South China Sea sponge Plakortis sp. The relative configuration of the new compound was elucidated by a detailed analysis of the spectroscopic data and quantum mechanical calculation of NMR chemical shifts, aided by the newly reported DP4+ approach. Its absolute configuration was determined by the TDDFT/ECD calculation. Simplextone E ( 1 ) is proven to be one of the isomers of simplextone D. The absolute configuration at C-8 in alkyl chain of plakortone Q ( 2 ) was also assigned based on the NMR calculation. In the preliminary in vitro bioassay, compounds 6 and 7 showed a selective growth inhibitory activity against HCT-116 human colon cancer cells with IC 50 values of 8.3 ± 2.4 and 8.4 ± 2.3 μM, corresponding to that of the positive control, adriamycin (IC 50 4.1 μM). The two compounds also showed selective activities towards MCF-7 human breast cancer and K562 human erythroleukemia cells while compound 3 only displayed weak activity against K562 cells.

Further purification of the apolar extracts of the sponge Plakinastrella mamillaris, afforded a new oxygenated polyketide named gracilioether K, together with the previously isolated gracilioethers E-G and gracilioethers I and J. The structure of the new compound has been elucidated by extensive NMR (1H and 13C, COSY, HSQC, HMBC, and ROESY) and ESI-MS analysis. With the exception of gracilioether F, all compounds are endowed with potent pregnane-X-receptor (PXR) agonistic activity and therefore represent a new chemotype of potential anti-inflammatory leads. Docking calculations suggested theoretical binding modes of the identified compounds, compatible with an agonistic activity on hPXR, and clarified the molecular basis of their biological activities.

Using theonellasterol as a novel FXR antagonist hit, we prepared a series of semi-synthetic derivatives in order to gain insight into the structural requirements for exhibiting antagonistic activity. These derivatives are characterized by modification at the exocyclic carbon-carbon double bond at C-4 and at the hydroxyl group at C-3 and were prepared from theonellasterol using simple reactions. Pharmacological investigation showed that the introduction of a hydroxyl group at C-4 as well as the oxidation at C-3 with or without concomitant modification at the exomethylene functionality preserve the ability of theonellasterol to inhibit FXR transactivation caused by CDCA. Docking analysis showed that the placement of these molecules in the FXR-LBD is well stabilized when on ring A functional groups, able to form hydrogen bonds and π interactions, are present.