Efficacy of Dan'e Fukang Soft Extract in Moderate Ovarian Hyperstimulation Syndrome for Concurrent Treatment of Blood and Fluid Guided by the "Triple Prevention" Principle.

Objective: This study aimed to evaluate the therapeutic efficacy and safety of Dan'e Fukang soft extracts in moderate ovarian hyperstimulation syndrome (OHSS) for the simultaneous treatment of blood and fluid, guided by the traditional Chinese medicine principle of "triple prevention". Methods: This study conducted a retrospective analysis of clinical data from outpatients who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection embryo transfer (ICSI-ET). A total of 2245 cases were included and divided into a treatment group (1002 cases) and a control group (1243 cases). Patients in the treatment group were administered Dan'e Fukang soft extracts orally in addition to conventional Western medicine. Comparative assessments were made between the two groups on pelvic ascites volume, maximum ovary diameter, dysmenorrhea incidence post-oocyte retrieval, and safety indicators. Results: There were no statistically significant differences between the treatment group and the control group in terms of general characteristics or the levels of follicle-stimulating hormone (FSH), luteotropic hormone (LH), estradiol (E2), or progesterone (P) at the time of gonadotropin (Gn) initiation. The groups did not differ significantly when we compared the levels of LH, E2, or P on the day of human chorionic gonadotropin (hCG) injection and during ovarian hyperstimulation protocols (P > 0.05 for all indicators). The differences in the volume of pelvic ascites, the maximum ovarian diameter, and the incidence of dysmenorrhea after oocyte retrieval were statistically significant between the treatment group and the control group (P < 0.05 in both). There were no instances of adverse reactions in either group. Conclusion: Based on the traditional Chinese medicine principle of "triple prevention", the use of Dan'e Fukang soft extracts for the simultaneous treatment of blood and fluid in moderate OHSS significantly improved the absorption of pelvic ascites, promoted ovarian recovery, and reduced the incidence of dysmenorrhea after oocyte retrieval.

Enabling Systemic Identification and Functionality Profiling for Cdc42 Homeostatic Modulators.

Homeostatic modulation is pivotal in modern therapeutics. However, the discovery of bioactive materials to achieve this functionality is often random and unpredictive. Here, we enabled a systemic identification and functional classification of chemicals that elicit homeostatic modulation of signaling through Cdc42, a classical small GTPase of Ras superfamily. Rationally designed for high throughput screening, the capture of homeostatic modulators (HMs) along with molecular re-docking uncovered at least five functionally distinct classes of small molecules. This enabling led to partial agonists, hormetic agonists, bona fide activators and inhibitors, and ligand-enhanced agonists. Novel HMs exerted striking functionality in bradykinin-Cdc42 activation of actin remodelingand modified Alzheimer's disease-like behavior in mouse model. This concurrent computer-aided and experimentally empowered HM profiling highlights a model path for predicting HM landscape. One Sentence Summary: With concurrent experimental biochemical profiling and in silico computer-aided drug discovery (CADD) analysis, this study enabled a systemic identification and holistic classification of Cdc42 homeostatic modulators (HMs) and demonstrated the power of CADD to predict HM classes that can mimic the pharmacological functionality of interests. Introduction: Maintainingbody homeostasisis the ultimate keyto health. Thereare rich resources of bioactive materials for this functionality from both natural and synthetic chemical repertories including partial agonists (PAs) and various allosteric modulators. These homeostatic modulators (HMs) play a unique role in modern therapeutics for human diseases such as mental disorders and drug addiction. Buspirone, for example, acts as a PA for serotonin 5-HT 1A receptor but is an antagonist of the dopamine D 2 receptor. Such medical useto treat general anxietydisorders (GADs) has become one of the most-commonly prescribed medications. However, most HMs in current uses target membrane proteins and are often derived from random discoveries. HMs as therapeutics targeting cytoplasmic proteins are even more rare despite that they are in paramount needs (e. g. targeting Ras superfamily small GTPases). Rationale: Cdc42, a classical member of small GTPases of Ras superfamily, regulates PI3K-AKT and Raf-MEK-ERK pathways and has been implicated in various neuropsychiatric and mental disorders as well as addictive diseases and cancer. We previously reported the high-throughput in-silico screening followed by biological characterization of novel small molecule modulators (SMMs) of Cdc42-intersectin (ITSN) protein-protein interactions (PPIs). Based on a serendipitously discovered SMM ZCL278 with PA profile as a model compound, we hypothesized that there are more varieties of such HMs of Cdc42 signaling, and the model HMs can be defined by their distinct Cdc42-ITSN binding mechanisms using computer-aided drug discovery (CADD) analysis. We further reasoned that molecular modeling coupled with experimental profiling can predict HM spectrum and thus open the door for the holistic identification and classification of multifunctional cytoplasmic target-dependent HMs as therapeutics. Results: The originally discovered Cdc42 inhibitor ZCL278 displaying PA properties prompted the inquiry whether this finding represented a random encounter of PAs or whether biologically significant PAs can be widely present. The top ranked compounds were initially defined by structural fitness and binding scores to Cdc42. Because higher binding scores do not necessarily translate to higher functionality, we performed exhaustive experimentations with over 2,500 independent Cdc42-GEF (guanine nucleotide exchange factor) assays to profile the GTP loading activities on all 44 top ranked compounds derived from the SMM library. The N-MAR-GTP fluorophore-based Cdc42-GEF assay platform provided the first glimpse of the breadth of HMs. A spectrum of Cdc42 HMs was uncovered that can be categorized into five functionally distinct classes: Class I-partial competitive agonists, Class II-hormetic agonists, Class III- bona fide inhibitors (or inverse agonists), Class IV- bona fide activators or agonists, and Class V-ligand-enhanced agonists. Remarkably, model HMs such as ZCL278, ZCL279, and ZCL367 elicited striking biological functionality in bradykinin-Cdc42 activation of actin remodeling and modified Alzheimer's disease (AD)-like behavior in mouse model. Concurrently, we applied Schrödinger-enabled analyses to perform CADD predicted classification of Cdc42 HMs. We modified the classic molecular docking to instill a preferential binding pocket order (PBPO) of Cdc42-ITSN, which was based on the five binding pockets in interface of Cdc42-ITSN. We additionally applied a structure-based pharmacophore hypothesis generation for the model compounds. Then, using Schrödinger's Phase Shape, 3D ligand alignments assigned HMs to Class I, II, III, IV, and V compounds. In this HM library compounds, PBPO, matching pharmacophoric featuring, and shape alignment, all put ZCL993 in Class II compound category, which was confirmed in the Cdc42-GEF assay. Conclusion: HMs can target diseased cells or tissues while minimizing impacts on tissues that are unaffected. Using Cdc42 HM model compounds as a steppingstone, GTPase activation-based screening of SMM library uncovered five functionally distinct Cdc42 HM classes among which novel efficacies towards alleviating dysregulated AD-like features in mice were identified. Furthermore, molecular re-docking of HM model compounds led to the concept of PBPO. The CADD analysis with PBPO revealed similar profile in a color-coded spectrum to these five distinct classes of Cdc42 HMs identified by biochemical functionality-based screening. The current study enabled a systemic identification and holistic classification of Cdc42 HMs and demonstrated the power of CADD to predict an HM category that can mimic the pharmacological functionality of interests. With artificial intelligence/machine learning (AI/ML) on the horizon to mirror experimental pharmacological discovery like AlphaFold for protein structure prediction, our study highlights a model path to actively capture and profile HMs in potentially any PPI landscape. Identification and functional classification of Cdc42 homeostatic modulators HMs: Using Cdc42 HM model compounds as reference, GTPase activation-based screening of compound libraries uncovered five functionally distinct Cdc42 HM classes. HMs showed novel efficacies towards alleviating dysregulated Alzheimer's disease (AD)-like behavioral and molecular deficits. In parallel, molecular re-docking of HM model compounds established their preferential binding pocket orders (PBPO). PBPO-based profiling (Red reflects the most, whereas green reflects the least, preferable binding pocket) revealed trends of similar pattern to the five classes from the functionality-based classification.

The Role of Traditional Chinese Formula Ding-Kun Pill (DKP) in Expected Poor Ovarian Response Women (POSEIDON Group 4) Undergoing In Vitro Fertilization-Embryo Transfer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: The primary objective of the study was to assess traditional Chinese formula DKP supplementation in terms of efficacy and safety on reproductive outcomes of expected poor ovarian responder (POR, POSEIDON Group 4) undergoing in vitro fertilization-embryo transfer (IVF-ET). Design Setting and Participants: Women eligible for IVF-ET were invited to participate in this randomized, double-blind, placebo-controlled, superiority trial at academic fertility centers of ten public hospitals in Chinese Mainland. A total of 462 patients (35-44 years) equally divided between DKP and placebo groups with antral follicle count (AFC) <5 or anti-müllerian hormone (AMH) <1.2 ng/ml were randomized. Interventions: All participants were given DKP or 7 g placebo twice daily on the previous menstrual cycle day 5 until oocyte retrieval, which took approximately 5 to 6 weeks. Main Outcome Measure: The primary outcome was the ongoing pregnancy defined as more than 20 gestational weeks of an intrauterine living fetus confirmed by pelvic ultrasonography. Results: Demographic characteristics were equally distributed between the study populations. Intention-to-treat (ITT) analysis revealed that ongoing pregnancy rate (OPR) was not significantly different between DKP and placebo groups [26.4% (61/231) versus 24.2% (56/231); relative risk (RR) 1.09, 95% confidence interval (CI) 0.80 to 1.49, P = 0.593]. No significant differences between groups were observed for the secondary outcomes. The additional per protocol (PP) analysis was in line with ITT results: OPR in DKP group was 27.2% (61/224) versus 24.1% (55/228) in placebo group [RR 1.13, 95%CI (0.82 to 1.55), P = 0.449]. After subgroup analysis the findings concluded that POR population of 35-37 years had a significantly higher OPR after 5-6 weeks of oral DKP (41.8%, 33/79) versus placebo (25.4%, 18/71) [RR 1.65, 95% CI (1.02 to 2.65), P = 0.034, P for interaction = 0.028]. Conclusion: This well-designed randomized controlled trial (RCT) offers new high-quality evidence to supplement existing retrospective literature concerning DKP performance in expected PORs. DKP could be recommended as a safe and natural remedy for expected PORs (aged 35-37 years) who fulfill the POSEIDON group 4 criteria. However, additional interventional clinical studies are undoubtedly required to be conducted in the future to validate this hypothesis. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR1900026614.

Effects of a Chinese Patent Medicine Gushen'antai Pills on Ongoing Pregnancy Rate of Hormone Therapy FET Cycles: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

In the past decade, the number of frozen-thawed embryo transfer (FET) has increased dramatically with the expansion of surgical indications and the improvement of freezing related technologies. How to improve the success rate and reduce the adverse effects of FET is our research priorities. This study aimed to investigate the safety and effectiveness of Gushen'antai pills (GSATP) by measuring the ongoing pregnancy rate (OPR) in patients from FET and hormone therapy (HT) cycle. From November 2019 to May 2020, 5 Chinese hospitals conducted a multi-center, randomized, double-blind, placebo-controlled study. In total, 271 HT FET cycles in patients were randomly divided (1:1 ratio) to receive GSATP (6 g, tid) or placebo (6g, tid) for 12 weeks of pregnancy. Patients, clinicians, and researchers were blinded to treatment allocation. The primary endpoint was the OPR at week 12 of pregnancy. The secondary endpoints were vaginal bleeding or brown discharge rate, implantation rate (IR), clinical pregnancy rate (CPR) and abortion rate (AR). Adverse events were recorded during the treatment period. The results showed that the OPR remained higher in the GSATP group when compared to placebo group (56.62% vs. 44.44%, p = 0.045). Vaginal bleeding or brown discharge rate was lower in the GSATP group than the placebo group (10% vs. 23.08%, p = 0.032), while the IR (35.16% vs. 27.64%, p = 0.070), CPR (58.82% vs. 48.15%, p = 0.078), incidence of total adverse events (8.09% vs. 3.22%, p = 0.051) and AR (3.75% vs. 7.69%, p = 0.504) were similar between GSATP and placebo groups. Subgroup analysis showed that there were significant differences in CPR (74.19% vs. 54.17%, p = 0.004) and OPR (72.04% vs. 51.04%, p = 0.003) between GSATP group and Placebo group when the patient was younger than 35 years old. This multi-center, randomized, double-blinded, placebo-controlled clinical study showed for the first evidence that GSATP may have potential to improve the OPR and decrease vaginal bleeding or brown discharge rate in HT FET cycle patients.

Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility.

Signaling through the Rho family of small GTPases has been intensely investigated for its crucial roles in a wide variety of human diseases. Although RhoA and Rac1 signaling pathways are frequently exploited with the aid of effective small molecule modulators, studies of the Cdc42 subclass have lagged because of a lack of such means. We have applied high-throughput in silico screening and identified compounds that are able to fit into the surface groove of Cdc42, which is critical for guanine nucleotide exchange factor binding. Based on the interaction between Cdc42 and intersectin (ITSN), a specific Cdc42 guanine nucleotide exchange factor, we discovered compounds that rendered ITSN-like interactions in the binding pocket. By using in vitro binding and imaging as well as biochemical and cell-based assays, we demonstrated that ZCL278 has emerged as a selective Cdc42 small molecule modulator that directly binds to Cdc42 and inhibits its functions. In Swiss 3T3 fibroblast cultures, ZCL278 abolished microspike formation and disrupted GM130-docked Golgi structures, two of the most prominent Cdc42-mediated subcellular events. ZCL278 reduces the perinuclear accumulation of active Cdc42 in contrast to NSC23766, a selective Rac inhibitor. ZCL278 suppresses Cdc42-mediated neuronal branching and growth cone dynamics as well as actin-based motility and migration in a metastatic prostate cancer cell line (i.e., PC-3) without disrupting cell viability. Thus, ZCL278 is a small molecule that specifically targets Cdc42-ITSN interaction and inhibits Cdc42-mediated cellular processes, thus providing a powerful tool for research of Cdc42 subclass of Rho GTPases in human pathogenesis, such as those of cancer and neurological disorders.

Clinical effects of shen-nourishing and menstruation-regulating method combined with triptorelin acetate injection on patient with luteinized unruptured follicle syndrome / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the clinical effects of Shen-nourishing and menstruation-regulating method (SNMRM) combined with Triptorelin Acetate Injection (TAI) on patients with luteinized unruptured follicle syndrome (LUFS).</p><p><b>METHODS</b>Sixty-two LUFS patients were randomly assigned to the treatment group and the control group. TAI was given to patients in the control group while SNMRM + TAI was given to those in the treatment group. The ovulation rate and the pregnancy rate were observed in the two groups.</p><p><b>RESULTS</b>The ovulation rate in the treatment group was higher than that in the control group, but without significant difference (85.53% versus 79.07%, P > 0.05). The pregnancy rate was significantly higher in the treatment group than in the control group (56.25% vs 30.00%, P < 0.05).</p><p><b>CONCLUSION</b>Treatment of LUFS by SNMRM + TAI could improve the ovulation rate and the pregnancy rate, indicating that LUFS patients' ovary functions could be improved by using different menstruation regulating methods during different follicular development phases.</p>

Pro-oncogenic and anti-oncogenic pathways: opportunities and challenges of cancer therapy.

Carcinogenesis is the uncontrolled growth of cells gaining the potential to invade and disrupt vital tissue functions. This malignant process includes the occurrence of 'unwanted' gene mutations that induce the transformation of normal cells, for example, by overactivation of pro-oncogenic pathways and inactivation of tumor-suppressive or anti-oncogenic pathways. It is now recognized that the number of major signaling pathways that control oncogenesis is not unlimited; therefore, suppressing these pathways can conceivably lead to a cancer cure. However, the clinical application of cancer intervention has not matched up to scientific expectations. Increasing numbers of studies have revealed that many oncogenic-signaling elements show double faces, in which they can promote or suppress cancer pathogenesis depending on tissue type, cancer stage, gene dosage and their interaction with other players in carcinogenesis. This complexity of oncogenic signaling poses challenges to traditional cancer therapy and calls for considerable caution when designing an anticancer drug strategy. We propose future oncology interventions with the concept of integrative cancer therapy.

[Brain arousal dysfunction in severe craniocerebral injury treated with acupuncture].

OBJECTIVE: To explore the early rehabilitation effect of acupuncture on brain arousal in severe craniocerebral injury. METHODS: One hundred and two cases of severe craniocerebral injury were randomly divided into an observation group and a control group, 51 cases in each one. Based on the conventional nursing care in neurological external medicine, in observation group, acupuncture was applied at Shuigou (GV 26), Neiguan (PC 6) and Sanyinjiao (SP 6) mainly. In control group, functional electric stimulation was applied at stimulate the affected muscles of the upper limbs. Thirty days later, the lucid rate from coma, lucid interval and clinical efficacy were compared between two groups. RESULTS; The lucid rate from coma was 82.4% (42/51) in observation group, which was higher than 56.9% (29/51) in control group (P < 0.01). The lucid interval in observation group was shortened remarkably as compared with control group (P < 0.01), and the clinical efficacy was superior apparently to that in control group (P < 0.01). CONCLUSION: On the basis of conventional treatment, acupuncture intervention at early stage can accelerate the recovery of brain arousal function in patients with severe craniocerebral injury.

The NGF point-injection for treatment of the sound-perceiving nerve deafness and tinnitus in 68 cases.

OBJECTIVE: To observe the therapeutic effects of the point-injection with nerve growth factor (NGF) for the sound-perceiving nerve deafness and tinnitus. METHODS: The 140 cases in this series were randomly divided into a treatment group of 68 cases treated by NGF injection at the points of Yifeng (TE 17) and Wangu (GB 12), and a control group of 72 cases orally taking Xibiling and adenosine triphosphate (ATP) and intramuscular injection with VB1 and VB12. RESULTS: The total effective rate was 78.6% in the treatment group and 31.8% in the control group, with significant difference between the two groups (P<0.05). CONCLUSION: For treating nervous deafness and tinnitus, NGF point-injection may show good therapeutic effects, but inversely proportional to the illness course, age and the extent of hypoacusis.

The combined antenatal corticosteroids and vitamin K therapy for preventing periventricular-intraventricular hemorrhage in premature newborns less than 35 weeks gestation.

We prospectively evaluated whether combined antenatal corticosteroid and vitamin K administration have any benefit, over and above that of corticosteroid or vitamin K used alone, in reducing the frequency and the degree of PIVH in premature newborns less than 35 weeks' gestation. All of these 280 pregnant women were randomly allocated into five groups according to the in-patient sequence. Group A (vitamin K1 group) including 38 pregnant women (40 newborns) received antenatal intramuscular or intravenously injection of vitamin K1 10 mg per day for 2-7 days. Group B (single dose corticosteroid group) including 57 pregnant women (63 newborns) received antenatal intramuscular or intravenously injection of dexamethasone 10 mg per day for 1 day. Group C (two dose corticosteroid group) including 62 pregnant women (70 newborns) received antenatal intramuscular or intravenously injection of dexamethasone 10 mg per day for 2 days. Group D (combined using dexamethasone and vitamin K1) including 41 pregnant women (44 newborns) received dexamethasone 10 mg per day for 1 day and vitamin K110 mg per day for 2-7 days. Control group, including 82 pregnant women (87 newborns) were received neither dexamethasone nor vitamin K1 injection. The results showed PIVH was diagnosed in 17 of 40 (42.5%) in Group A, 34 of 63 (54.0%) in Group B, 36 of 70 (51.4%) in Group C, 14 of 44 (31.8%) in Group D, and 57 of 87 (65.2%) in control infants (p = 0.004). More infants in the control group had grade III or IV intracranial hemorrhage after birth (p = 0.049). After antenatal supplement of dexamethasone and vitamin K1, both the total incidence of PIVH and the frequency of severe PIVH decreased significantly. The total and severe incidence of PIVH in Group B (single doses dexamethasone) and Group C (two courses dexamethasone) there were no significant difference. It showed that after antenatal supplement of dexamethasone and vitamin K1, both the total incidence of PIVH and the frequency of severe PIVH decreased significantly, and combined antenatal corticosteroid and vitamin K administration have much benefit, over and above that of corticosteroid or vitamin K used alone.