Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist.

A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure-activity relationship (SAR) studies led to the discovery of 17h (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of 17h suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties, 17h was advanced to Phase 1 human clinical trials in healthy volunteers with the goal of moving into patient trials to evaluate CRN04894 for the treatment of ACTH-dependent diseases, including congenital adrenal hyperplasia (CAH) and Cushing's disease (CD).

Hericium coralloides Ameliorates Alzheimer's Disease Pathologies and Cognitive Disorders by Activating Nrf2 Signaling and Regulating Gut Microbiota.

Alzheimer's disease (AD) is prone to onset and progression under oxidative stress conditions. Hericium coralloides (HC) is an edible medicinal fungus that contains various nutrients and possesses antioxidant properties. In the present study, the nutritional composition and neuroprotective effects of HC on APP/PS1 mice were examined. Behavioral experiments showed that HC improved cognitive dysfunction in APP/PS1 mice. Immunohistochemical and Western blotting results showed that HC reduced the levels of p-tau and amyloid-ß deposition in the brain. By altering the composition of the gut microbiota, HC promoted the growth of short-chain fatty acid-producing bacteria and suppressed the growth of Helicobacter. Metabolomic results showed that HC decreased D-glutamic acid and oxidized glutathione levels. In addition, HC reduced the levels of reactive oxygen species, enhanced the secretion of superoxide dismutase, catalase, and glutathione peroxidase, inhibited the production of malondialdehyde and 4-hydroxynonenal, and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Collectively, HC demonstrated antioxidant activity by activating Nrf2 signaling and regulating gut microbiota, further exerting neuroprotective effects. This study confirms that HC has the potential to be a clinically effective AD therapeutic agent and offers a theoretical justification for both the development and use of this fungus.

Surface plasmon resonance sensor composed of a D-type photonic crystal fiber with a three-layer coating.

A surface plasmon resonance sensor composed of photonic crystal fibers (PCF-SPR) with an A u-T i O 2-A u triple layer is designed for refractive index (RI) sensing and analyzed theoretically by the finite element method. The sensor exhibits enhanced resonance coupling between the core mode and surface plasmon polariton (SPP) mode as well as better sensitivity than the structure with a single gold coating. Furthermore, the A u-T i O 2-A u tri-layer structure narrows the linewidth of the loss spectrum and improves the figure of merit (FOM). In the analyte RI range of 1.30-1.42, the maximum wavelength sensitivity is 20,300 nm/RIU, resolution is 4.93×10-6, amplitude sensitivity is 6427R I U -1, and FOM is 559R I U -1. The results provide insights into the design of high-performance PCF-SPR sensors.

Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist.

The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline series of potent SST2 agonists is described. This class of molecules exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors. The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (22, paltusotine, formerly known as CRN00808) showed no direct inhibition of major cytochrome P450 enzymes or the hERG ion channel and had sufficient exposure in rats and excellent exposure in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge in both male and female rats following a single oral dose and suppressed IGF-1 levels with repeated oral administration in both rats and dogs. To the best of our knowledge, compound 22 is the first non-peptide SST2 agonist to advance to human clinical trials and is currently in Phase 3 trials in acromegaly patients and a Phase 2 trial in neuroendocrine tumor patients suffering from carcinoid syndrome.

Highly sensitive dual-core photonic quasicrystal fiber methane sensor based on surface plasmon resonance.

A highly sensitive dual-core photonic quasicrystal fiber methane sensor based on surface plasmon resonance is designed and analyzed. In this sensor, cryptophane E is doped with polysiloxane and Ag and used as the sensitive film and plasma medium, respectively, for sensitive detection of methane. The influence of the structural parameters on the sensor properties is analyzed by the finite element method. The optimized dual-quasi-D-shape structure has excellent methane-sensing properties such as maximum and average wavelength sensitivities of 14 and 10.98 nm/%, respectively, in the methane concentration range of 0%-3.5%. The sensitivity is better than that of similar sensors reported previously.

Discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridines as potent and selective SST5 agonists for the treatment of congenital hyperinsulinism.

SST5 receptor activation potently inhibits insulin secretion from pancreatic ß-cells, and an orally available nonpeptide selective SST5 agonist may be used to effectively manage the blood glucose levels of congenital HI patients to avoid severe hypoglycemia. Our medicinal chemistry efforts have led to the discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridine analogs as potent SST5 agonists. This class of molecules exhibits excellent human SST5 potency and selectivity against SST1, SST2, SST3 and SST4 receptors. Leading compound 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl-5-fluorobenzonitrile (28, CRN02481) showed limited off-target activity and good pharmacokinetic profiles in both male Sprague Dawley rats and Beagle dogs to advance into further preclinical evaluations.

Determination of free fatty acids in Antarctic krill meals based on matrix solid phase dispersion.

Amino-modified mesoporous silicawas prepared by modifying mesoporous silica with 3-aminopropyltriethoxysilane and used as adsorbents in matrix solid-phase dispersion (MSPD) to analyze free fatty acids (FFAs) in krill meals for the first time. The adsorption-desorption experiments and Fourier-transform infrared spectroscopy showed amino-modified mesoporous silica with ordered mesoporous structure was successfully synthesized. The adsorption experiments including static and dynamic adsorption showed thatabsorption capacity of amino-modified mesoporous silica towards FFAs was better than that of aminated silicon microspheres at all concentrations. Under optimal extraction conditions, outstanding linearity (0.1-12000 nmol g-1), low LODs (0.05-1.25 nmol g-1), satisfactory recoveries (82.17-96.43%) and precisions (0.19-5.26%) were obtained. Moreover, the application of MSPD for FFAs analysis avoided complicated lipid extraction procedures and accomplished the homogenization, crushing, extraction and cleaning of the samples in one step. Consequently, this approach provides an alternative choice to the existing approach for analyzing FFAs in solid and semi-solid samples.

The Neuroprotection of Verbascoside in Alzheimer's Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling.

Verbascoside (VB) is a phenylethanoid glycoside extracted from the herbaceous plant Verbascum sinuatum and plays a neuroprotective role in Alzheimer's disease (AD). The goal of this study was to explore the neuroprotective mechanism of VB. Based on the proteomics analysis, immunohistochemistry, immunofluorescence, Western blot, and ELISA were utilized to explore the neuroprotective mechanism of VB in context of neuroinflammation in APP/PS1 mice, LPS-induced BV2 cells, and/or Aß1-42-stimulated N2a cells. Proteomic analysis demonstrated that the neuroprotection of VB correlated closely to its anti-inflammatory effect. VB significantly blocked microglia and astrocyte against activation in brains of APP/PS1 mice, suppressed the generation of IL-1ß as well as IL-6, and boosted that of IL-4, IL-10 and TGF-ß in vivo, which were analogous to results acquired in vitro. Furthermore, VB effectively restrained the phosphorylation of IKKα+ß, IκBα, and NF-κB-p65 in APP/PS1 mice; LPS-induced BV2 cells, and Aß1-42-stimulated N2a cells and lowered the tendency of NF-κB-p65 translocation towards nucleus in vitro. These results demonstrate that the neuroprotective effect of VB correlates to the modulation of neuroinflammation via NF-κB-p65 pathway, making VB as a hopeful candidate drug for the prevention and treatment of AD.

A Modified Power-on Programming Method after Deep Brain Stimulation for Parkinson Disease.

OBJECTIVE: To explore the feasibility of using a modified power-on programming method in deep brain stimulation (DBS) for Parkinson disease (PD). METHODS: We conducted a retrospective cohort study including 151 PD patients with bilateral robot-assisted DBS surgery from July 2017 to June 2020. Ninety-seven patients were adopted to the modified power-on programming method (Group I) and 54 patients were adopted to the traditional power-on programming method (Group II). In one-year follow-up, power-on programming duration, stimulation parameters, scores of Unified PD Rating Scale (UPDRS) and UPDRS-III of the 2 groups were recorded and compared. RESULTS: There were no significant differences in the postoperative UPDRS, UPDRS-III improvement rate, and stimulation parameters between the 2 groups. The duration of power-on programming of Group I (1.7 ± 1.1 hours) was significantly less than that of Group II (3.5 ± 1.8 hours, P < 0.0001). CONCLUSIONS: The modified power-on programming method can achieve a similar clinical effect to the traditional method, with the advantage of more efficiency.

The Involvement of Macrophage Colony Stimulating Factor on Protein Hydrolysate Injection Mediated Hematopoietic Function Improvement.

Protein hydrolysate injection (PH) is a sterile solution of hydrolyzed protein and sorbitol that contains 17 amino acids and has a molecular mass of 185.0-622.0 g/mol. This study investigated the effect of PH on hematopoietic function in K562 cells and mice with cyclophosphamide (CTX)-induced hematopoietic dysfunction. In these myelosuppressed mice, PH increased the number of hematopoietic cells in the bone marrow (BM) and regulated the concentration of several factors related to hematopoietic function. PH restored peripheral blood cell concentrations and increased the numbers of hematopoietic stem cells and progenitor cells (HSPCs), B lymphocytes, macrophages, and granulocytes in the BM of CTX-treated mice. Moreover, PH regulated the concentrations of macrophage colony stimulating factor (M-CSF), interleukin (IL)-2, and other hematopoiesis-related cytokines in the serum, spleen, femoral condyle, and sternum. In K562 cells, the PH-induced upregulation of hematopoiesis-related proteins was inhibited by transfection with M-CSF siRNA. Therefore, PH might benefit the BM hematopoietic system via the regulation of M-CSF expression, suggesting a potential role for PH in the treatment of hematopoietic dysfunction caused by cancer therapy.

Fast Determination of Carbamates in Environmental Water Based on Magnetic Molecularly Imprinted Polymers as Adsorbent.

Magnetic molecularly imprinted polymers (MMIPs) were prepared with isoprocarb as template molecule and applied to extraction of carbamates pesticides in different water samples. This method based on magnetic solid-phase extraction (SPE) avoided the time-consuming column-passing process of loading large volume samples in conventional SPE. In the study, only 0.1 g MMIPs could be used to obtain satisfactory recoveries, due to the high-surface area and excellent adsorption capacity of these nano-magnetic adsorbents. Owing to the excellent selectivity of MMIPs, in high-performance liquid chromatography-mass spectrometry analysis, the matrix effects of this technique were obviously lower than the conventional SPE method. Under the optimal conditions, the detection limits of carbamates were in the range of 2.7-11.7 ng L-1. The relative standard deviations of intra-day and inter-day were 2.5-7.4% and 3.6-8.4%, respectively. At all the spiked level, the recoveries of four analyzed carbamates in environmental water samples were in the range of 74.2-94.2%. The significant positive results were achieved in the proposed method for the determination of four carbamates in water samples from different lakes and rivers. In the three samples we tested, the carbaryl was found in the lake water obtained from Yitong River, and the content was 2.4 ng L-1.

Tristability in mitochondrial permeability transition pore opening.

Mitochondrial permeability transition pore (PTP), a key regulator of cell life and death processes, is triggered by calcium ions (Ca2+) and potentiated by reactive oxygen species (ROS). Although the two modes of PTP opening, i.e., transient and persistent, have been identified for a long time, its dynamical mechanism is still not fully understood. To test a proposed hypothesis that PTP opening acts as a tristable switch, which is characterized by low, medium, and high open probability, we develop a three-variable model that focused on PTP opening caused by Ca2+ and ROS. For the system reduced to two differential equations for Ca2+ and ROS, both the stability analysis and the potential landscape feature that it exhibits tristability under standard parameters. For the full system, the bifurcation analysis suggests that it can achieve tristability over a wide range of input parameters. Furthermore, parameter sensitivity analysis demonstrates that the existence of tristability is a robust property. In addition, we show how the deterministic tristable property can be understood within a stochastic framework, which also explains the PTP dynamics at the level of a single channel. Overall, this study may yield valuable insights into the intricate regulatory mechanism of PTP opening.

A comparative study of asleep and awake deep brain stimulation robot-assisted surgery for Parkinson's disease.

To compare the differences between asleep and awake robot-assisted deep brain stimulation (DBS) surgery for Parkinson's Disease (PD), we conducted this retrospective cohort study included 153 PD patients undergoing bilateral robot-assisted DBS from June 2017 to August 2019, of which 58 cases were performed under general anesthesia (GA) and 95 cases under local anesthesia (LA). Procedure duration, stimulation parameters, electrode implantation accuracy, intracranial air, intraoperative electrophysiological signal length, complications, and Unified PD Rating Scale (UPDRS) measurements were recorded and compared. The clinical evaluation was conducted by two raters who were blinded to the choice of anesthesia. Procedure duration was significantly shorter in the GA group, while on stimulation off medication motor scores (UPDRS-III) were significantly improved in both the GA and LA group. ANCOVA covariated for the baseline UPDRS-III and levodopa challenge exhibited no significant differences. In terms of amplitude, frequency, and pulse width, the stimulation parameters used for DBS power-on were similar. There were no significant differences in electrode implantation accuracy, intraoperative electrophysiological signal length, or intracerebral hemorrhage (no occurrences in either group). The pneumocephalus volume was significantly smaller in the GA group. Six patients exhibited transient throat discomfort associated with tracheal intubation in the GA group. The occurrence of surgical incision infection was similar in both groups. Compared with the awake group, the asleep group exhibited a shorter procedure duration with a similar electrode implantation accuracy and short-term motor improvement. Robot-assisted asleep DBS surgery is a promising surgical method for PD.

Discovery of nonpeptide 3,4-dihydroquinazoline-4-carboxamides as potent and selective sst2 agonists.

Nonpeptide sst2 agonists can provide a new treatment option for patients with acromegaly, carcinoid tumors, and neuroendocrine tumors. Our medicinal chemistry efforts have led to the discovery of novel 3,4-dihydroquinazoline-4-carboxamides as sst2 agonists. This class of molecules exhibits excellent human sst2 potency and selectivity against sst1, sst3, sst4 and sst5 receptors. Leading compound 3-(3-chloro-5-methylphenyl)-6-(3-fluoro-2-hydroxyphenyl)-N,7-dimethyl-N-{[(2S)-pyrrolidin-2-yl]methyl}-3,4-dihydroquinazoline-4-carboxamide (28) showed no inhibition of major CYP450 enzymes (2C9, 2C19, 2D6 and 3A4) and weak inhibition of the hERG channel.

Assessment of Deep Brain Stimulation Implantation Surgery: A Practical Scale.

BACKGROUND: Patients requiring deep brain stimulation (DBS) will undergo extensive preoperative and postoperative evaluations. However, the field lacks a robust scoring system for quantifying the outcomes of DBS surgery. We sought to determine whether a practical scale could assess the outcomes of DBS surgery and the clinical significance. METHODS: A retrospective study was performed of the data from 150 patients who had undergone DBS from February 2017 to February 2019. An independence analysis and multivariate testing were used to identify significant independent predictors. The scale scores were computed by summing across the weighted predictors. The correlation between the scale scores and the intraoperative electrophysiological signal length (IESL), DBS power-on voltage, improvement rate in the unified Parkinson disease rating scale (UPDRS) and UPDRS part III (UPDRS III) scores was analyzed. Receiver operating characteristics curve analysis was used to quantify the discriminative capacity of the scale for predicting the prognosis. RESULTS: Listwise exclusion of patients with incomplete data sets yielded a final sample of 130 patients with Parkinson disease who had undergone bilateral DBS. Multivariate testing identified 3 independent predictors of the prognosis, including electrode implantation duration, postoperative pneumocephalus volume, and electrode fusion error. The scale scores correlated significantly with the subthalamic nucleus DBS power-on voltage (r = -0.4063; P < 0.0001), globus pallidus internus DBS power-on voltage (r = -0.4723; P = 0.0014), and improvement rate of the UPDRS (r = 0.3490; P < 0.0001) and UPDRS III (r = 0.6623; P < 0.0001) scores. However, the scale scores did not significantly correlate with the subthalamic nucleus IESL and globus pallidus internus IESL. Receiver operating characteristics curve analysis revealed impressive outcome discrimination for the UPDRS and UPDRS III scores (UPDRS: area under the curve, 0.62, P = 0.0219; UPDRS III: area under the curve, 0.85, P < 0.0001). CONCLUSIONS: We have introduced a novel practical scale capable of assessing the outcomes of DBS surgery and predicting the prognosis of patients after DBS surgery.

Comparison of Subthalamic Nucleus and Globus Pallidus Internus Deep Brain Stimulation Surgery on Parkinson Disease-Related Pain.

OBJECTIVE: To analyze and compare the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) and globus pallidus internus (GPi)-DBS on Parkinson disease (PD)-related pain. METHODS: A retrospective study was performed of 64 patients (28 who underwent GPi-DBS and 36 who underwent STN-DBS) with PD-related pain in our hospital between January 2017 and July 2019. A numerical rating scale (NRS) was used to evaluate the degree of pain preoperatively and 4 months after operation, and the unified PD scale III (UPDRS-III) was completed simultaneously to assess motor symptoms. RESULTS: The average NRS score of all 64 patients after surgery was 1.09 ± 1.39, which was significantly lower than that before operation (4.44 ± 1.67; P < 0.0001). The improvement rate of NRS was 75 ± 27% in the 28 GPi-DBS patients and 79 ± 27% in the 36 STN-DBS patients, with no significant difference (P = 0.577). The improvements in NRS and UPDRS-III were significantly correlated in the STN-DBS group (r = 0.3707, P = 0.026) but not significantly correlated in the GPi-DBS group (P = 0.516). CONCLUSIONS: Both GPi-DBS and STN-DBS were effective for analyzing PD-related pain and seemed to have similar efficacy. This study provides an important first-step toward determining different DBS targets for controlling PD-related pain. Follow-up prospective research is an appropriate next step on the path to multicenter clinical trials.

Efficacy Analysis of Robot-Assisted Minimally Invasive Surgery for Small-Volume Spontaneous Thalamic Hemorrhage.

OBJECTIVE: To test whether robot-assisted surgery can improve prognosis of small-volume thalamic hemorrhage and to provide a surgical basis for treatment of small-volume thalamic hemorrhage. METHODS: This retrospective study included patients with thalamic hemorrhage and hematoma volume of 5-15 mL treated from December 2015 to December 2018. Patients were divided into an operation group and a nonoperation group. General data, types of hematoma, incidence of complications, Scandinavian Stroke Scale score, and modified Rankin Scale score were recorded and analyzed. RESULTS: Retrospectively, 84 cases met inclusion criteria: 35 cases in operation group and 49 cases in nonoperation group. At 90 days after onset, mortality was 11.4% in the operation group and 4.1% in the nonoperation group (P > 0.05). The Scandinavian Stroke Scale score in the operation group (43.3 ± 8.5) was higher than in the nonoperation group (36.1 ± 10.0) (P < 0.05). The modified Rankin Scale score in the operation group (2.9 ± 0.3) was lower than in the nonoperation group (3.7 ± 0.2) (P < 0.05). The incidence of pneumonia (8.6%) and renal dysfunction (14.3%) was lower in the operation group than in the nonoperation group (28.6% and 34.7%, respectively) (P < 0.05). There was no significant difference between the 2 groups in the incidence of central fever (5.7% vs. 12.2%), stress ulcer (11.4% vs. 16.3%), and ion balance disturbance (20.0% vs. 26.5%) (P > 0.05). CONCLUSIONS: Robot-assisted drainage of thalamic hemorrhage can improve prognosis and reduce the incidence of pneumonia and renal dysfunction.

Over-expression of Beclin-1 facilitates acquired resistance to histone deacetylase inhibitor-induced apoptosis.

Apoptotic cell death plays a predominant role in histone deacetylase (HDAC) inhibitor-induced cytotoxicity. Nuclear morphological changes and activation of apoptotic executors are involved in CTS203-induced cell death. However, emerging issues of HDAC inhibitor-resistance have been observed in patients. Herein, MCF-7 cells were continuously exposed to CTS203 until the derived cells could proliferate normally in its presence. The newly obtained CTS203-resistant cells were nominated as MCF-7/203R. Compared to MCF-7 original cells, the MCF-7/203R cells were less sensitive to CTS203-induced apoptosis, with a minimal 6-fold higher IC50 value. In contrast, the expression of Beclin-1 was dramatically up-regulated, positively correlated to the acquisition of CTS203-resistance. Our results revealed the participation of autophagy in acquired HDAC inhibitor-resistance and further identified Beclin-1 as a promising target for anti-drug resistance.

Discovery of potent HDAC inhibitors based on chlamydocin with inhibitory effects on cell migration.

The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, and the resulting scaffolds were combined with various zinc binding domains. Remarkably, cyclo(L-Asu(NHOH)-L-A3mc6c-L-Phe-D-Pro, compound 1 b), with a methyl group at positions 3 or 5 on the aliphatic ring, exhibited better antiproliferative effects than trichostatin A (TSA) against MCF-7 and K562 cell lines. In addition to cell-cycle arrest and apoptosis, cell migration inhibition was observed in cells treated with compound 1 b. Subsequent western blot analysis revealed that the balance between matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 1 (TIMP1) determines the degree of metalloproteinase activity in MCF-7 cells, thereby regulating cell migration. The improved inhibitory activity imparted by altering the hydrophobic substitution pattern at the bulky cap group is a valuable approach in the development of novel HDAC inhibitors.