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Critical ovarian hyperstimulation syndrome during assisted reproductive techniques (ARTs) is a life-threatening condition and is preventable when adequate steps are taken at the right time. A 30-yearold woman, who is married for 10 years, with known polycystic ovarian syndrome (PCOS), type II diabetes mellitus (DM), and hypothyroidism, was transferred to our center in critical condition a day after oocyte retrieval. This is her second intracytoplasmic sperm injection (ICSI) cycle and she was given growth hormone along with antagonist and 23 oocytes were retrieved. In the past, she had more than 12 cycles of ovulation induction, ovarian drilling, and one cycle of ICSI with 3 embryo transfers, which did not result in pregnancy. She had tachycardia, tachypnea, decreased saturation, hypotension, tense ascites, and oliguria. She was resuscitated and the computed tomography pulmonary angiogram (CTPA) showed pulmonary thromboembolism. She was managed in the intensive care unit (ICU) with intravenous (IV) fluids, oxygen, IV heparin, and tablet cabergoline 0.5 mg (Sun Pharma, Bayer House, 2nd Floor, Central Avenue, Hiranandani Estate, Thane (W) 400 607. Maharashtra, India). An abdominal paracentesis was done due to increasing distension and tachypnea and >1700 mL hemorrhagic fluid was drained. The drain was kept for 1 week, and she was started on oral anticoagulants (rivaroxaban 15 mg, Bayer Pharmaceuticals) twice daily after 10 days. She was discharged with advice to continue medication for 12 weeks. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a disease which affects the cardiopulmonary system; it is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as measured by right heart catheterization at rest, and is caused by complex and diverse mechanisms. In response to stimuli such as hypoxia and ischemia, the expression and synthesis of endothelin (ET) increase, leading to the activation of various signaling pathways downstream of it and producing effects such as the induction of abnormal vascular proliferation during the development of the disease. This paper reviews the regulation of endothelin receptors and their pathways in normal physiological processes and disease processes, and describes the mechanistic roles of ET receptor antagonists that are currently approved and used in clinical studies. Current clinical researches on ET are focused on the development of multi-target combinations and novel delivery methods to improve efficacy and patient compliance while reducing side effects. In this review, future research directions and trends of ET targets are described, including monotherapy and precision medicine. [ABSTRACT FROM AUTHOR]

The article analyzes the visual actions of Agitazo for the wetlands in Argentina, a collaborative artivism project that seeks to protect the wetlands of the Paraná Delta. Intentional fires in these areas are denounced and the causes, consequences, and responsible parties of the fires are examined. The article highlights the importance of collective action and the use of visual action in the defense of territory and life. It also reflects on the concept of "sacrifice zones" in the context of Latin American political ecology and questions the current economic model. Night projections and images shared on social media are mentioned as ways to make environmental damage and socio-environmental demands visible. [Extracted from the article]

Osteoarthritis (OA) is a prevalent joint condition that affects areas such as the knee, hip, hand, and spine. In treating mild to moderate cases of OA, treatment options such as intraarticular corticosteroids, viscosupplementation, glucosamine and chondroitin sulfate, PRP, and IL-1Ra are commonly used. This study aimed to compare the effects of IL-1 receptor antagonist (IL-1Ra) and platelet-rich plasma (PRP) on patients with Kellgren-Lawrence (KG) stage 2-3 knee osteoarthritis in terms of Visual Analog Scale (VAS) and Knee injury and osteoarthritis outcome score (KOOS). Ninety patients with KG stage 2-3 knee primary osteoarthritis were divided into two groups, with one group receiving three intraarticular IL-1Ra injections and the other group receiving three PRP injections. VAS and KOOS scores were recorded at the beginning and after six months to evaluate clinical improvement. Both the IL-1Ra and PRP groups showed statistically significant improvement in all scores, including the VAS and KOOS. After six months, the KOOS score in the IL-1Ra group was significantly higher than the PRP group, while the first-year VAS score after treatment in the IL-1Ra group was significantly lower compared to the PRP group. The mean KOOS scores increased from 44.1 to 87.8 and 46.04 to 84.43 at the end of six months in both groups, while the mean VAS scores decreased from 7.27 to 1.02 and 7.29 to 1.71 in the IL-1Ra and PRP groups, respectively. Administering intra-articular IL-1Ra once a week for three weeks can effectively improve function and reduce pain in patients with Kellgren-Lawrence stage 2-3 osteoarthritis. However, more research is necessary to validate the use of IL-1 receptor antagonists in OA treatment. [ABSTRACT FROM AUTHOR]

As a critical resource of human capital, employees might be the leading supporters of innovation management considering the integrated intellectual capital. In addition to the formal organizational structure, employees in an organization usually group informally within the institution. They conflict by taking an opposing role to other informal groups. When a manager/leader comes from outside or "someone from within the organization" takes a new position, conflicting groups quickly take a stand against the newcomer and even come together spontaneously with other groups. Hence, opposition groups' unity against this newcomer within the organization has been defined as an "Antagonist Coalition in Organizations". The antagonist action structure that is the subject of this article plays a role in innovation management and negatively affects the process. This research examines the chaotic effect of antagonist coalitions on innovation. The semi-structured observation questionnaire was used as a data collection tool in the research. The tables containing the frequency values were used to analyze the survey data. The answers to the open-ended question were analyzed by qualitative data analysis. As a result of the research, most of the participants expressed a positive opinion on an antagonist coalition in organizations and that this would drive innovation into chaos. Study findings indicate a significant relationship between the antagonist coalition in organizations and the chaos of innovation. [ABSTRACT FROM AUTHOR]

Exploration of epiphytic microorganisms from different plant parts and their exploitation for the management of plant pathogens is a relevant approach in view of greater awareness of pollution free environment. The aim of the present study was to analyze the microbial communities with special focus on antagonists isolated from the fructosphere of cowpea (Vigna unguiculata L. Walp.) and the use of organic preparations such as panchagavya, jeevamruth, compost tea, vermiwash and fish amino acid for suppression of Choanephora cucurbitarum, the pathogen inciting pod rot in cowpea. A collection of six isolates of bacteria and fungi were isolated through serial dilution technique, and their efficacy in suppressing the pathogen were tested under in vitro conditions. Among the six isolates, the bacteria and fungi with maximum inhibitory activity against the targeted pathogen were selected for further identification and in vivo assay. Based on the cultural, morphological and biochemical characters, the bacterial and fungal antagonists were identified as Pseudomonas fluorescens and Trichoderma virens, respectively. In vitro assay of the organic preparations revealed that vermiwash (5% and 10%), jeevamurth (10%) and panchagavya (10%) completely inhibited the growth of pathogen. Application of effective dose of organic preparations and the selected antagonists on the excised cowpea pods revealed that, among organic preparations jeevamurth (10%) exhibited maximum suppression of pod rot by 60.64%, however the selected bacterial antagonist, i.e., P. fluorescens gave complete suppression of the pathogen. Under in vivo conditions, jeevamurth (10%), vermiwash (5%), T. virens (106cfu/ml), and P. fluorescens (106cfu/ml) showed the maximum suppression of the pathogen and the percentage suppression was recorded as 87.33, 75.22, 75.27 and 72.31% respectively. Therefore, the present study revealed that the organic preparations such as jeevamurth (10%), vermiwash (5%), and the indigenous species of Pseudomonas fluorescens and Trichoderma virens obtained from the fructosphere can be used in integrated disease management strategies against Choanephora pod rot of cowpea. [ABSTRACT FROM AUTHOR]

Malignant melanoma is a highly metastatic tumour, resistant to treatment. Serotonin type-3 (5-HT3) receptor antagonists, such as tropisetron and ondansetron, are well-tolerated antiemetic drugs commonly used to prevent nausea caused by chemotherapy or radiotherapy. We investigated the anticancer effects of these drugs on melanoma cancer cell lines WM-266–4 and B16F10 with or without paclitaxel. We constructed IC50 curves and performed Chou–Talalay analysis, using data obtained with the MTT assay. Flow cytometry and fluorescent microscopy were used to examine characteristics of the cell cycle, cell death and cytoskeleton changes. Protein levels and activation were analysed by western blotting and molecular docking studies carried out. Data were analysed by one way ANOVA and post hoc testing. Ondansetron and tropisetron showed selective concentration-dependent cytotoxicity in melanoma cell lines WM-266–4 and B16F10. The effect in combination with paclitaxel was synergistic. The drugs did not cause cell cycle arrest but did promote characteristics of classical apoptosis, including accumulation of subG1 DNA, cleaved caspase-3, mitochondrial membrane permeability and phosphatidylserine exposure. As well, the cytosolic calcium level in the melanoma cells was enhanced, phosphorylated ERK1/2 induced and NF-κB inhibited. Finally, the formation of microtubules was shown to be impaired in melanoma cells treated with ondansetron or tropisetron. Docking studies were used to predict that these drugs could bind to the colchicine binding site on the tubulin molecule. Antiemetic drugs, already given in combination with chemotherapy, may enhance the cytotoxic effect of chemotherapy, following successful delivery to the tumour site. [ABSTRACT FROM AUTHOR]

The electromyography (EMG) cocontraction index (CCI) given by the antagonistic/agonistic Root Mean Square (RMS) amplitude ratio of the same muscle is a qualified biomarker used for spastic cocontraction quantification and management in cerebral palsy children. However, this normative EMG ratio is likely subject to a potential source of errors with biased estimates when measuring the gastrocnemius plantar flexors activity. Due to the uneven distribution of electrical activity within the muscle volume, cocontraction levels can be misestimated, if EMGs are obtained from the sole traditional bipolar sensor location recommended by SENIAM. This preliminary study, on 10 healthy children (mean age 10 yr), investigated whether surface EMG detected proximally and distally via two pairs of bipolar electrodes, within the medial gastrocnemius (MG), provides a significant difference in CCI estimates during non-dynamic (isometric dorsiflexion) and dynamic (swing phases of gait) conditions. Gait cycles were extracted from Inertial Measurement Unit sensors. Medial gastrocnemius activity was greater distally than proximally during plantar flexion when it acts as an agonist (~24±18%) and it was greater proximally during dorsiflexion (~23±9%) when it is acting as an antagonist. As a direct consequence, CCI estimates from the conventional sensor location were significantly different (~36%) from the CCIs computed by considering broader MG regions. This difference arose in all subjects during isometric efforts and in two of 10 healthy children during the swing phase of gait who presented cocontraction patterns ( $\text{p} < 0.05$ ). EMG bipolar sampling encompassing proximal and distal gastrocnemius muscle regions may reduce bias in CCI computation and provide a more representative and accurate cocontraction index that is especially important for comparisons to the diseased state.

Context The sleep-promoting activity of Nelumbo nucifera Gaertn. (Nymphaeaceae) alkaloids in leaves or seeds are well known. However, the sleep-promoting activity of the lotus rhizome (LE), which is used mainly as food, has not yet been evaluated.Objective We investigated the sleep-promoting activity of LE water extract.Materials and methods Institute of Cancer Research (ICR) mice (n = 8) were subject to a pentobarbital-induced sleep test to assess changes in sleep latency and duration following the administration of LE (80–150 mg/kg). In addition, electroencephalography analysis was performed to determine the sleep quality after LE treatment as well as the sleep recovery effect of LE using a caffeine-induced insomnia SD rat model. Real-time PCR and western blot analysis were performed to investigate the expression of neurotransmitter receptors, and the GABAA receptor antagonists were used for receptor binding analysis.Results An oral administration of 150 mg/kg LE significantly increased sleep duration by 24% compared to the control. Furthermore, LE increased nonrapid eye movement (NREM) sleep by increasing theta and delta powers. In the insomnia model, LE increased sleep time by increasing NREM sleep. Moreover, treatment with picrotoxin and flumazenil decreased the sleep time by 33% and 23%, respectively, indicating an involvement of the GABAA receptor in the sleep-enhancing activity of LE. The expression of GABAA receptors and the concentration of GABA in the brain were increased by LE.Discussion and conclusions The results suggest that the sleep-promoting activity of LE was via the GABAA receptor. Collectively, these data show that LE may promote sleep.

Abstract Background TGF-β superfamily signaling is indispensable for bone homeostasis. However, the global expression profiles of all the genes that make up this signaling module in bone and bone-related diseases have not yet been well characterized. Methods Transcriptomic datasets from human bone marrows, bone marrow-derived mesenchymal stem cells (MSCs) and MSCs of primary osteoporotic patients were used for expression profile analyses. Protein treatments, gene quantification, reporter assay and signaling dissection in MSC lines were used to clarify the interactive regulations and feedback mechanisms between TGF-β superfamily ligands and antagonists. Ingenuity Pathway Analysis was used for network construction. Results We identified TGFB1 in the ligand group that carries out SMAD2/3 signaling and BMP8A, BMP8B and BMP2 in the ligand group that conducts SMAD1/5/8 signaling have relatively high expression levels in normal bone marrows and MSCs. Among 16 antagonist genes, the dominantly expressed TGF-β superfamily ligands induced only NOG, GREM1 and GREM2 via different SMAD pathways in MSCs. These induced antagonist proteins further showed distinct antagonisms to the treated ligands and thus would make up complicated negative feedback networks in bone. We further identified TGF-β superfamily signaling is enriched in MSCs of primary osteoporosis. Enhanced expression of the genes mediating TGF-β-mediated SMAD3 signaling and the genes encoding TGF-β superfamily antagonists served as significant features to osteoporosis. Conclusion Our data for the first time unveiled the transcription landscape of all the genes that make up TGF-β superfamily signaling module in bone. The feedback mechanisms and regulatory network prediction of antagonists provided novel hints to treat osteoporosis. Video Abstract

Experiments with small laboratory animals are required for better understanding of a disease flow, for studying the mechanisms of it’s development and for the development of new therapeutic strategies. A significant part of experimental studies involve anesthesia. In this regard, the choice of the optimal anesthesia protocol is an important point of research, since an inadequate depth of anesthesia or the influence of undesirable factors can lead to death; the type, duration, and goals of the procedure should be also taken into account.We have aimed to find out what has changed in anesthesia of laboratory animals lately, which drugs are currently relevant and what is the reason for their popularity.Anesthesia of mice is challenging for several reasons: animal size, metabolic rate, and high risk of hypothermia and hypoglycemia. In addition, anesthetics affect physiological parameters and therefore even more affect the results of experiments. At the moment, there is a large list of drugs used in laboratory animals. Since they are divided into groups depending on the routes of administration, we selected the following drugs from a number of articles: injectable anesthetics (medetomidine, dexmedetomidine, zoletil‑100, ketamine, xyla, propofol) and inhalation anesthetics (isoflurane, sevoflurane). Advantages and disadvantages of the drugs and their combinations were studied and described.An analysis of the literature showed that injection anesthesia is considered the main method of anesthesia for experimental animals and is relatively well tolerated by animals; it also does not require additional bulky equipment and additional staff qualifications, there are antagonists for a number of drugs, and is also affordable.In the majority of studies inhalation anesthesia was used in long-term complex manipulations/operations, since it is more manageable, agents require minimal metabolism, and in some cases do not require additional sedation.

Abstract Background Paraoxonase 2 (PON2) is an intracellular antioxidant enzyme located at the inner mitochondrial membrane. Previous studies have found PON2 to be an important antioxidant in a variety of cellular systems, such as the cardiovascular and renal system. Recent work has also suggested that PON2 plays an important role in the central nervous system (CNS), as decreased PON2 expression in the CNS leads to higher oxidative stress and subsequent cell toxicity. However, the precise role of PON2 in the CNS is still largely unknown, and what role it may play in specific regions of the brain remains unexamined. Dopamine metabolism generates considerable oxidative stress and antioxidant function is critical to the survival of dopaminergic neurons, providing a potential mechanism for PON2 in the dopaminergic system. Methods In this study, we investigated the role of PON2 in the dopaminergic system of the mouse brain by comparing transcript and protein expression of dopaminergic-related genes in wildtype (WT) and PON2 deficient (PON2-def) mouse striatum, and exposing WT cultured primary neurons to dopamine receptor agonists. Results We found alterations in multiple key dopaminergic genes at the transcript level, however many of these changes were not observed at the protein level. In cultured neurons, PON2 mRNA and protein were increased upon exposure to quinpirole, a dopamine receptor 2/3 (DRD2/3) agonist, but not fenoldopam, a dopamine receptor 1/5 (DRD1/5) agonist, suggesting a receptor-specific role in dopamine signaling. Conclusions Our findings suggest PON2 deficiency significantly impacts the dopaminergic system at the transcript level and may play a role in mitigating oxidative stress in this system further downstream through dopamine receptor signaling.

This study examines the properties of novel guanidines, designed and synthesized as histamine H3R antagonists/inverse agonists with additional pharmacological targets. We evaluated their potential against two targets viz., inhibition of MDA-MB-231, and MCF-7 breast cancer cells viability and inhibition of AChE/BuChE. ADS10310 showed micromolar cytotoxicity against breast cancer cells, combined with nanomolar affinity at hH3R, and may represent a promising target for the development of an alternative method of cancer therapy. Some of the newly synthesized compounds showed moderate inhibition of BuChE in the single-digit micromolar concentration ranges. H3R antagonist with additional AChE/BuChE inhibitory effect might improve cognitive functions in Alzheimer's disease. For ADS10310, several in vitro ADME-Tox parameters were evaluated and indicated that it is a metabolically stable compound with weak hepatotoxic activity and can be accepted for further studies. [ABSTRACT FROM AUTHOR]

Terpenoids, one of the most important plant volatiles, mediate the communication between plants and pollinators, herbivores as well as pathogens. Recently, researchers have shown intensive interest in the complicated interactions. Linalool, an acyclic monoterpene, is one of the common flavor‐related volatiles across the plant kingdom. In this review, we summarized the biosynthesis and transcriptional regulation of terpenoids, and then focused on the biological function of linalool in plant–insect interactions. We found that flowers emitting linalool as the dominant volatile appeal to broad assemblages of pollinators, while some pollinators typically have strong preferences for these flowers as well. Hereinto, moths and bees are the main pollinators of linalool‐dominant flowers. Additionally, linalool produced by plants could defend against insect pests and pathogens. It is noteworthy that the two enantiomers of linalool have distinct functions. (S)‐(+)‐linalool mainly attracts pollinators, while (R)‐(−)‐linalool seems to act as insect repellents. Further research on the biofunctional diversity and genetic mechanisms of linalool enantiomers will reveal the complexity of plant survival strategies, and the increasing understanding of the molecular mechanisms underlying their biosynthesis and transcriptional regulation will provide theoretical foundation and practical basis for directional transformation of plants. [ABSTRACT FROM AUTHOR]

The United States is experiencing the most profound and devastating opioid crisis in history, with the number of deaths involving opioids, including prescription and illegal opioids, continuing to climb over the past two decades. This severe public health issue is difficult to combat as opioids remain a crucial treatment for pain, and at the same time, they are also highly addictive. Opioids act on the opioid receptor, which in turn activates its downstream signaling pathway that eventually leads to an analgesic effect. Among the four types of opioid receptors, the µ subtype is primarily responsible for the analgesic cascade. This review describes available 3D structures of the µ opioid receptor in the protein data bank and provides structural insights for the binding of agonists and antagonists to the receptor. Comparative analysis on the atomic details of the binding site in these structures was conducted and distinct binding interactions for agonists, partial agonists, and antagonists were observed. The findings in this article deepen our understanding of the ligand binding activity and shed some light on the development of novel opioid analgesics which may improve the risk benefit balance of existing opioids. [ABSTRACT FROM AUTHOR]

Background and purpose: GPR35, a member of the orphan G-protein-coupled receptor, was recently implicated in colorectal cancer (CRC). However, whether targeting GPR35 by antagonists can inhibit its pro-cancer role has yet to be answered. Experimental approach: We applied antagonist CID-2745687 (CID) in established GPR35 overexpressing and knock-down CRC cell lines to understand its anti-cell proliferation property and the underlying mechanism. Key results: Although GPR35 did not promote cell proliferation in 2D conditions, it promoted anchorage-independent growth in soft-agar, which was reduced by GPR35 knock-down and CID treatment. Furthermore, YAP/TAZ target genes were expressed relatively higher in GPR35 overexpressed cells and lower in GPR35 knock-down cells. YAP/TAZ activity is required for anchorageindependent growth of CRC cells. By detecting YAP/TAZ target genes, performing TEAD4 luciferase reporter assay, and examining YAP phosphorylation and TAZ protein expression level, we found YAP/TAZ activity is positively correlated to GPR35 expression level, which CID disrupted in GPR35 overexpressed cells, but not in GPR35 knock-down cells. Intriguingly, GPR35 agonists did not promote YAP/TAZ activity but ameliorated CID's inhibitory effect; GPR35-promoted YAP/TAZ activity was only partly attenuated by ROCK1/2 inhibitor. Conclusion and implications: GPR35 promoted YAP/TAZ activity partly through Rho-GTPase with its agonist-independent constitutive activity, and CID exhibited its inhibitory effect. GPR35 antagonists are promising anti-cancer agents that target hyperactivation and overexpression of YAP/TAZ in CRC. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the utility of using serum gonadotropin levels to predict optimal luteinizing hormone (LH) response to gonadotropin releasing hormone agonist (GnRHa) trigger. A retrospective cohort study was performed of all GnRH-antagonist controlled ovarian hyperstimulation (COH) cycles at an academic fertility center from 2017–2020. Cycles that utilized GnRHa alone or in combination with human chorionic gonadotropin (hCG) for trigger were included. Patient and cycle characteristics were collected from the electronic medical record. Optimal LH response was defined as a serum LH ≥ 40 mIU/mL on the morning after trigger. Total sample size was 3865 antagonist COH cycles, of which 91% had an optimal response to GnRHa trigger. Baseline FSH (B-FSH) and earliest in-cycle LH (EIC-LH) were significantly higher in those with optimal response. Multivariable logistic regression affirmed association of optimal response with EIC-LH, total gonadotropin dosage, age, BMI and Asian race. There was no difference in the number of oocytes retrieved (p = 0.14), maturity rate (p = 0.40) or fertilization rates (p = 0.49) based on LH response. There was no difference in LH response based on use of combination vs. GnRHa alone trigger (p = 0.21) or GnRHa trigger dose (p = 0.46). The EIC-LH was more predictive of LH trigger response than B-FSH (p < 0.005).The optimal B-FSH and EIC-LH values to yield an optimal LH response was ≥ 5.5 mIU/mL and ≥ 1.62 mIU/mL, respectively. In an era of personalized medicine, utilizing cycle and patient characteristics, such as early gonadotropin levels, may improve cycle outcomes and provide further individualized care. [ABSTRACT FROM AUTHOR]

Two herbal plants, Akebia quinata D. leaf/fruit and Clitoria ternatea L. flower, well-known in traditional medicine systems, were investigated using a non-target effect-directed profiling. High-performance thin-layer chromatography (HPTLC) was combined with 11 different effect-directed assays, including two multiplex bioassays, for assessing their bioactivity. Individual active zones were heart-cut eluted for separation via an orthogonal high-performance liquid chromatography column to heated electrospray ionization high-resolution mass spectrometry (HPLC–HESI-HRMS) for tentative assignment of molecular formulas according to literature data. The obtained effect-directed profiles provided information on 2,2-diphenyl-1-picrylhydrazyl scavenging, antibacterial (against Bacillus subtilis and Aliivibrio fischeri), enzyme inhibition (tyrosinase, α-amylase, β-glucuronidase, butyrylcholinesterase, and acetylcholinesterase), endocrine (agonists and antagonists), and genotoxic (SOS-Umu-C) activities. The main bioactive compound zones in A. quinata leaf were tentatively assigned to be syringin, vanilloloside, salidroside, α-hederin, cuneataside E, botulin, and oleanolic acid, while salidroside and quinatic acids were tentatively identified in the fruit. Taraxerol, kaempherol-3-rutinoside, kaempferol-3-glucoside, quercetin-3-rutinoside, and octadecenoic acid were tentatively found in the C. ternatea flower. This straightforward hyphenated technique made it possible to correlate the biological properties of the herbs with possible compounds. The meaningful bioactivity profiles contribute to a better understanding of the effects and to more efficient food control and food safety. [ABSTRACT FROM AUTHOR]

Background: Follitropin alfa (FA) is one of the most widely used exogenous gonadotropins in both agonist and antagonist protocols for controlled ovarian stimulation (COS) and in vitro fertilization (IVF). However, reports of its effectiveness are limited, particularly in terms of its impact on overall IVF outcomes and ovarian hyperstimulation syndrome (OHSS). Therefore, in this study, FA competency was investigated by evaluating its effect on IVF outcomes and OHSS, administering agonist and antagonist COS protocols. Methods: A retrospective study with 120 subjects was conducted. Outcomes comprising the number of retrieved and fertilized oocytes, quality of embryos, and clinical pregnancies were assessed. Statistical correlation between FA dose, IVF outcomes, and the incidence of OHSS was also analyzed. All statistical analyses were performed at 95% confidence level. Results: There was no significant difference in both protocols regarding retrieved oocytes (p=0.604), fertilized oocytes (p=0.761), embryo quality including good, average, poor embryo (p=0.875, p=0.565, p=0.785), and clinical pregnancy (p= 0.844). However, FA doses in the agonist protocol were shown notably higher (p= 0.001). Negative correlations were also observed between FA dose and the number of retrieved oocytes (r=-0.255, p<0.01), fertilized oocytes (r=-0.296, p<0.01), and good quality embryos (r=-0.231, p<0.05). Conclusion: Our study suggested that FA yields similar outcomes in both COS protocols, but agonist protocols require higher doses of FA and evaluation of its effect on OHSS is an important area of research for further investigation. [ABSTRACT FROM AUTHOR]

Ashwagandha (Withania somnifera L. Dunal), an Indian medicinal plant that has been used for centuries to treat insomnia, exhibits a variety of biological activities, such as improving cognitive function, immunity and anxiety. In this study, the effect of enzyme-treated Ashwagandha root extract (EA) and on sleep was evaluated using rodent models. Starch contained in the Ashwagandha root extract was removed by amylase treatment to prepare EA. To evaluate the sleep-promoting activity of EA, a pentobarbital-induced sleep test and electroencephalogram analysis were performed. In addition, the sleep-promoting mechanism of EA was elucidated by analyzing the expression of sleep-related receptors. In the pentobarbital-induced sleep test, EA dose-dependently increased sleep duration. Additionally, electroencephalogram analysis revealed that EA significantly increased δ-wave and non-rapid eye movement sleep times, which are involved in deep sleep, thereby improving sleep quality and quantity. EA also effectively relieved caffeine-induced insomnia symptoms. Furthermore, the γ-aminobutyric acid (GABA) content in the brain and mRNA and protein expression of GABAA GABAB1, and serotonin receptors were significantly increased by EA compared to the normal group. In particular, EA showed sleep-promoting activity by binding to various GABAA receptor sites. Collectively, EA exhibited sleep-promoting activity through the GABAergic system and may be used as a functional material to improve sleep deprivation. [ABSTRACT FROM AUTHOR]

Shikonin, a natural ingredient produced by Lithospermum erythrorhizon, has anti-inflammatory, anti-cancer, and anti-obesity effects. It also inhibits adipocyte differentiation; however, the underlying molecular and epigenetic mechanisms remain unclear. We performed RNA-sequencing of shikonin-treated 3T3-L1 cells. Gene ontology and gene set enrichment analysis showed that shikonin is significantly associated with genes related to adipogenesis, histone modification, and PPARγ. Shikonin treatment downregulated the mRNA expression of PPARγ-responsive genes and rosiglitazone-induced transcriptional activity of PPARγ. Microscale thermophoresis assays showed a KD value 1.4 ± 0.13 μM for binding between shikonin and PPARγ. Glutathione S-transferase pull-down assays exhibited that shikonin blocked the rosiglitazone-dependent association of PPARγ with its coactivator CBP. In addition, shikonin decreased the enrichment of the active histone code H3K4me3 and increased the repressive code H3K27me3 of PPARγ target promoters. Shikonin is a PPARγ antagonist that suppresses adipogenesis by regulating the enrichment of histone codes during adipogenesis. Therefore, it may be used to treat obesity-related disorders via epigenetic changes. [ABSTRACT FROM AUTHOR]

With interest in the development of somatostatin receptor (SSTR) targeting agents for potential application in diagnostic SPECT imaging (99mTc) or Peptide Radionuclide Receptor Therapy (PRRT, 186Re or 188Re) of neuroendocrine tumors, we present herein 99mTc/Re (radio)complexes synthesized by the integrated (radio)labeling approach of peptide cyclization via metal complexation. In particular, we utilized the potent SSTR2 peptide antagonist sequence DOTA-4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2 (DOTA-sst2-ANT) and report the syntheses and in vitro evaluations of its respective [99mTc]Tc/Re-cyclized peptides ([99mTc]Tc/Re-cyc-DOTA-sst2-ANT). The Re-cyc-DOTA-sst2-ANT complex was synthesized via an on-resin Re(V)-cyclization reaction using the ReOCl3(PPh3)2 precursor and consisted of three isomers characterized by LC–ESI-MS. The [99mTc]Tc-cyclized analogue was prepared via a ligand exchange reaction of the [99mTc][TcO]3+ core through a [99mTc]Tc-glucoheptonate intermediate with linear DOTA-sst2-ANT and was characterized by comparative HPLC studies against Re-cyc-DOTA-sst2-ANT. Good in vitro binding affinity was demonstrated in SSTR-expressing cells (AR42J) by the Re-cyc-DOTA-sst2-ANT major isomer, similar to the potent binder Lu-DOTA-sst2-ANT, in which the Lu metal was complexed by the bifunctional chelator DOTA versus via peptide cyclization. [99mTc]Tc-cyc-DOTA-sst2-ANT was obtained in high radiochemical yield, also with an elution pattern of three isomers observed by HPLC analysis, which were comparable yet not identical to those of Re-cyc-DOTA-sst2-ANT. The [99mTc]Tc-tracer complex was shown to be hydrophilic, and stability studies at 4 h demonstrated that it remained intact in both PBS and in rat serum, with low non-specific rat serum protein binding, while exhibiting more moderate stability in 1 mM cysteine. These findings demonstrate that direct Re/[99mTc]Tc-cyclization of DOTA-sst2-ANT is feasible and may be used as an alternative approach to the bifunctional chelate labeling strategy. However, given that the non-radioactive (Re) and radiotracer (99mTc) analogues are not identical and both form isomeric products in equilibrium, additional design modifications will be necessary prior to in vivo application of [99mTc]Tc/Re-cyc-DOTA-sst2-ANT. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy is the mainstay of medical treatment for prostate cancer (Pca); however, it is associated with an increased risk of adverse cardiovascular (CV) events and death. To date, CV death has been the leading noncancer cause of death in Pca patients. Both GnRH antagonists (an emerging class of drugs) and GnRH agonists (most frequently prescribed) are efficacious against Pca. However, the adverse effects, especially the adverse CV effect between them remain unclear. Methods: Through a literature search using MEDLINE, EMBASE and the Cochrane Library, all available studies comparing the safety of CV risk between GnRH antagonists and GnRH agonists in Pca patients were extracted. Comparisons of outcomes of interest between these two classes of drugs were calculated using the risk ratio (RR). Subgroup analyses were performed depending on the study design and preexisting CV disease at baseline. Results: Nine randomized controlled clinical trials (RCTs) and five real-world observational studies comprising 62160 Pca patients were included in our metaanalysis. Patients receiving GnRH antagonists experienced fewer CV events (RR: 0.66, 95% CI:0.53-0.82, P<0.001), CV death (RR:0.4, 95% CI: 0.24-0.67, P<0.001) and myocardial infarctions (RR: 0.71, 95% CI: 0.52-0.96, P=0.03). No difference was found in the incidence of stroke and heart failure. Moreover, GnRH antagonists were associated with fewer CV events in patients with preexisting CV disease but not in those without preexisting CV disease in the RCT series. Conclusion: GnRH antagonists appear to offer favorable safety in terms of adverse CV events and CV death compared with GnRH agonists among men diagnosed with Pca, especially those who had established CV disease at baseline. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate and breast cancers are the most common malignancies. Accurate diagnosis and staging of diseases are important for the prognosis and determination of treatment tactics. The gastrin-releasing peptide receptor is overexpressed in over 80% of estrogen receptor-positive breast cancers and in up to 100% of primary prostate cancers, particularly in prostate cancers of lower grades and smaller sizes. Our group has developed an imaging agent [99mTc]Tc-maSSS-PEG2-RM26 suitable for the detection of gastrin-releasing peptide receptors' expression using SPECT. We aimed to perform a first-in-human study to test the safety of [99mTc]Tc-maSSS-PEG2-RM26 administration, to study its biological distribution in normal organs, and to evaluate the agent's targeting of receptors in tumors. This phase I study was performed in six prostate and seven breast cancer patients. Single injections of the new agent were well tolerated and a number of prostate and breast cancer primary tumors as well as metastases were visualized with SPECT/CT shortly after administration. The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [99mTc]Tc-maSSS-PEG2-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 µg of [99mTc]Tc-maSSS-PEG2-RM26 (600–700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [99mTc]Tc-maSSS-PEG2-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 ± 0.0007 for male patients and 0.008 ± 0.003 mSv/MBq for female patients. The accumulation of [99mTc]Tc-maSSS-PEG2-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [99mTc]Tc-maSSS-PEG2-RM26 was safe and well tolerated. [99mTc]Tc-maSSS-PEG2-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies. [ABSTRACT FROM AUTHOR]

Purpose: Exendin, an analogue of the glucagon-like peptide 1 (GLP1), is an excellent tracer for molecular imaging of pancreatic beta cells and beta cell-derived tumours. The commonly used form, exendin-4, activates the GLP1 receptor and causes internalisation of the peptide-receptor complex. As a consequence, injection of exendin-4 can lead to adverse effects such as nausea, vomiting and hypoglycaemia and thus requires close monitoring during application. By comparison, the antagonist exendin(9-39) does not activate the receptor, but its lack of internalisation has precluded its use as a tracer. Improving the cellular uptake of exendin(9-39) could turn it into a useful alternative tracer with less side-effects than exendin-4. Methods: We conjugated exendin-4 and exendin(9-39) to the well-known cell-penetrating peptide (CPP) penetratin. We evaluated cell binding and internalisation of the radiolabelled peptides in vitro and their biodistribution in vivo. Results: Exendin-4 showed internalisation irrespective of the presence of the CPP, whereas for exendin(9-39) only the penetratin conjugate internalised. Conjugation to the CPP also enhanced the in vivo tumour uptake and retention of exendin(9-39). Conclusion: We demonstrate that penetratin robustly improves internalisation and tumour retention of exendin(9-39), opening new avenues for antagonist-based in vivo imaging of GLP1R. [ABSTRACT FROM AUTHOR]

Chemokine G-protein coupled receptors are validated drug targets for many diseases, including cancer, neurological, and inflammatory disorders. Despite much time and effort spent on therapeutic development, very few chemokine receptor antagonists are approved for clinical use. Among potential reasons for the slow progress in developing chemokine receptor inhibitors, antagonist tolerance, a progressive reduction in drug efficacy after repeated administration, is likely to play a key role. The mechanisms leading to antagonist tolerance remain poorly understood. In many cases, antagonist tolerance is accompanied by increased receptor concentration on the cell surface after prolonged exposure to chemokine receptor antagonists. This points to a possible role of altered receptor internalization and presentation on the cell surface, as has been shown for agonist (primarily opioid) tolerance. In addition, examples of antagonist tolerance in the context of other G-protein coupled receptors suggest the involvement of noncanonical signal transduction in opposing the effects of the antagonists. In this review, we summarize the available progress and challenges in therapeutic development of chemokine receptor antagonists, describe the available knowledge about antagonist tolerance, and propose new avenues for future investigation of this important phenomenon. Furthermore, we highlight the modern methodologies that have the potential to reveal novel mechanisms leading to antagonist tolerance and to propel the field forward by advancing the development of potent “tolerance-free” antagonists of chemokine receptors.

Research on transient receptor potential vanilloid-4 (TRPV4) can provide a promising potential therapeutic target in the development of novel medicines for lung disorders. TRPV4 expresses in lung tissue and plays an important role in the maintenance of respiratory homeostatic function. TRPV4 is upregulated in life-threatening respiratory diseases like pulmonary hypertension, asthma, cystic fibrosis, and chronic obstructive pulmonary diseases. TRPV4 is linked to several proteins that have physiological functions and are sensitive to a wide variety of stimuli, such as mechanical stimulation, changes in temperature, and hypotonicity, and responds to a variety of proteins and lipid mediators, including anandamide (AA), the arachidonic acid metabolite, 5,6-epoxyeicosatrienoic acid (5,6-EET), a plant dimeric diterpenoid called bisandrographolide A (BAA), and the phorbol ester 4-alpha-phorbol-12,13-didecanoate (4α-PDD). This study focused on relevant research evidence of TRPV4 in lung disorders and its agonist and antagonist effects. TRPV4 can be a possible target of discovered molecules that exerts high therapeutic potential in the treatment of respiratory diseases by inhibiting TRPV4.

ApTOLL is an aptamer that antagonizes Toll-like receptor 4 and improves functional outcomes in models of ischemic stroke and myocardial infarction. The aim of this study was to characterize the safety and pharmacokinetics of ApTOLL in healthy volunteers. A first-in-human dose-ascending, randomized, placebo-controlled phase I clinical trial to assess safety and pharmacokinetics of ApTOLL (30-min infusion intravenously) was performed in 46 healthy adult male volunteers. The study was divided into two parts: part A included seven single ascending dose levels, and part B had one multiple dose cohort. Safety and pharmacokinetic parameters were evaluated. No serious adverse events or biochemistry alterations were detected at any dose nor at any administration pattern studied. Maximum concentration was detected at the end of the infusion and mean half-life was 9.3 h. Interestingly, exposure increased in the first four levels receiving doses from 0.7 mg to 14 mg (AUC of 2,441.26 h∗ng/mL to 23,371.11 h∗ng/mL) but remained stable thereafter (mean of 23,184.61 h∗ng/mL after 70 mg). Consequently, the multiple dose study did not show any accumulation of ApTOLL. These results show an excellent safety and adequate pharmacokinetic profile that, together with the efficacy demonstrated in nonclinical studies, provide the basis to start clinical trials in patients.

Eyeblink conditioning is associated with motor learning, which requires the cerebellum and the brainstem. This article provides behavioral data on whether JNJ16259685, a selective metabotropic glutamate receptor type 1 (mGluR1) antagonist, affects eyeblink conditioning in wild-type mice (C57BL/6 J strain). The dataset contains four types of behavioral outputs pertinent to eyeblink conditioning. We used a t-test and an analysis of variance (ANOVA) to analyze the percentage of conditioned responses (CR%), peak CR latencies, onset CR latencies, and electromyography (EMG) amplitudes. The information obtained in this dataset adds to our knowledge of the molecular mechanisms underlying eyeblink conditioning and can prove beneficial for investigators studying the pharmacological effects of mGluR1 on motor learning. Future research might use this dataset as a basis for conducting experiments with different JNJ16259685 doses, administration methods, and durations than the ones used in the described procedures.

BackgroundAndrogen deprivation therapy is the mainstay of medical treatment for prostate cancer (Pca); however, it is associated with an increased risk of adverse cardiovascular (CV) events and death. To date, CV death has been the leading noncancer cause of death in Pca patients. Both GnRH antagonists (an emerging class of drugs) and GnRH agonists (most frequently prescribed) are efficacious against Pca. However, the adverse effects, especially the adverse CV effect between them remain unclear.MethodsThrough a literature search using MEDLINE, EMBASE and the Cochrane Library, all available studies comparing the safety of CV risk between GnRH antagonists and GnRH agonists in Pca patients were extracted. Comparisons of outcomes of interest between these two classes of drugs were calculated using the risk ratio (RR). Subgroup analyses were performed depending on the study design and preexisting CV disease at baseline.ResultsNine randomized controlled clinical trials (RCTs) and five real-world observational studies comprising 62160 Pca patients were included in our meta-analysis. Patients receiving GnRH antagonists experienced fewer CV events (RR: 0.66, 95% CI:0.53-0.82, P

Planar chromatography has recently been combined with six different effect-directed assays for three golden root (Rhodiola rosea L.) samples. However, the profiles obtained showed an intense tailing, making zone differentiation impossible. The profiling was therefore improved to allow for the detection of individual bioactive compounds, and the range of samples was extended to 15 commercial golden root products. Further effect-directed assays were studied providing information on 15 different effect mechanisms, i.e., (1) tyrosinase, (2) acetylcholinesterase, (3) butyrylcholinesterase, (4) β-glucuronidase, and (5) α-amylase inhibition, as well as endocrine activity via the triplex planar yeast antagonist-verified (6–8) estrogen or (9–11) androgen screen, (12) genotoxicity via the planar SOS-Umu-C bioassay, antimicrobial activity against (13) Gram-negative Aliivibrio fischeri and (14) Gram-positive Bacillus subtilis bacteria, and (15) antioxidative activity (DPPH• radical scavengers). Most of the golden root profiles obtained were characteristic, but some samples differed substantially. The United States Pharmacopeia reference product showed medium activity in most of the assays. The six most active compound zones were further characterized using high-resolution mass spectrometry, and the mass signals obtained were tentatively assigned to molecular formulae. In addition to confirming the known activities, this study is the first to report that golden root constituents inhibit butyrylcholinesterase (rosin was tentatively assigned), β-glucuronidase (rosavin, rosarin, rosiridin, viridoside, and salidroside were tentatively assigned), and α-amylase (stearic acid and palmitic acid were tentatively assigned) and that they are genotoxic (hydroquinone was tentatively assigned) and are both agonistic and antagonistic endocrine active. [ABSTRACT FROM AUTHOR]

Recent progress in the structural and molecular pharmacological understanding of the nuclear receptor, peroxisome proliferator-activated receptor gamma (hPPARγ)—a transcription factor with pleiotropic effects on biological responses—has enabled the investigation of various graded hPPARγ ligands (full agonist, partial agonist, and antagonist). Such ligands are useful tools to investigate the functions of hPPARγ in detail and are also candidate drugs for the treatment of hPPARγ-mediated diseases, such as metabolic syndrome and cancer. This review summarizes our medicinal chemistry research on the design, synthesis, and pharmacological evaluation of a covalent-binding and non-covalent-binding hPPARγ antagonist, both of which have been created based on our working hypothesis of the helix 12 (H12) holding induction/inhibition concept. X-ray crystallographic analyses of our representative antagonists complexed with an hPPARγ ligand binding domain (LBD) indicated the unique binding modes of hPPARγ LBD, which are quite different from the binding modes observed for hPPARγ agonists and partial agonists. [ABSTRACT FROM AUTHOR]

Recently, increasing numbers of studies have demonstrated that transient receptor potential ankyrin 1 (TRPA1) can be used as a potential target for the treatment of inflammatory diseases. TRPA1 is expressed in both neuronal and nonneuronal cells and is involved in diverse physiological activities, such as stabilizing of cell membrane potential, maintaining cellular humoral balance, and regulating intercellular signal transduction. TRPA1 is a multi-modal cell membrane receptor that can sense different stimuli, and generate action potential signals after activation via osmotic pressure, temperature, and inflammatory factors. In this study, we introduced the latest research progress on TRPA1 in inflammatory diseases from three different aspects. First, the inflammatory factors released after inflammation interacts with TRPA1 to promote inflammatory response; second, TRPA1 regulates the function of immune cells such as macrophages and T cells, In addition, it has anti-inflammatory and antioxidant effects in some inflammatory diseases. Third, we have summarized the application of antagonists and agonists targeting TRPA1 in the treatment of some inflammatory diseases. [ABSTRACT FROM AUTHOR]

The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor. [ABSTRACT FROM AUTHOR]

The mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expanding its interest as a pharmacological target. Non-steroidal MR antagonists (MRAs) are of particular interest to avoid side effects and achieve tissue-specific modulation of the receptor. The 1,4-dihydropyridine (1,4-DHP) ring has been identified as an appropriate scaffold to develop non-steroidal MRAs. We report the identification of a novel series of 1,4-DHP that has been guided by structure-based drug design, focusing on the less explored DHP position 2. Interestingly, substituents at this position might interfere with MR helix H12 disposition, which is essential for the recruitment of co-regulators. Several of the newly synthesized 1,4-DHPs show interesting properties as MRAs and have a good selectivity profile. These 1,4-DHPs promote MR nuclear translocation with less efficiency than the natural agonist aldosterone, which explains, at least in part, its antagonist character. Molecular dynamic studies are suggestive of several derivatives interfering with the disposition of H12 in the agonist-associated conformation, and thus, they might stabilize an MR conformation unable to recruit co-activators. [ABSTRACT FROM AUTHOR]

Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward 'non-NMDA' (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds. [ABSTRACT FROM AUTHOR]

Figs C and D show the remimazolam equivalent effect-site concentration with flumazenil bolus (bold line) and remimazolam effect-site concentration without flumazenil bolus (thin line) for 0.2 or 0.5 mg flumazenil bolus, respectively, after 6 h remimazolam infusion in the virtual patient as the same above. Reappearance of remimazolam effect after a flumazenil bolus: a larger bolus of flumazenil and a lower total remimazolam clearance are higher risks The equation 3 and pharmacokinetic simulations of remimazolam and flumazenil gives us the time course of remimazolam equivalent effect-site concentration to understand the antagonistic effect of flumazenil after a flumazenil bolus in patients undergoing remimazolam anesthesia. 1 Time course of benzodiazepine receptor occupancy rate of remimazolam and effect-site concentration of remimazolam in patients undergoing remimazolam anesthesia followed by a flumazenil bolus of 0.2 or 0.5 mg. [Extracted from the article]

Root-knot nematodes (Meloidogyne spp.) are sedentary endoparasites that cause severe economic losses to agricultural crops globally. Due to the regulations of the European Union on the application of nematicides, it is crucial now to discover eco-friendly control strategies for nematode management. Biocontrol is one such safe and reliable method for managing these polyphagous nematodes. Biocontrol agents not only control these parasitic nematodes but also improve plant growth and induce systemic resistance in plants against a variety of biotic stresses. A wide range of organisms such as bacteria, fungi, viruses, and protozoans live in their natural mode as nematode antagonists. Various review articles have discussed the role of biocontrol in nematode management in general, but a specific review on biocontrol of root-knot nematodes is not available in detail. This review, therefore, focuses on the biocontrol of root-knot nematodes by discussing their important known antagonists, modes of action, and interactions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ceramic materials are widely used in the field of prosthodontics because of their excellent mechanical properties, good biocompatibility with oral tissues, and high aesthetic properties. Good wear properties have important clinical significance for prosthodontics. OBJECTIVE: To review the mechanisms and clinical studies on the wear properties of ceramic materials for prosthodontics in order to provide ideas for the clinical selection of suitable ceramic materials. METHODS: A computer search was conducted on PubMed and Web of Science databases for studies involving the wear properties of dental restorative ceramic materials between January 2016 and April 2021. The English search terms were “dental ceramic material; wear property”. Finally, 36 articles were included for analysis. RESULTS AND CONCLUSION: (1) The wear resistance of all-ceramic materials was higher than that of resin-ceramic composites. Among the all-ceramic materials, zirconia had the best wear properties and weaker aesthetic properties. (2) Among glass ceramics, zirconia-reinforced lithium silicate glass ceramic has better wear property, but the clinical application time is short, and the long-term efficacy needs more experimental research. (3) Among the resin-ceramic composites, nano-ceramic resin materials have better wear properties than ceramic-polymer. (4) Zirconia can be chosen for full-crown restorations in the posterior region, and high-translucent zirconia ceramics or glass ceramics can be chosen for full-crown restorations in the anterior region, depending on the patient’s aesthetic needs. (5) Veneers, inlays and onlays restorations can be selected from feldspathic porcelain, glass ceramic and resin-ceramic composites, but resin-ceramic composites have poor wear resistance and need to be avoided for high stress bearing areas. (6) Nano-ceramic resin can be considered for patients with exposed dentin, fluorosis and dental erosion, but experimental studies of suitable ceramic materials for these patients are scarce. (7) Surface roughness has a significant effect on the wear properties of ceramic materials, and good polishing in clinical applications can improve the wear properties of ceramic materials, and regular review of the restorations is essential. [ABSTRACT FROM AUTHOR]

Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT2A (h5-HT2A) serotonin receptor agonists. Activation of a related receptor population, h5-HT2B receptors, has been demonstrated to result in adverse effects including cardiac valvulopathy. We previously published on the binding of several such agents at the two receptor subtypes. We hypothesized that, due to their structural similarity, the 5-HT2A and 5-HT2B receptor affinities of these agents might be related, and that QSAR studies might aid future studies. For a series of 13 compounds, it is demonstrated here that i) their published rat brain 5-HT2 receptor affinities are significantly correlated with their h5-HT2A (r = 0.942) and h5-HT2B (r = 0.916) affinities, ii) as with r5-HT2 receptor affinity, h5-HT2A affinity is correlated with the lipophilicity of the 4-position substituent (r = 0.798), iii) that eight of the ten compounds examined in functional (Ca+2 mobilization in stable cell lines generated expressing the human 5-HT2B receptor using the Flp-In T-REx system) assays acted as h5-HT2B agonists (4-substituent = H, F, Br, I, OCH2CH3, NO2, nC3H7, tC4H9) and two (n-hexyl and benzyl) as antagonists, iv) h5-HT2B affinity but not action was correlated with the lipophilicity of the 4-position substituent (r = 0.750; n = 10). The findings suggest that h5-HT2B receptor affinity, and its relationship to substituent lipophilicity, might be approximated by rat and h5-HT2A affinity but cannot be used as a predictor of h5-HT2B agonist action of 2,5-DMA analogs. Furthermore, given that certain 2,5-DMA analogs are on the clandestine market, their potential to produce cardiac side effects following persistent or chronic use via activation of h5-HT2B receptors should be considered. [ABSTRACT FROM AUTHOR]

The intracellular viral, bacterial, or parasitic pathogens evade the host immune challenges to propagate and cause fatal diseases. The microbes overpower host immunity at various levels including during entry into host cells, phagosome formation, phagosome maturation, phagosome–lysosome fusion forming phagolysosomes, acidification of phagolysosomes, and at times after escape into the cytosol. Phagolysosome is the final organelle in the phagocyte with sophisticated mechanisms to degrade the pathogens. The immune evasion strategies by the pathogens include the arrest of host cell apoptosis, decrease in reactive oxygen species, the elevation of Th2 anti-inflammatory response, avoidance of autophagy and antigen cross-presentation pathways, and escape from phagolysosomal killing. Since the phagolysosome organelle in relation to infection/cure is seldom discussed in the literature, we summarize here the common host as well as pathogen targets manipulated or utilized by the pathogens established in phagosomes and phagolysosomes, to hijack the host immune system for their benefit. These common molecules or pathways can be broad-spectrum therapeutic targets for drug development for intervention against infectious diseases caused by different intracellular pathogens. [ABSTRACT FROM AUTHOR]

Transient Receptor Potential (TRP) channels are multifunctional sensory molecules that are abundant in the skin and are involved in the sensory pathways of itch, pain, and inflammation. In this review article, we explore the complex physiology of different TRP channels, their role in modulating itch sensation, and their contributions to the pathophysiology of acute and chronic itch conditions. We also cover small molecule and topical TRP channel agents that are emerging as potential anti-pruritic treatments; some of which have shown great promise, with a few treatments advancing into clinical trials—namely, TRPV1, TRPV3, TRPA1, and TRPM8 targets. Lastly, we touch on possible ethnic differences in TRP channel genetic polymorphisms and how this may affect treatment response to TRP channel targets. Further controlled studies on the safety and efficacy of these emerging treatments is needed before clinical use. [ABSTRACT FROM AUTHOR]

Corynespora cassiicola is a pathogen that causes lesions in different organs of tomato crops. For its control, synthetic fungicides are used that require more than one application. Trichoderma spp. is a highly interactive saprophytic fungus in the rhizosphere known as a biological control agent against plant diseases and promoter of plant growth due to its different modes of action. The effect on physiological and growth variables in Solanum lycopersicum plants inoculated with spore concentrations 1x100, 1x105, 1x106, 1x107 and 1x108 of Trichoderma asperellum Ta-13-17 and Fithan®, (as a commercial control) was evaluated. As a biocontrol agent for C. cassiicola under protected conditions. The 1x106, 1x108 and Fithan® treatments obtained the highest photosynthetic rates with 20.7, 20.6 and 19.6 µmol m-2 s-1 respectively. The 1x108 conidia mL-1 treatment obtained the highest means in the photosynthesis variables 20.6 µmol m-2 s-1, yield 1347.02 g per plant and presented a lower percentage of final severity, lower speed in the distribution of the disease and lower accumulation of area under the disease progress curve. [ABSTRACT FROM AUTHOR]

This paper presents a process for preparing from sea buckthorn branches sawdust of a compost by using a multipurpose Trichoderma strain (T. harzianum Td50b). The used strain accelerates the degradation of the lignocellulosic material and has biocontrol and plant biostimulant characteristics. The branches, resulting as a byproduct of harvesting sea buckthorn berries and leaves, were grounded and extracted to recover bioactive ingredients - flavonols, flavones, phenolic acids, proanthocyanidins, triterpenoids, hydrolysable tannins, serotonin. The resulting sawdust, depleted in polyphenols with potential anti-fungal activity, was normalized to 90% water activity with ammonium nitrate solution 0.2M, supplemented with 10% eggshells powder, and inoculated with 2% alginates beads granules containing 109 spores T. harzianum Td50b per gram. After incubation for 50 days at room temperature in aerobic conditions, the survival of Trichoderma was analyzed by cultivation on selective media. The Trichoderma reisolated from sea buckthorn branch compost maintained its antagonistic and plant biostimulant characteristics. [ABSTRACT FROM AUTHOR]