Showing papers in "Acta Pharmacologica Sinica in 2012"
TL;DR: The most widely used GPCR assays and recent advances in HTS technologies for G PCR drug discovery are summarized.
Abstract: G-protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic targets for a broad spectrum of diseases. The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery. Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation. Taking advantage of the continuously deepening understanding of GPCR signal transduction, many G-protein-independent pathways are utilized to detect the activity of GPCRs, and may provide additional information on functional selectivity of candidate compounds. With the combination of automated imaging systems and label-free detection systems, such assays are now suitable for high-throughput screening (HTS). In this review, we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery.
282 citations
TL;DR: In the current mini-review, a number of monogenetic and polygenic models of obesity will be discussed in view of their translational character.
Abstract: Obesity and obesity-related metabolic diseases represent a growing socioeconomic problem throughout the world. Great emphasis has been put on establishing treatments for this condition, including pharmacological intervention. However, there are many obstacles and pitfalls in the development process from pre-clinical research to the pharmacy counter, and there is no certainty that what has been observed pre-clinically will translate into an improvement in human health. Hence, it is important to test potential new drugs in a valid translational model early in their development. In the current mini-review, a number of monogenetic and polygenic models of obesity will be discussed in view of their translational character.
236 citations
TL;DR: Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved.
Abstract: Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field.
234 citations
TL;DR: In this article, the authors provide an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades.
Abstract: This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented.
173 citations
TL;DR: It is demonstrated that piperine is an effective antitumor compound in vitro and in vivo, and has the potential to be developed as a new anticancer drug.
Abstract: Aim: To investigate the effects of piperine, a major pungent alkaloid present in Piper nigrum and Piper longum , on the tumor growth and metastasis of mouse 4T1 mammary carcinoma in vitro and in vivo , and elucidate the underlying mechanisms.
Methods: Methods: Growth of 4T1 cells was assessed using MTT assay. Apoptosis and cell cycle of 4T1 cells were evaluated with flow cytometry, and the related proteins were examined using Western blotting. Real-time quantitative PCR was applied to detect the expression of matrix metalloproteinases (MMPs). A highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model was used to evaluate the in vivo antitumor activity. Piperine was injected into tumors every 3 d for 3 times.
Results: Results: Piperine (35–280 μmol/L) inhibited the growth of 4T1 cells in time- and dose-dependent manners (the IC 50 values were 105±1.08 and 78.52±1.06 μmol/L, respectively, at 48 and 72 h). Treatment of 4T1 cells with piperine (70–280 μmol/L) dose-dependently induced apoptosis of 4T1 cells, accompanying activation of caspase 3. The cells treated with piperine (140 and 280 μmol/L) significantly increased the percentage of cells in G 2 /M phase with a reduction in the expression of cyclin B1. Piperine (140 and 280 μmol/L) significantly decreased the expression of MMP-9 and MMP-13, and inhibited 4T1 cell migration in vitro . Injection of piperine (2.5 and 5 mg/kg) dose-dependently suppressed the primary 4T1 tumor growth and injection of piperine (5 mg/kg) significantly inhibited the lung metastasis.
Conclusion: Conclusion: These results demonstrated that piperine is an effective antitumor compound in vitro and in vivo , and has the potential to be developed as a new anticancer drug.
163 citations
TL;DR: This review focuses on the signaling transduction pathways of the adhesion GPCR family, the LGR sub family, and the PSGR subfamily, and their potential functions in immunology, development, and cancers.
Abstract: The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. GPCRs are the most successful targets of modern medicine, and approximately 36% of marketed pharmaceuticals target human GPCRs. However, the endogenous ligands of more than 140 GPCRs remain unidentified, leaving the natural functions of those GPCRs in doubt. These are the so-called orphan GPCRs, a great source of drug targets. This review focuses on the signaling transduction pathways of the adhesion GPCR family, the LGR subfamily, and the PSGR subfamily, and their potential functions in immunology, development, and cancers. In this review, we present the current approaches and difficulties of orphan GPCR deorphanization and characterization.
153 citations
TL;DR: Current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo are delineated.
Abstract: The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC50, but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.
151 citations
TL;DR: It is envisioned that activation of β2AR in combination with clinically used β1AR blockade should provide a safer and more effective therapy for the treatment of heart failure.
Abstract: β-adrenergic receptor (βAR) stimulation by the sympathetic nervous system or circulating catecholamines is broadly involved in peripheral blood circulation, metabolic regulation, muscle contraction, and central neural activities. In the heart, acute βAR stimulation serves as the most powerful means to regulate cardiac output in response to a fight-or-flight situation, whereas chronic βAR stimulation plays an important role in physiological and pathological cardiac remodeling.There are three βAR subtypes, β(1)AR, β(2)AR and β(3)AR, in cardiac myocytes. Over the past two decades, we systematically investigated the molecular and cellular mechanisms underlying the different even opposite functional roles of β(1)AR and β(2)AR subtypes in regulating cardiac structure and function, with keen interest in the development of novel therapies based on our discoveries. We have made three major discoveries, including (1) dual coupling of β(2)AR to G(s) and G(i) proteins in cardiomyocytes, (2) cardioprotection by β(2)AR signaling in improving cardiac function and myocyte viability, and (3) PKA-independent, CaMKII-mediated β(1)AR apoptotic and maladaptive remodeling signaling in the heart. Based on these discoveries and salutary effects of β(1)AR blockade on patients with heart failure, we envision that activation of β(2)AR in combination with clinically used β(1)AR blockade should provide a safer and more effective therapy for the treatment of heart failure.
138 citations
TL;DR: An understanding of the signaling paradigms of GPCRs in inflammatory cells is likely to facilitate translational research and development of improved anti-inflammatory therapies.
Abstract: G protein-coupled receptors (GPCRs) play important roles in inflammation. Inflammatory cells such as polymorphonuclear leukocytes (PMN), monocytes and macrophages express a large number of GPCRs for classic chemoattractants and chemokines. These receptors are critical to the migration of phagocytes and their accumulation at sites of inflammation, where these cells can exacerbate inflammation but also contribute to its resolution. Besides chemoattractant GPCRs, protease activated receptors (PARs) such as PAR1 are involved in the regulation of vascular endothelial permeability. Prostaglandin receptors play different roles in inflammatory cell activation, and can mediate both proinflammatory and anti-inflammatory functions. Many GPCRs present in inflammatory cells also mediate transcription factor activation, resulting in the synthesis and secretion of inflammatory factors and, in some cases, molecules that suppress inflammation. An understanding of the signaling paradigms of GPCRs in inflammatory cells is likely to facilitate translational research and development of improved anti-inflammatory therapies.
129 citations
TL;DR: In this article, lymphatic decongestive therapy, medications and supplements are recommended to reduce the abnormal subcutaneous adipose tissue (SAT) of rare adipose disorders.
Abstract: Rare adipose disorders (RADs) including multiple symmetric lipomatosis (MSL), lipedema and Dercum's disease (DD) may be misdiagnosed as obesity. Lifestyle changes, such as reduced caloric intake and increased physical activity are standard care for obesity. Although lifestyle changes and bariatric surgery work effectively for the obesity component of RADs, these treatments do not routinely reduce the abnormal subcutaneous adipose tissue (SAT) of RADs. RAD SAT likely results from the growth of a brown stem cell population with secondary lymphatic dysfunction in MSL, or by primary vascular and lymphatic dysfunction in lipedema and DD. People with RADs do not lose SAT from caloric limitation and increased energy expenditure alone. In order to improve recognition of RADs apart from obesity, the diagnostic criteria, histology and pathophysiology of RADs are presented and contrasted to familial partial lipodystrophies, acquired partial lipodystrophies and obesity with which they may be confused. Treatment recommendations focus on evidence-based data and include lymphatic decongestive therapy, medications and supplements that support loss of RAD SAT. Associated RAD conditions including depression, anxiety and pain will improve as healthcare providers learn to identify and adopt alternative treatment regimens for the abnormal SAT component of RADs. Effective dietary and exercise regimens are needed in RAD populations to improve quality of life and construct advanced treatment regimens for future generations.
123 citations
TL;DR: Rutin exerts stronger protection against nitrosative stress and hepatocellular damage but has weaker antioxidant and anti-inflammatory activities and antifibrotic potential than quercetin, which may be attributed to the presence of a rutinoside moiety in position 3 of the C ring.
Abstract: To investigate the mechanisms underlying the protective effects of quercetin-rutinoside (rutin) and its aglycone quercetin against CCl4-induced liver damage in mice. BALB/cN mice were intraperitoneally administered rutin (10, 50, and 150 mg/kg) or quercetin (50 mg/kg) once daily for 5 consecutive days, followed by the intraperitoneal injection of CCl4 in olive oil (2 mL/kg, 10% v/v). The animals were sacrificed 24 h later. Blood was collected for measuring the activities of ALT and AST, and the liver was excised for assessing Cu/Zn superoxide dismutase (SOD) activity, GSH and protein concentrations and also for immunoblotting. Portions of the livers were used for histology and immunohistochemistry. Pretreatment with rutin and, to a lesser extent, with quercetin significantly reduced the activity of plasma transaminases and improved the histological signs of acute liver damage in CCl4-intoxicated mice. Quercetin prevented the decrease in Cu/Zn SOD activity in CCl4-intoxicated mice more potently than rutin. However, it was less effective in the suppression of nitrotyrosine formation. Quercetin and, to a lesser extent, rutin attenuated the inflammation in the liver by down-regulating the CCl4-induced activation of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α) and cyclooxygenase (COX-2). The expression of inducible nitric oxide synthase (iNOS) was more potently suppressed by rutin than by quercetin. Treatment with both flavonoids significantly increased NF-E2-related factor 2 (Nrf2) and heme oxygenase (HO-1) expression in injured livers, although quercetin was less effective than rutin at an equivalent dose. Quercetin more potently suppressed the expression of transforming growth factor-β1 (TGF-β1) than rutin. Rutin exerts stronger protection against nitrosative stress and hepatocellular damage but has weaker antioxidant and anti-inflammatory activities and antifibrotic potential than quercetin, which may be attributed to the presence of a rutinoside moiety in position 3 of the C ring.
TL;DR: The present review briefly describes efforts made by researchers in China, particularly in this Institute on synthesis of new qinghaosu derivatives and analogs, investigation on their bioactivities and mode of actions.
Abstract: Qinghaosu and its derivatives are widely used in the world as a new generation of antimalarial drug. Up to now, some important progresses of Qinghaosu research have been made, including synthesis of new qinghaosu derivatives and analogs, investigation on their bioactivities and mode of actions. The present review briefly describes these efforts made by researchers in China, particularly in this Institute.
TL;DR: In the mice models, oral administration of AA significantly attenuated cognitive deficits in the Morris water maze test, and restored lipid peroxidation and glutathione and the activity of SOD in the hippocampus and cortex to the control levels.
Abstract: Asiatic acid, a pentacyclic triterpene in Centella asiatica , attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells
TL;DR: The general structural principles that guide hormone binding by Class B ECDs are summarized and their implications in the design of peptide hormone analogs for therapeutic purposes are summarized.
Abstract: Class B G-protein-coupled receptors (GPCRs) are receptors for peptide hormones that include glucagon, parathyroid hormone, and calcitonin. These receptors are involved in a wide spectrum of physiological activities, from metabolic regulation and stress control to development and maintenance of the skeletal system. As such, they are important drug targets for the treatment of diabetes, osteoporosis, and stress related disorders. Class B GPCRs are organized into two modular domains: an extracellular domain (ECD) and a helical bundle that contains seven transmembrane helices (TM domain). The ECD is responsible for the high affinity and specificity of hormone binding, and the TM domain is required for receptor activation and signal coupling to downstream G-proteins. Although the structure of the full-length receptor remains unknown, the ECD structures have been well characterized for a number of Class B GPCRs, revealing a common fold for ligand recognition. This review summarizes the general structural principles that guide hormone binding by Class B ECDs and their implications in the design of peptide hormone analogs for therapeutic purposes.
TL;DR: GLP-1 may prevent or delay the formation of atherosclerosis in diabetes mellitus by improving the function of eNOS in HUVECs through the GLp-1R-dependent and GLP- 1(9–36)-related pathways.
Abstract: To investigate the effects of glucagon-like peptide-1 (GLP-1) on endothelial NO synthase (eNOS) in human umbilical vein endothelial cells (HUVECs), and elucidate whether GLP-1 receptor (GLP-1R) and GLP-1(9–36) are involved in these effects. HUVECs were used. The activity of eNOS was measured with NOS assay kit. Phosphorylated and total eNOS proteins were detected using Western blot analysis. The level of eNOS mRNA was quantified with real-time RT-PCR. Incubation of HUVECs with GLP-1 (50–5000 pmol/L) for 30 min significantly increased the activity of eNOS. Incubation of HUVECs with GLP-1 (500–5000 pmol/L) for 5 or 10 min increased eNOS phosphorylated at ser-1177. Incubation with GLP-1 (5000 pmol/L) for 48 h elevated the level of eNOS protein, did not affect the level of eNOS mRNA. GLP-1R agonists exenatide and GLP-1(9–36) at the concentration of 5000 pmol/L increased the activity, phosphorylation and protein level of eNOS. GLP-1R antagonist exendin(9–39) or DPP-4 inhibitor sitagliptin, which abolished GLP-1(9–36) formation, at the concentration of 5000 pmol/L partially blocked the effects of GLP-1 on eNOS. GLP-1 upregulated the activity and protein expression of eNOS in HUVECs through the GLP-1R-dependent and GLP-1(9–36)-related pathways. GLP-1 may prevent or delay the formation of atherosclerosis in diabetes mellitus by improving the function of eNOS.
TL;DR: The results demonstrate that Cur-NPs-APgp targeted to P-gp on the cell surface membrane of KB-V1 cells, thus enhancing the cellular uptake and cytotoxicity of Cur.
Abstract: To compare the anti-cancer activity and cellular uptake of curcumin (Cur) delivered by targeted and non-targeted drug delivery systems in multidrug-resistant cervical cancer cells. Cur was entrapped into poly (DL-lactide-co-glycolide) (PLGA) nanoparticles (Cur-NPs) in the presence of modified-pluronic F127 stabilizer using nano-precipitation technique. On the surface of Cur-NPs, the carboxy-terminal of modified pluronic F127 was conjugated to the amino-terminal of anti-P-glycoprotein (P-gp) (Cur-NPs-APgp). The physical properties of the Cur-NPs, including particle size, zeta potential, particle morphology and Cur release kinetics, were investigated. Cellular uptake and specificity of the Cur-NPs and Cur-NPs-APgp were detected in cervical cancer cell lines KB-V1 (higher expression of P-gp) and KB-3-1 (lower expression of P-gp) using fluorescence microscope and flow cytometry, respectively. Cytotoxicity of the Cur-NPs and Cur-NPs-APgp was determined using MTT assay. The particle size of Cur-NPs and Cur-NPs-APgp was 127 and 132 nm, respectively. The entrapment efficiency and actual loading of Cur-NPs-APgp (60% and 5 μg Cur/mg NP) were lower than those of Cur-NPs (99% and 7 μg Cur/mg NP). The specific binding of Cur-NPs-APgp to KB-V1 cells was significantly higher than that to KB-3-1 cells. Cellular uptake of Cur-NPs-APgp into KB-V1 cells was higher, as compared to KB-3-1 cells. However, the cellular uptake of Cur-NPs and Cur-NPs-IgG did not differ between the two types of cells. Besides, the cytotoxicity of Cur-NPs-APgp in KB-V1 cells was higher than those of Cur and Cur-NPs. The results demonstrate that Cur-NPs-APgp targeted to P-gp on the cell surface membrane of KB-V1 cells, thus enhancing the cellular uptake and cytotoxicity of Cur.
TL;DR: In this article, the importance of childhood obesity for disease susceptibility later in life, and the need for prevention and treatment are also discussed, as well as the importance to recognize childhood obesity as a disease condition and its permissive role in aggravating the development of other diseases.
Abstract: Childhood obesity has become major health concern for physicians, parents, and health agencies around the world. Childhood obesity is associated with an increased risk for other diseases not only during youth but also later in life, including diabetes, arterial hypertension, coronary artery disease, and fatty liver disease. Importantly, obesity accelerates atherosclerosis progression already in children and young adults. With regard to pathophysiological changes in the vasculature, the striking similarities between physiological changes related to aging and obesity-related abnormalities are compatible with the concept that obesity causes “premature” vascular aging. This article reviews factors underlying the accelerated vascular disease development due to obesity. It also highlights the importance of recognizing childhood obesity as a disease condition and its permissive role in aggravating the development of other diseases. The importance of childhood obesity for disease susceptibility later in life, and the need for prevention and treatment are also discussed.
TL;DR: This paper reviews the recent findings regarding the mechanisms underlying the pharmacological actions of the active components of S miltiorrhiza depside salt, based on published works and the authors' own observations.
Abstract: Salvia miltiorrhiza, a traditional medical herb known as danshen, has been widely used in China to improve blood circulation, relieve blood stasis, and treat coronary heart disease. S miltiorrhiza depside salt is a novel drug recently developed at the Shanghai Institute of Materia Medica; it contains magnesium lithospermate B (MLB) and its analogs, rosmarinic acid (RA) and lithospermic acid (LA), as active components. The drug has been used in the clinic to improve blood circulation and treat coronary heart disease. The pharmacological effects of the depside salt from S miltiorrhiza and its components have been extensively investigated. Experimental studies have demonstrated that magnesium lithospermate B possesses a variety of biological activities, especially protective effects in the cardiovascular system such as attenuation of atherosclerosis and protection against myocardial ischemia-reperfusion injury. Rosmarinic acid and lithospermic acid also show beneficial effects on the cardiovascular system. This paper reviews the recent findings regarding the mechanisms underlying the pharmacological actions of the active components of S miltiorrhiza depside salt, based on published works and our own observations.
TL;DR: The precise steps that occur during the receptor activation process are demonstrated, which underlie the possibilities by which receptor function may be altered by different approaches.
Abstract: The G-protein-coupled receptors (GPCRs) are one of the largest super families of cell-surface receptors and play crucial roles in virtually every organ system. One particular family of GPCRs, the class C GPCRs, is distinguished by a characteristically large extracellular domain and constitutive dimerization. The structure and activation mechanism of this family result in potentially unique ligand recognition sites, thereby offering a variety of possibilities by which receptor activity might be modulated using novel compounds. In the present article, we aim to provide an overview of the exact sites and structural features involved in ligand recognition of the class C GPCRs. Furthermore, we demonstrate the precise steps that occur during the receptor activation process, which underlie the possibilities by which receptor function may be altered by different approaches. Finally, we use four typical family members to illustrate orthosteric and allosteric sites with representative ligands and their corresponding therapeutic potential.
TL;DR: Results demonstrate that GL alleviates rat myocardial I/R-induced injury via directly inhibiting extracellular HMGB1 cytokine activity and blocking the phospho-JNK/Bax pathway.
Abstract: Glycyrrhizin protects rat heart against ischemia-reperfusion injury through blockade of HMGB1-dependent phospho-JNK/Bax pathway
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TL;DR: A broad overview on the biological activity elicited by GPCRs in tumor cells and the molecular mechanisms by which these receptors exert a primary action in cancer progression are provided to contribute to the identification of novel pharmacological approaches for cancer patients.
Abstract: G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.
TL;DR: Gly can attenuate the transient spinal cord ischemic injury in rats via reducing inflammatory cytokines and inhibiting the release of HMGB1 through reduced inflammatory cytokine levels and the number of apoptotic neurons.
Abstract: To investigate the neuroprotective effect of glycyrrhizin (Gly) against the ischemic injury of rat spinal cord and the possible role of the nuclear protein high-mobility group box 1 (HMGB1) in the process. Male Sprague-Dawley rats were subjected to 45 min aortic occlusion to induce transient lumbar spinal cord ischemia. The motor functions of the animals were assessed according to the modified Tarlov scale. The animals were sacrificed 72 h after reperfusion and the lumbar spinal cord segment (L2–L4) was taken out for histopathological examination and Western blotting analysis. Serum inflammatory cytokine and HMGB1 levels were analyzed using ELISA. Gly (6 mg/kg) administered intravenously 30 min before inducing the transient lumbar spinal cord ischemia significantly improved the hind-limb motor function scores, and reduced the number of apoptotic neurons, which was accompanied by reduced levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the plasma and injured spinal cord. Moreover, the serum HMGB1 level correlated well with the serum TNF-α, IL-1β and IL-6 levels during the time period of reperfusion. The results suggest that Gly can attenuate the transient spinal cord ischemic injury in rats via reducing inflammatory cytokines and inhibiting the release of HMGB1.
TL;DR: An overview of the pharmacokinetics of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials are started.
Abstract: Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.
TL;DR: Oral administration of LF preserves the bone mass and improves the bone microarchitecture, and enhances bone formation, reduces bone resorption, and decreases bone mass loss, possibly through the regulation of OPG/RANKL/ RANK pathway.
Abstract: Bovine lactoferrin improves bone mass and microstructure in ovariectomized rats via OPG/RANKL/RANK pathway
TL;DR: Hh signaling pathway mediates invasion and metastasis of human HCC by up-regulating the protein expression of MMP-9 via ERK pathway.
Abstract: Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway
TL;DR: This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of butyrylcholinesterase (BChE) activity.
Abstract: Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors
TL;DR: GA inhibits TNF-α-induced invasion of PC3 cells via inactivation of the PI3K/Akt and NF-κB signaling pathways, which may offer a novel approach for the treatment of human prostate cancer.
Abstract: Gambogic acid inhibits TNF-α-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-κB signaling pathways
TL;DR: A possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH is highlighted.
Abstract: Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences. Chronic intermittent hypoxia (IH) is a major component of OSA. In recent years, substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions, many of which are based on studies in animal models. A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions. Among these, the roles of oxidative stress and apoptosis-related neural injury are widely accepted. Here, focusing on results derived from animal studies, we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH. The possible relationship between BDNF and previous findings on this subject will be elucidated.
TL;DR: The present article is made to discuss the current progress and future perspective for huperzine A therapy in AD.
Abstract: Huperzine A, an active Lycopodium alkaloid extracted from traditional Chinese herb, is a potent, selective and reversible acetylcholinesterase (AChE) inhibitor and has been widely used in China for the treatment of Alzheimer's disease (AD). Accordingly, some new mechanisms of action for huperzine A have been discovered over the past decades. In addition to its AChE inhibitory effect, potent multifaceted neuroprotective effect through activating cholinergic system and directly acting on mitochondria have been explored. Moreover, in order to maximize the efficacy and safety of huperzine A therapy, great efforts have been made to optimize drug delivery system. In the present article, an attempt is made to discuss the current progress and future perspective for huperzine A therapy in AD.
TL;DR: β-Asarone protects PC12 cells against OGD/R-induced injury partly due to attenuating Beclin-1-dependent autophagy caused by decreasing [Ca2+]i and increasing MMP.
Abstract: Aim: To explore the effects of β-asarone from Acorus Tatarinowii Schott on autophagy in an ischemic stroke model of PC12 cells.
Methods: The ischemic stroke model of PC12 cells was made by OGD/R (2 h oxygen-glucose deprivation followed by 24 h reperfusion). Drug administration was started 1 h before OGD and last for 3 h. Then the cells were incubated in the drug-free and full culture medium under normoxic conditions for 24 h. After the treatments, Beclin-1, intracellular free calcium concentration ([Ca 2+ ] i ) and mitochondrial membrane potential (MMP) were analyzed using flow cytometry. Cell viability was measured using MTT assay. Cell morphology was studied under inverted phase contrast microscope, and autophagosomes were observed under transmission electron microscope.
Results: Pretreatment with β-asarone (20, 30, or 45 μg/mL) or the calcium channel antagonist nimodipine (10 μmol/L) significantly increased the cell viability and MMP, and decreased Beclin-1 expression and [Ca 2+ ] i in OGD/R-treated PC12 cells. Under inverted phase contrast microscope, pretreatment with β-asarone or nimodipine dramatically increase the number of cells and improved the cellular morphology. Autophagosomes were found in OGD/R-treated PC12 cells as well as in drug plus OGD/R-treated PC12 cells.
Conclusion: β-Asarone protects PC12 cells against OGD/R-induced injury partly due to attenuating Beclin-1-dependent autophagy caused by decreasing [Ca 2+ ] i and increasing MMP.