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The insulin and dopaminergic systems in the brain are associated with schizophrenia and Parkinson's disease with respect to etiology and treatment. The present study investigated the crosstalk between the insulin receptor (IR) and dopamine receptor and found that insulin stimulation selectively inhibits signaling of D3R in a PKCβII‐dependent manner. Upon insulin stimulation, E3 ligase enzyme Mdm2 moves out of the nucleus to ubiquitinate PKCβII. Subsequently, ubiquitinated PKCβII translocates to the cell membrane and interacts with D3R in a phosphorylation‐dependent manner at S229/257, resulting in the attenuation of D3R signaling and initiating clathrin‐mediated endocytosis and downregulation. Considering that both IR and D3R are closely related to some neuropsychosis, this study could provide new molecular insight into the etiology of the disorder. [ABSTRACT FROM AUTHOR]

Dopamine D2 receptor (D2R) has been shown to activate extracellular signal‐regulated kinases (ERKs) via distinct pathways dependent on either G‐protein or β‐arrestin. However, there has not been a systematic study of the regulatory process of D2R‐mediated ERKs activation by G protein‐ versus β‐arrestin‐dependent signaling since D2R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D2R‐mediated ERKs activation via these two pathways. Our results showed that G protein‐dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β‐arrestin‐dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein‐ and β‐arrestin‐dependent pathway‐mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2‐CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3‐kinase inhibitor all blocked G protein‐dependent ERKs activation. In contrast, GRK2 and β‐Arr2 played a main role in β‐arrestin‐dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho‐ERKs, β‐Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes. [ABSTRACT FROM AUTHOR]

A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and β-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson's disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying β-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R β-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R β-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) lies at the basis of carrying forward Chinese culture, and the characteristics of Chinese culture can be elucidated on the basis of Confucianism. Although the original meanings of medicine and Confucianism are quite different, the two have been blended in the long history of Chinese civilization. This article first analyzes the unidirectional relationship between Confucianism and medical application, including the combination of technique and knowledge, the lack of essentials, failure to connect to each other, and difficulty in interpretation. Second, it horizontally explains the reverse creation of classic medical books with a Confucian interpretation, including improving the medical state, interpreting scriptures quoting scriptures to interpret scriptures, textual research of the medical compendium, and introducing new knowledge. Third, it expounds their mutual involvement and application in the multivariate harmony of medical and Confucian interests. Whether it is the benevolent talk of Confucianism by doctors or the sincere words on medicine by Confucianists, they areit is one of the powers that shape the style of Chinese medicine. Only by intensively studying classics detailing, deeply examining and reasoning, and seeking common grounds while preserving differences reserving differences, can we accurately explore the influence of academic thoughts on TCM and comprehensively describe the cultural trajectory of the integration of medicine and Confucianism. [ABSTRACT FROM AUTHOR]

Bi2Sn2O7 with flower-like hierarchical architecture was successfully synthesized via a facile template-free hydrothermal method. The structure–property relationships of such unique structured Bi2Sn2O7 were studied. The results show that the 3D flower-like Bi2Sn2O7 hierarchical architecture is composed of 2D Bi2Sn2O7 nanosheets, which increases the specific surface area of Bi2Sn2O7, which is about four times that of Bi2Sn2O7 nanoparticles. Meanwhile, 2D nanosheets result in an effective separation of photo-generated carries, and the average carrier lifetime of flower-like Bi2Sn2O7 is 3.26 ns, which is longer than that of Bi2Sn2O7 nanoparticles (1.88 ns). Therefore, the flower-like Bi2Sn2O7 displays excellent photocatalytic activity for degrading tetracycline hydrochloride compared with Bi2Sn2O7 nanoparticles. The active species trapping test confirmed that h+ and ˙O2− are dominant reactive species in the photocatalytic reaction. Moreover, this novel structure can also integrate the advantages of nano-sized materials with high surface area and micro-sized materials with good dispersion, exhibiting excellent properties of high photocatalytic activity, easy recyclability and good catalytic stability. [ABSTRACT FROM AUTHOR]

CcmG is a periplasmic, membrane-anchored protein widely distributed in a variety of species. In Escherichia coli, the CcmG protein always acts as a weak reductant in the electron transport chain during cytochrome c maturation (Ccm). Here we report H, N and C backbone and side-chain resonance assignments of the reduced CcmG protein (residues 19-185, renumbered as 1-167) from E. coli. This work lays the essential basis for the further structural and functional analysis of reduced CcmG. [ABSTRACT FROM AUTHOR]

Dopamine D 2 receptor (D 2 R) plays a key role in the regulation of glucose homeostasis by stimulating the secretion of many glucoregulatory hormones. Insulin resistance (IR) is associated with the pathogenesis of metabolic disorders which occurs when PI3K/Akt signaling pathway is downregulated. However, the potential involvement of D 2 R in insulin resistance remains unclear. In the present study, we investigated the regulation of glucose transport by D2-like receptors and discovered that activation of D 2 R, but not D 3 R or D 4 R, suppressed insulin-induced 2-DOG uptake and Glut4 membrane translocation in a GRK2- and Src-dependent manner. Further study revealed that activation of D 2 R inhibits insulin-induced phosphorylation of Akt at Thr308 and Ser473, which are hallmarks of its kinase activity, by increasing the interaction of tyrosine phosphorylated GRK2 with Akt and then preventing Akt from interacting with PDK1. Thus, this study demonstrates that Src mediated GRK2 tyrosine phosphorylation is an essential physiological event that mediates the roles of D 2 R in insulin resistance. • D2-like receptors were studied in correlation with their roles in insulin resistance. • D 2 R, not D 3 R or D 4 R, exerted negative effects on insulin-induced 2-DOG uptake and Glut4 translocation. • Tyrosine-phosphorylated GRK2 interacts with Akt, resulting in the suppression of insulin-induced Akt kinase activity. • Activation of D 2 R mediated inhibition of insulin-induced interaction between PDK1 and Akt. [ABSTRACT FROM AUTHOR]

The insulin and dopaminergic systems in the brain are associated with schizophrenia and Parkinson's disease with respect to etiology and treatment. The present study investigated the crosstalk between the insulin receptor (IR) and dopamine receptor and found that insulin stimulation selectively inhibits signaling of D 3 R in a PKCβII-dependent manner. Upon insulin stimulation, E3 ligase enzyme Mdm2 moves out of the nucleus to ubiquitinate PKCβII. Subsequently, ubiquitinated PKCβII translocates to the cell membrane and interacts with D 3 R in a phosphorylation-dependent manner at S229/257, resulting in the attenuation of D 3 R signaling and initiating clathrin-mediated endocytosis and downregulation. Considering that both IR and D 3 R are closely related to some neuropsychosis, this study could provide new molecular insight into the etiology of the disorder., (© 2024 Federation of European Biochemical Societies.)

Dopamine D 2 receptor (D 2 R) has been shown to activate extracellular signal-regulated kinases (ERKs) via distinct pathways dependent on either G-protein or β-arrestin. However, there has not been a systematic study of the regulatory process of D 2 R-mediated ERKs activation by G protein- versus β-arrestin-dependent signaling since D 2 R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D 2 R-mediated ERKs activation via these two pathways. Our results showed that G protein-dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β-arrestin-dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein- and β-arrestin-dependent pathway-mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2-CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3-kinase inhibitor all blocked G protein-dependent ERKs activation. In contrast, GRK2 and β-Arr2 played a main role in β-arrestin-dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho-ERKs, β-Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes., (© 2023 Federation of European Biochemical Societies.)

Objective: To analyze treatment effectiveness in terms of the medication injection site., Methods: The medical records of 423 patients with cerebral palsy who were admitted to Maternal and Child Health Hospital between January 2009 and December 2016 were collected. All cases were divided into T1, T2, T3, and T4 groups based on the use of conventional medication sites and acupoints for administering injectable medicines., Results: In the T1 group, patients received injections at conventional medication sites between 2009 and 2010. In the T2 group, patients received injections at conventional medication sites combined with acupoint injection therapy I from 2011 to 2012. In the T3 group, injection at conventional medication sites plus acupoint injection II was applied between 2013 and 2014. Acupoint injection only was used in the T4 group from 2015 to 2016. Therapeutic effects were statistically compared among the different injection procedures. The overall Gross Motor Function Measure (GMFM) and Fine Motor Function Measure (FMFM) scores were significantly improved after hospital discharge. The GMFM score was considerably higher in the T4 group than in the other groups (all P = 0.001 < 0.05). The GMFM scores were significantly higher in the T2 groups than in the T1 group (P = 0.001< 0.05), but no significant difference was observed between the other paired comparions (P > 0.05). Meanwhile, the FMFM scores were significantly higher in the T2 and T4 groups than in the T1 and T3 groups (all P = 0.001 < 0.05).Site injection therapy can significantly improve gross and fine motor function in children with cerebral palsy., Conclusion: It is feasible to administer injectable medicines at acupoints instead of convention sites to enhance the therapeutic effect of treatment in patients with cerebral palsy.

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1 , a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC 50 of 3 μM after 6 h., Competing Interests: The authors declare no competing financial interest.