The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the ...RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.
Prostate cancer (PCa) is a cancer that occurs in the prostate with high morbidity and mortality. Danggui Beimu Kushen Wan (DBKW) is a classic formula for patients with difficult urination including ...PCa. This study aimed to investigate the molecular mechanisms of DBKW for PCa. We obtained DBKW compounds from our previous reviews. We identified potential targets for PCa from literature search, currently approved drugs and Open Targets database and filtered them by protein-protein interaction network analysis. We selected 26 targets to predict three cancer-related pathways. A total of 621 compounds were screened via molecular docking using PyRx and AutoDock Vina against 21 targets for PCa, producing 13041 docking results. The binding patterns and positions showed that a relatively small number of tight-binding compounds from DBKW were predicted to interact strongly and selectively with three targets. The top five high-binding-affinity compounds were selected to generate a network, indicating that compounds from all three herbs had high binding affinity against the 21 targets and may have potential biological activities with the targets. DBKW contains multi-targeting agents that could act on more than one pathway of PCa simultaneously. Further studies could focus on validating the computational results via experimental studies.
Purpose: To determine the chair stand test protocol that is most suitable for older adults in clinical settings by reviewing the currently available methods.
Methods: Five electronic English ...databases were searched and details of methods used on individuals aged ≥65 years in the included studies were compared, including the instrument used to record time, units of measurement, chair characteristics (seat height, armrests), footwear, permission to use upper extremities and walking aids, pace of performance, total number of chair stands, timing points, total number of recorded and practice tests.
Results: A total of 23 eligible studies were identified. The type of instrument to record performance time, characteristics of the chair and footwear were not frequently mentioned. A majority of studies did not permit the use of the upper extremities or walking aids during assessment. The performance of five chair stands at a fast pace recorded in seconds was most common, with the majority of studies recording the initial and end time point in a seated position. The total number of performed tests and practice tests was not specified in a majority of studies.
Conclusion: A feasible and safe protocol for the chair stand test is proposed for assessment of older adults.
Implications for Rehabilitation
The chair stand test may provide valuable information on declines in mobility in older adults.
The use of the chair stand test within clinical settings of older adults may provide a measure to identify frail individuals and to determine their level of frailty.
Using the proposed protocol for the chair stand test may allow for the comparability of results.
Background. Phellodendri Cortex (PC) or Huang Bai. According to the scientific database of China Plant Species and Chinese pharmacopeia 2015 edition, PC has two main species which are Phellodendron ...amurense Rupr (PAR) or “Guan Huang bai” in Chinese and Phellodendron chinense Schneid (PCS) or “Chuan Huang bai” in Chinese. The crude drugs of PAR and PCS are also called Phellodendri amurensis cortex (PAC) and Phellodendri chinense cortex (PCC), respectively. The medicinal part of the plant is the dried trunk bark. PC has comprehensive therapeutic effects which include anti-inflammatory, antimicrobial, anticancer, hypotensive, antiarrhythmic, antioxidant, and antipyretic agents. The exact ingredients in PC and its species are not fully summarised. Aim of the Study. This study was designed to review and evaluate the pharmacological actions of compounds and to explore the pharmacokinetic knowledge of PC and its species and to also identify the chemical compound(s) with a potential therapeutic effect on atopic dermatitis. Methods. “Huang Bai” and its English, botanical, and pharmaceutical names were used as keywords to perform database search in Encyclopaedia of traditional Chinese Medicines, PubMed, EMBASE, MEDLINE, Science Direct, Scopus, Web of Science, and China Network Knowledge Infrastructure. The data selection criteria included all the studies that were related to the phytochemical, pharmacological, and pharmacokinetic perspectives of PC and its species or their active constituents. More importantly, the voucher number has been provided to ensure the genuine bark of PC used as the medicinal part in the studies. Results. 140 compounds were summarized from PC and its species: specifically, 18 compounds from PCC, 44 compounds from PCS, 34 compounds from PAC, and 84 compounds from PAR. Obacunone and obaculactone are probably responsible for antiatopic dermatitis effect. PC and its species possess a broad spectrum of pharmacological actions including anti-inflammatory effect, antibacterial effect, antiviral effect, antitumor effect, antigout effect, antiulcer effect, neuroprotective effect, and antiatopic dermatitis effect. PC could widely distribute in plasma, liver, spleen, kidney, and brain. Berberine may be responsible for the toxic effect on the susceptible users with hemolytic disease or in the peripartum and neonatal period. Conclusions. The compounds of the crude bark of PC and its subspecies have showcased a wide range of pharmacological effects. Pharmacological efficacies of PC are supported by its diverse class of alkaloid, limonoid, phenolic acid, quinic acid, lignan, and flavonoid. Obacunone and obaculactone could be the bioactive compounds for atopic dermatitis management. PC and its subspecies are generally safe to use but extra care is required for certain conditions and group of people.
Hand grip strength has been widely used as a lead measure in geriatric conditions such as frailty. However, diversity in assessment protocols and methodologies creates uncertainty in the comparison ...of outcome measurements. The aim of this study was to review the literature relating to the measurement of hand grip strength in older adults, in order to develop further consensus in relation to the use of existing protocols in clinical and community settings, with an emphasis on practicality and suitability for frail persons.
Five electronic English databases were searched using keywords such as ‘hand grip strength’, ‘clinimetric assessment’, and their synonyms. Age-related trends in adults aged ≥65 years were assessed, and comparisons were made of the following variables: dynamometer model and handle setting, hand positioning, warm-up trials, grip duration, number of repeated tests, rest periods, laterality of tested hand, and whether encouragement was given to the subjects.
Thirty-four research papers met the inclusion criteria and were included. A Jamar hand dynamometer was most frequently used. Variations were found in the positioning of the subject and in the duration of the rest period, which ranged from 10 to 20 s to 1 min. Grip strength was typically measured three times in the dominant hand, with the strongest grip being recorded and no encouragement being provided during assessment.
Based on the scoping review, we propose a detailed and standardised protocol that is suitable for the assessment of hand grip strength in frail older adults.
Understanding the mechanisms of androgen receptor (AR) activation in the milieu of low androgen is critical to effective treatment of castration-resistant prostate cancer (CRPC). Here, we report ...HOTAIR as an androgen-repressed lncRNA, and, as such, it is markedly upregulated following androgen deprivation therapies and in CRPC. We further demonstrate a distinct mode of lncRNA-mediated gene regulation, wherein HOTAIR binds to the AR protein to block its interaction with the E3 ubiquitin ligase MDM2, thereby preventing AR ubiquitination and protein degradation. Consequently, HOTAIR expression is sufficient to induce androgen-independent AR activation and drive the AR-mediated transcriptional program in the absence of androgen. Functionally, HOTAIR overexpression increases, whereas HOTAIR knockdown decreases, prostate cancer cell growth and invasion. Taken together, our results provide compelling evidence of lncRNAs as drivers of androgen-independent AR activity and CRPC progression, and they support the potential of lncRNAs as therapeutic targets.
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•The lncRNA HOTAIR is repressed by androgen and, thus, upregulated in CRPC•HOTAIR inhibits AR degradation by blocking its binding to E3 ubiquitin ligase MDM2•HOTAIR increases AR chromatin targeting and enhances the AR-mediated gene program•HOTAIR drives androgen-independent AR activation and promotes CRPC
Castration-resistant prostate cancer (CRPC) is a lethal disease. Zhang et al. show that HOTAIR is an AR-repressed lncRNA that is upregulated in CRPC. HOTAIR binds to AR and reduces AR degradation by blocking its interaction with E3 ubiquitin ligase MDM2, thereby enhancing AR transcriptional activity and potentiating CRPC cell growth.
(L.) Cusson (CMC) is a traditional Chinese herbal medicine that has been widely grown and used in Asia. It is also known as "She chuang zi" in China (Chinese: ), "Jashoshi" in Japan, "Sasangia" in ...Korea, and "Xa sang tu" in Vietnam. This study aimed to provide an up-to-date review of its phytochemistry, ethnopharmacology, pharmacokinetics, and toxicology. All available information on CMC was collected from the Encyclopedia of Traditional Chinese Medicines, PubMed, EMBASE, ScienceDirect, Scopus, Web of Science, and China Network Knowledge Infrastructure. The updated chemical structures of the compounds are those ones without chemical ID numbers or references from the previous review. A total of 429 chemical constituents have been elucidated and 56 chemical structures have been firstly identified in CMC with traceable evidence. They can be categorized as coumarins, volatile constituents, liposoluble compounds, chromones, monoterpenoid glucosides, terpenoids, glycosides, glucides, and other compounds. CMC has demonstrated impressive potential for the management of various diseases in extensive preclinical research. Since most of the studies are overly concentrated on osthole, more research is needed to investigate other chemical constituents.
Rumex japonicus Houtt. (RJH‐Yang Ti) RJH has been used as a folk medicine in East Asian countries for thousands of years. It has a wide range of therapeutic effects in terms of anti‐microorganic, ...anti‐oxidant, anti‐inflammatory, and antitumor effects. Therefore, it is urgent to thoroughly review the existing knowledge for this herb from phytochemical, pharmacological, and pharmacokinetic perspectives. “Yang Ti” and its English, botanical and pharmaceutical names used as keywords to perform database search which included the Encyclopaedia of traditional Chinese Medicines, PubMed, EMBASE, AMED, CINAHL, Cochrane Library, MEDLINE, Science Direct, Scopus, Web of Science, and China Network Knowledge Infrastructure. Forty‐five compounds identified from RJH. Besides, the therapeutic effects of RJH have been summarized as well. The root of RJH contains derivatives of anthraquinones, phytosterols, nepodin, oxanthrone c‐glycosides, phenolic acid, cinnamic acid, flavonoid, epoxynaphthoquinol, triterpenoids, methoxynaphthalene, trihydroxybenzene, anthracene‐9,10‐dione, and other compounds. The extract of RJH and its chemical compounds showed the potentials as a complementary agent to exert antioxidant, antimicrobial, antisepsis, anticancer, anti‐haematological disease, anti‐dermatological disease, and antidiabetic activities. For the record, there is no study conducted on RJH regarding its pharmacokinetic aspect. Notably, Emodin may require additional attention due to its multiple organ toxicity concerns.
Fritillariae Thunbergii Bulbus (FTB) has been widely used as an antitussive herb for thousands of years in China. However, FTB's traditional uses, chemical compounds and pharmacological activities ...have not been systematically reviewed. This study aimed to review its traditional uses, phytochemistry, pharmacodynamics, pharmacokinetics and toxicity. We searched the Encyclopedia of Traditional Chinese Medicine to explore the historical records which indicate that it acts to clear heat, resolve phlegm, relieve cough, remove toxicity and disperse abscesses and nodules. We searched 11 databases to identify potential phytochemical or pharmacological studies. Characteristics of its chemical constituents, pharmacological effects, pharmacokinetic and toxicity were descriptively summarized. A total of 9706 studies were identified and 83 of them were included. As a result, 134 chemical constituents were identified, including 26 alkaloids, 29 compounds found in essential oils, 13 diterpenoids, two carbohydrates, two sterols, 18 amino acids, six nucleosides, four nucleobases, four fatty acids, three lignans, and 27 elements. Thirteen pharmacological effects of FTB were identified, including anti-cancer, tracheobronchial relaxation, antitussive, expectorant, anti-muscarinic, anti-inflammation, anti-thyroid, regulation of blood rheology, antiulcer, anti-diarrhea, pain suppression, antioxidation and neuroprotection. These pharmacological activities may be mainly attributed to the alkaloids in FTB. Further phytochemical, pharmacological and network pharmacological studies are recommended.
The nucleus accumbens (NAc) contributes to behavioral inhibition and compulsions, but circuit mechanisms are unclear. Recent evidence suggests that amygdala and thalamic inputs exert opposing control ...over behavior, much like direct and indirect pathway output neurons. Accordingly, opponent processes between these NAc inputs or cell types may underlie efficient reward seeking. We assess the contributions of these circuit elements to mouse operant behavior during recurring conditions when reward is and is not available. Although direct pathway stimulation is rewarding and indirect pathway stimulation aversive, the activity of both cell types is elevated during periods of behavioral suppression, and the inhibition of either cell-type selectively increases unproductive reward seeking. Amygdala and thalamic inputs are also necessary for behavioral suppression, even though they both support self-stimulation and innervate different NAc subregions. These data suggest that efficient reward seeking relies on complementary activity across NAc cell types and inputs rather than opponent processes between them.
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•D1 and D2 neuron activity in the NAc is elevated during behavioral suppression•Inhibition of D1 or D2 neurons in the NAc increases unproductive reward seeking•BLA and PVT axons innervate distinct NAc subregions, yet both inputs are reinforcing•Inhibition of BLA or PVT inputs to the NAc increases unproductive reward seeking
Although previous work highlights antagonistic interactions between NAc cell types and inputs, Lafferty et al. show that the suppression of behavioral responding is distributed across D1 and D2 neurons and PVT and BLA inputs. Efficient reward seeking thus arises from complementary activity, rather than opponent processes between these circuit elements.
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