The art of finding the right drug target: emerging methods and strategies.

Drug targets are specific molecules in biological tissues and body fluids that interact with drugs. Drug target discovery is a key component of drug discovery and is essential for the development of new drugs in areas such as cancer therapy and precision medicine. Traditional in vitro or in vivo target discovery methods are time-consuming and labour-intensive, limiting the pace of drug discovery. With the development of modern discovery methods, the discovery and application of various emerging technologies have greatly improved the efficiency of drug discovery, shortened the cycle time and reduced the cost. This review provides a comprehensive overview of various emerging drug target discovery strategies, including computer-assisted approaches, drug affinity response target stability, multiomics analysis, gene editing, and NMD, and discusses the effectiveness and limitations of the various approaches, as well as their application in real cases. Through the review of the above related contents, a general overview of the development of novel drug targets and disease treatment strategies will be provided, and a theoretical basis will be provided for those who are engaged in pharmaceutical science research. Significance Statement Target-based drug discovery has been the main approach to drug discovery in the pharmaceutical industry for the past three decades. Traditional drug target discovery methods based on in vivo or in vitro validation are time-consuming and costly, greatly limiting the development of new drugs. Therefore, the development and selection of new methods in the drug target discovery process is crucial.

Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer.

BACKGROUND: Conventional chemotherapy is based on the maximum tolerated dose (MTD) and requires treatment-free intervals to restore normal host cells. MTD chemotherapy may induce angiogenesis or immunosuppressive cell infiltration during treatment-free intervals. Low-dose metronomic (LDM) chemotherapy is defined as frequent administration at lower doses and causes less inflammatory change, whereas MTD chemotherapy induces an inflammatory change. Although several LDM regimens have been applied, LDM cisplatin (CDDP) has been rarely reported. This study addressed the efficacy of LDM CDDP on tumour endothelial cell phenotypic alteration compared to MTD CDDP. METHODS: Tumour growth and metastasis were assessed in bladder cancer-bearing mice treated with LDM or MTD gemcitabine (GEM) and CDDP. To elucidate the therapeutic effects of LDM CDDP, the change of tumour vasculature, tumour-infiltrating immune cells and inflammatory changes were evaluated by histological analysis and mRNA expression in tumour tissues. RESULTS: Tumour growth and bone metastasis were more suppressed by LDM CDDP + MTD GEM treatment than MTD CDDP + MTD GEM. Myeloid-derived suppressor cell accumulation was reduced by LDM CDDP, whereas inflammatory change was induced in the tumour microenvironment by MTD CDDP. CONCLUSION: LDM CDDP does not cause inflammatory change unlike MTD CDDP, suggesting that it is a promising strategy in chemotherapy.

Plant serine/arginine-rich proteins: versatile players in RNA processing.

MAIN CONCLUSION: Serine/arginine-rich (SR) proteins participate in RNA processing by interacting with precursor mRNAs or other splicing factors to maintain plant growth and stress responses. Alternative splicing is an important mechanism involved in mRNA processing and regulation of gene expression at the posttranscriptional level, which is the main reason for the diversity of genes and proteins. The process of alternative splicing requires the participation of many specific splicing factors. The SR protein family is a splicing factor in eukaryotes. The vast majority of SR proteins' existence is an essential survival factor. Through its RS domain and other unique domains, SR proteins can interact with specific sequences of precursor mRNA or other splicing factors and cooperate to complete the correct selection of splicing sites or promote the formation of spliceosomes. They play essential roles in the composition and alternative splicing of precursor mRNAs, providing pivotal functions to maintain growth and stress responses in animals and plants. Although SR proteins have been identified in plants for three decades, their evolutionary trajectory, molecular function, and regulatory network remain largely unknown compared to their animal counterparts. This article reviews the current understanding of this gene family in eukaryotes and proposes potential key research priorities for future functional studies.

Enantioselective Synthesis of Diarylmethylamines through the Aza-Friedel-Crafts Reaction of 1,3,5-Trialkoxy Benzenes and N-Sulfonyl Aldimines Catalyzed by BINOL-Derived Disulfonimides.

A 1,1'-bi-2-naphthol (BINOL)-derived disulfonimide (DSI)-catalyzed enantioselective aza-Friedel-Crafts reaction between 1,3,5-trialkoxy benzenes and N-sulfonyl aldimines gives direct access to a series of chiral diarylmethylamines in good yields and good to excellent enantioselectivities (up to 97% ee). This reaction provides a useful protocol for the direct synthesis of diarylmethylamine derivatives.

Discovery of novel 2-oximino-2-indolylacetamide derivatives as potent anticancer agents capable of inducing cell autophagy and ferroptosis.

A series of 2-oximino-2-indolylacetamide derivatives were designed, synthesized and evaluated for their antitumour effects. Among them, 4d exhibited the most potent antiproliferative effect in vitro on the tested human cancer cells. Additionally, 4d significantly induced cell apoptosis, caused mitochondrial dysfunction, promoted Bax, cleaved-PARP and p53 expression and inhibited Bcl-2 expression in 5-8F cells. Moreover, 4d remarkably promoted autophagosome formation, leading to cell apoptosis. Further investigation indicated that 4d could trigger cell death through cell ferroptosis, including increased ROS generation and lipid peroxidation and decreased glutathione peroxidase 4 (GPx4) expression and glutathione (GSH) levels. More importantly, 4d induced 5-8F cell death by activating ROS/MAPK and inhibiting the AKT/mTOR and STAT3 signalling pathways. Interestingly, 4d significantly suppressed tumour growth in a 5-8F cell xenograft model without obvious toxicity to mice. Overall, these results demonstrate that 4d may be a potential compound for cancer therapy.

Enantioselective synthesis of 2-indolyl methanamine derivatives through disulfonimide-catalyzed Friedel-Crafts C2-alkylation of 3-substituted indoles with imines.

An asymmetric Friedel-Crafts C2-alkylation between 3-substituted indoles and imines catalyzed by chiral BINOL-derived disulfonimides (DSIs) has been developed. This reaction tolerated a wide range of 3-substituted indoles and imines, affording a series of chiral 2-indolyl methanamine derivatives in good yields with good to excellent enantioselectivities (up to 98% ee). This is a useful protocol for the direct synthesis of 2-indolyl methanamine derivatives. It is worth noting that increasing the temperature in this reaction could result in a better enantioselectivity, making it different from the other common organocatalytic systems.

The Importance of a Genome-Wide Association Analysis in the Study of Alternative Splicing Mutations in Plants with a Special Focus on Maize.

Alternative splicing is an important mechanism for regulating gene expressions at the post-transcriptional level. In eukaryotes, the genes are transcribed in the nucleus to produce pre-mRNAs and alternative splicing can splice a pre-mRNA to eventually form multiple different mature mRNAs, greatly increasing the number of genes and protein diversity. Alternative splicing is involved in the regulation of various plant life activities, especially the response of plants to abiotic stresses and is also an important process of plant growth and development. This review aims to clarify the usefulness of a genome-wide association analysis in the study of alternatively spliced variants by summarizing the application of alternative splicing, genome-wide association analyses and genome-wide association analyses in alternative splicing, as well as summarizing the related research progress.

[Lignans from Agrimonia pilosa].

Thirteen lignans were isolated from 60% ethanol extract of Agrimonia pilosa by column chromatography over silica gel, ODS, and MCI and preparative high performance liquid chromatography(HPLC). Their chemical structures were identified by physiochemical properties and spectral data as(7S,8S)-threo-4,7,9,9'-tetrahydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan(1),(+)-4,9,9'-trihydroxy-3-methoxy-3',7-epoxy-8,4'-oxyneolignan(2), dihydrodehydro-diconiferyl alcohol(3), 4,9,9'-trihydroxy-3,3',5-trimethoxy-4',7-epoxy-8,5'-neolignan(4),(-)-secoisolariciresinol(5), 4,7,9,9'-tetrahydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan(6),(+)-isolariciresinol(7), 4,7,9,9'-tetrahydroxy-3,3'-dimethoxy-8-O-4'-neolignan(8), burselignan(9),(-)-evofolin B(10), icariol A2(11), ciwujiatone(12), and(+)-4″,4-dihydroxy-3,3',3″,3,5,5'-hexamethoxy-7,9';7',9-diepoxy-4,8″;4',8-bisoxy-8,8'-dineolignan-7″,7,9″,9-tetraol(13). Compound 1 was a new compound, and compounds 1-13 were isolated from Agrimonia plant for the first time. This study can enrich the chemical components in A. pilosa and provide material conditions for the follow-up study of its biological activity and the elucidation of its pharmacodynamic substances.

Does really selection of nostril affect performance of nasotracheal intubation with nasotracheal Airtraq®?

No abstract.

[The Therapeutic Effect and Mechanism of Static Progressive Stretching in Different Durations on Traumatic Knee Contracture in Rats].

OBJECTIVE: To investigate the effect and mechanism of static progressive stretching (SPS) in different durations on traumatic knee contracture in rats. METHODS: Seventy male Wistar rats were randomly divided into three groups, including surgical modeling group ( n=50), control group (CON, no surgery, no treatment, n=10) and trauma without immobilization group (TRA, no treatment, n=10). The knee contracture model was established, and 50 surgical modeling rats were randomly divided into five groups including static progressive stretching treatment for 20 minutes group (S20 min, n=10), treatment for 30 minutes group (S30 min, n=10), treatment for 40 minutes group (S40 min, n=10), untreatment group (UNT, no SPS, n=10) and modeling group (MOD, n=10, euthanized after immobilization for histological staining and Western blot). Individuals in the S20 min, S30 min, and S40 min groups were anesthetized and submitted to SPS. One treatment session took place every other day. A total of 8 sessions were given till the final treatment session on the day 16. On the day 0, 8, and 16 of intervention, the range of joint motion (ROM) and gait analysis were measured and compared. After the ROM measurements and gait analysis, the rats were euthanized on the day 16 and the samples were stained with HE and Masson methods. The changes of pathological organization were observed. Western blot was used to detect the expressions of transforming growth factor-ß1 (TGF-ß1) and interleukin-6 (IL-6). RESULTS: ① ROM：the ROM of S30 min group recovered similar to that of the S20 min and S40 min groups after 8 days of treatment ( P>0.05), and was the best among all the surgical modeling groups after 16 d of treatment ( P<0.05). The ROM of S20 min, S30 min and S40 min groups significantly improved on the day 8 and day 16 comparing with that on day 0 ( P<0.01). ② Gait analysis: the stands in the S30min group improved best on the day 8 and day 16 ( P<0.05) , and better than that on day 0 ( P<0.05). The stride length of the S30 min group progressed similar to that of the S40 min group on the day 8 ( P>0.05), and there was no difference among three groups on the day 16 ( P>0.05). The stride length of the S30 min group appeared to recover more quickly on the day 8 ( P<0.05), and those of S20 min and UNT groups recovered significantly on the day 16 ( P<0.05). In addition, the swings in the S30 min group improved best ( P<0.05), and it appeared to recover better on the day 16 ( P<0.05). There was no statistical difference in terms of the swing speed among the four surgical modeling groups on the day 8 ( P>0.05). The swing speed of the S30min group increased most than those of the other three groups ( P<0.05), and it was much better on the day 8 and day 16 comparing with that on the day 0 ( P<0.05 ). ③ HE and Masson staining: the fibrosis and inflammation of the S30min group were significantly suppressed comparing to the other groups on the day 16. ④ Western blot: The protein expression levels of TGF-ß1 and IL-6 were significantly lower than those in the other intervention groups including the S20 min, S40 min and UNT groups on the day 16 ( P<0.05). CONCLUSION: Static progressive stretching treatment for 30 min could significantly improve the traumatic knee contracture in rats. The mechanism may be that the SPS decreased the expressions of TGF-ß1 and IL-6, reduced the adhesion and inflammation of joint capsule. Therefore it relieved the pain and increased the joint mobility by reconstructing the structure of the capsule and suppressing the fibrotic changes.

The 8th edition of the American Joint Committee on Cancer tumor-node-metastasis staging system for gastric cancer is superior to the 7th edition: results from a Chinese mono-institutional study of 1663 patients.

BACKGROUND: We investigated the superiority of the 8th edition of the tumor-node-metastasis (TNM) system for patients in China with gastric cancer. METHODS: The survival outcomes of 1663 patients with gastric cancer undergoing radical resection were analyzed. RESULTS: In the 8th edition system, homogeneous 5-year survival rates among different pathological TNM (pTNM) categories belonging to the same stage were observed. However, in the 7th edition system, the differences of 5-year survival rate among pTNM categories belonging to the same stage were observed in stages IIB (P = 0.010), IIIB (P = 0.004), and IIIC (P < 0.001). For patients in the pT1-3 (P < 0.001) and pT4a (P < 0.001) categories, there were significant differences in survival between patients in the pN3a and pN3b categories. Furthermore, partial cases (pT4bN0M0/T4aN2M0) of stage IIIB were downstaged to stage IIIA in the 8th edition system, and the 5-year survival rate of these patients was significantly better than that of patients in stage IIIB in the 8th edition system. Similarly, the 5-year survival rate of patients in p4bN2M0/T4aN3aM0 downstaged from stage IIIC to IIIB was significantly better than that of patients in stage IIIC. Compared with the 7th edition system, the 8th edition system had a higher likelihood ratio and linear trend chi-squared score and a smaller Akaike information criteria value. CONCLUSIONS: The 8th edition system is superior to the 7th edition system in terms of homogeneity, discriminatory ability, and monotonicity of gradients for Chinese patients with gastric cancer.

Highly efficient high-performance liquid chromatographic separation of xylene isomers and phthalate acid esters on a homemade DUT-67(Zr) packed column.

In this study, the baseline separations of xylene isomers and phthalate acid esters on a homemade DUT-67(Zr) packed column were achieved, respectively. The high selectivity for xylene isomers and phthalate acid esters was obtained with the increase in temperature and decrease in the retention time. The hydrophobicity of xylene isomers and phthalate acid esters resulted in the different separation time on the DUT-67(Zr) packed column. The relative standard deviation values of retention time, peak area, peak height, and half peak width for five repeat separation of the xylene isomers were 0.26-0.35, 2.11-2.26, 1.51-2.03, and 0.29-0.77%, and the values of the phthalate acid esters on DUT-67(Zr) column were 0.1-0.4, 4.4-5.2, 3.9-6.3, and 0.6-2.1%, respectively. The thermodynamic properties indicated that the separation of xylene isomers was controlled by ΔH and ΔS, but the separation of phthalate acid esters was mainly controlled by ΔS.

Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling.

BACKGROUND: Recent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown. METHODS: lncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs. RESULTS: The microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway. CONCLUSIONS: MRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC.

Nanoparticle-crystal towards an absorbing meta-coating.

In this paper, a double layer nanoparticle-crystal has been proposed, which shown incident and polarization angle, substrate independences for spectral absorptivity. Such phenomenon originates from the near-field light redistribution and excitation of internal collective oscillating. This kind of nanoparticle-crystal can be made of various types of metal with similar optical responses. A three oscillators mode has been proposed in this paper to understand the shift between global and internal collective oscillating, and verify the physical picture demonstrated. That kind of near-field redistribution result in a prototype of novel meta-coating, and facilitates the large scale application of metamaterial.

Responses transition in a monolayer Al-Al2O3 nanoparticle-crystal due to oxidation.

Nanoparticle is a promising candidate for large scale fabrication of metamaterial. However, optical responses for metamaterial made of abound metal like Al can be thoroughly changed due to oxidization. Especially for nanoparticle whose aspect ratio is extremely high, oxidation usually occurs. So to understand how the responses shift in a nanoparticle system due to oxidization is essential for large scale application of metamaterial. In this paper, we have concluded and quantified two general principles describing this transition in a monolayer Al-Al2O3 nanoparticle-crystal, which can be used in a thermophotovoltaic system. Square pattern, in which the unit of changing crystal is a square cell made up of Al and Al2O3 particles, is firstly demonstrated. A double oscillators model has been proposed to understand the interference between different absorption modes and their coupling. Using near-field distribution, equivalent inductor-capacitor model and dispersion relationship of surface Plasmon polariton, we have distinguished the resonance modes, concluded the transition principles in a simple case. Then the two principles are applied in a larger cell to verify its university. After detailed demonstration of symmetric square pattern, models and principles are extrapolated to more complex non-symmetric systems. The basic understanding gained here will help the design of robust large-scale metamaterial.

Prognostic significance of the total number of harvested lymph nodes for lymph node-negative gastric cancer patients.

BACKGROUND: The relationship between the number of harvested lymph nodes (HLNs) and prognosis of gastric cancer patients without an involvement of lymph nodes has not been well-evaluated. The objective of this study is to further explore this issue. METHODS: We collected data from 399 gastric cancer patients between November 2006 and October 2011. All of them were without metastatic lymph nodes. RESULTS: Survival analyses showed that statistically significant differences existed in the survival outcomes between the two groups allocated by the total number of HLNs ranging from 16 to 22. Therefore, we adopted 22 as the cut-off value of the total number of HLNs for grouping (group A: HLNs <22; group B: HLNs≥22). The intraoperative and postoperative characteristics, including operative blood loss (P=0.096), operation time (P=0.430), postoperative hospital stay (P=0.142), complications (P=0.552), rate of reoperation (P=0.966) and postoperative mortality (P=1.000), were comparable between the two groups. T-stage-stratified Kaplan-Meier analyses revealed that the 5-year survival rate of patients at the T4 stage was better in group B than in group A (76.9% vs. 58.5%; P=0.004). An analysis of multiple factors elucidated that the total number of HLNs, T stage, operation time and age were independently correlated factors of prognosis. CONCLUSIONS: Regarding gastric cancer patients without the involvement of lymph nodes, an HLN number ≥22 would be helpful in prolonging their overall survival, especially for those at T4 stage. The total number of HLNs was an independent prognostic factor for this population of patients.

The optimal extent of gastrectomy for middle-third gastric cancer: distal subtotal gastrectomy is superior to total gastrectomy in short-term effect without sacrificing long-term survival.

BACKGROUND: The optimal extent of gastrectomy for middle-third gastric cancer remains controversial. In our study, the short-term effects and longer-term survival outcomes of distal subtotal gastrectomy and total gastrectomy are analysed to determine the optimal extent of gastrectomy for middle-third gastric cancer. METHODS: We retrospectively collect and analyse clinicopathologic data and follow-up outcomes from a prospectively collected database at the Peking University Cancer Hospital. Patients with middle-third gastric adenocarcinoma who underwent curative resection are enrolled in our study. RESULTS: We collect data of 339 patients between January 2005 and October 2011. A total of 144 patients underwent distal subtotal gastrectomy, and 195 patients underwent total gastrectomy. Patients in the total gastrectomy group have longer operative duration (P < 0.001) and postoperative hospital stay (P = 0.001) than those in the distal subtotal gastrectomy group. In the total gastrectomy group, more lymph nodes are harvested (P < 0.001). Meanwhile, the rate of postoperative complications is lower in the distal subtotal gastrectomy group than in the total gastrectomy group (8% vs 15%, P = 0.047). Further analysis demonstrates that the rate of anastomosis leakage is lower in the distal subtotal gastrectomy group than in the total gastrectomy group (0% vs 4%, P = 0.023). Kaplan-Meier (log rank test) analysis shows a significant difference in overall survival between the two groups. The 5-year overall survival rates in the distal subtotal gastrectomy and total gastrectomy groups are 65% and 47%, respectively (P < 0.001). Further stage-stratified analysis reveals that no statistical significance exists in 5-year survival rate between the distal subtotal gastrectomy and total gastrectomy groups at the same stage. Multivariate analysis shows that age (P = 0.046), operation duration (P < 0.001), complications (P = 0.037), usage of neoadjuvant chemotherapy (P < 0.001), tumor size (P = 0.012), presence of lymphovascular invasion (P = 0.043) and N stage (P < 0.001) are independent prognostic factors for survival. CONCLUSIONS: For patients with middle-third gastric cancer, distal subtotal gastrectomy shortens the operation duration and postoperative hospital stay and reduces postoperative complications. Meanwhile, the long-term survival of patients with distal subtotal gastrectomy is similar to that of those with total gastrectomy at the same stage. The extent of gastrectomy for middle-third gastric cancer is not an independent prognostic factor for survival.