Differential toxic and antiepileptic features of Vigabatrin raceme and its enantiomers.

BACKGROUND: The study aimed to investigate the potential pharmacological and toxicological differences between Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. The researchers focused on the toxic effects and antiepileptic activity of these compounds in a rat model. METHODS: The epileptic rat model was established by intraperitoneal injection of kainic acid, and the antiepileptic activity of VGB, S-VGB, and VGB was observed, focusing on the improvements in seizure latency, seizure frequency and sensory, motor, learning and memory deficits in epileptic rats, as well as the hippocampal expression of key molecular associated with synaptic plasticity and the Wnt/ß-catenin/GSK 3ß signaling pathway. The acute toxic test was carried out and the LD50 was calculated, and tretinal damages in epileptic rats were also evaluated. RESULT: The results showed that S-VGB exhibited stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. These findings suggest that S-VGB and VGB may modulate neuronal damage, glial cell activation, and synaptic plasticity related to epilepsy through the Wnt/ß-catenin/GSK 3ß signaling pathway. The study provides valuable insights into the potential differential effects of VGB enantiomers, highlighting the potential of S-VGB as an antiepileptic drug with reduced side effects. CONCLUSION: S-VGB has the highest antiepileptic effect and lowest toxicity compared to VGB and R-VGB.

Extreme Li-Mg selectivity via precise ion size differentiation of polyamide membrane.

Achieving high selectivity of Li+ and Mg2+ is of paramount importance for effective lithium extraction from brines, and nanofiltration (NF) membrane plays a critical role in this process. The key to achieving high selectivity lies in the on-demand design of NF membrane pores in accordance with the size difference between Li+ and Mg2+ ions, but this poses a huge challenge for traditional NF membranes and difficult to be realized. In this work, we report the fabrication of polyamide (PA) NF membranes with ultra-high Li+/Mg2+ selectivity by modifying the interfacial polymerization (IP) process between piperazine (PIP) and trimesoyl chloride (TMC) with an oil-soluble surfactant that forms a monolayer at oil/water interface, referred to as OSARIP. The OSARIP benefits to regulate the membrane pores so that all of them are smaller than Mg2+ ions. Under the solely size sieving effect, an exceptional Mg2+ rejection rate of over 99.9% is achieved. This results in an exceptionally high Li+/Mg2+ selectivity, which is one to two orders of magnitude higher than all the currently reported pressure-driven membranes, and even higher than the microporous framework materials, including COFs, MOFs, and POPs. The large enhancement of ion separation performance of NF membranes may innovate the current lithium extraction process and greatly improve the lithium extraction efficiency.

Clinical and endoscopic characteristics and management of 220 cases with serrated polyps.

BACKGROUND: Serrated polyps are considered the precursor lesions of colorectal cancer through the serrated pathway. In the present study, we aimed to evaluate and discuss the clinical and endoscopic characteristics and management of serrated polyps. METHODS: The data of 220 cases with serrated polyps between September 2018 and November 2021 in Shenzhen People's Hospital were retrospectively analyzed. RESULTS: Of all these cases, 32 were hyperplastic polyps, 36 were traditional serrated adenomas, 126 were sessile serrated lesions, 25 were SSLs with dysplasia, and one was an unclassified serrated adenoma. Although most patients were males aged ≥50 years and most serrated polyps were located in the distal colon and rectum with a size of 6-10 mm and the shape of type 0-Is, there was no significant difference (P > 0.05). Serrated polyps of ≤5 mm in size and type 0-IIa were mostly removed by cold biopsy forceps. Cold snare polypectomy was primarily used for those of 6-10 mm in size. Endoscopic mucosal resection was used for those of 6-20 mm, and endoscopic submucosal dissection was used for those of ≥20 mm (P < 0.05). All complications occurred in SSL patients with or without dysplasia (P < 0.05). CONCLUSIONS: Clinical and endoscopic characteristics were beneficial for distinguishing and diagnosing serrated polyps. In addition, management options were crucial to prevent recurrence and progression. However, the detection rate of serrated polyps was relatively low. Therefore, prospective multicenter studies with large samples are necessary to better assess colorectal serrated polyps.

A submucosal lesion of the rectum: an unexpected MALT.

A 57-year-old female was found a 12 mm × 10 mm submucosal lesion in the rectum with a smooth mucosa and telangiectasia The lesion was considered as a neuroendocrine tumor, and removed by endoscopic submucosal dissection (ESD) It was finally diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma with negative margin by pathological examination and histopathological test. MALT lymphoma in the rectum is rare and difficult to diagnose without histopathological test. In this case, the characteristic of this case is telangiectasia on the surface of lesion. Therefore, our findings suggested small lesion in rectum but big in impact.

Application of a novel and green temperature-responsive deep eutectic solvent system to simultaneously extract and separate different polar active phytochemicals from Schisandra chinensis (Turcz.) Baill.

In the present study, a novel and green temperature-responsive deep eutectic solvent (TRDES) system was developed and applied for the simultaneous extraction and separation of different polar active phytochemicals from Schisandra chinensis (Turcz.) Baill. The TRDES, consisting of amino alcohols and phenolic compounds, was chosen as the switching medium, and an upper critical solution temperature (UCST) type switchable solvent was obtained by adding an inorganic salt solution. The switchable phase diagram was plotted based on the relationship between the phase change temperature, the concentration and the amount of sodium chloride solution. Under optimal parameters, the yields with TRDES for different polar active phytochemicals (lignanoids and polysaccharides) from the dried fruit of Schisandra chinensis (DFSC) were 1.62 âˆ¼ 1.17-fold and 1.39-fold to those with conventional solvents. Also, the TRDES system was still effective on extraction of DFSC lignanoids and polysaccharides after four cycles of extraction. The separated polysaccharides and lignanoids both had strong antioxidant activities with IC50 values of 1.92 mg/ mL and 0.10 mg/ mL against 2,2'-Azinobis(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS), respectively. The extraction mechanism of TRDES was postulated by Density functional theory (DFT) calculations the hydrogen bonding in TRDES was the main factor to the higher extraction yield. This temperature-responsive deep eutectic solvent could be widely used for the efficient extraction and separation of multi-polar components. As a green and recyclable solvents, TRDES has great potential for the lower cost production from plants.

Effect of dietary concentrate level on digestibility of nutrients in each region of the gastrointestinal tract and rumen fermentation in goats.

This study evaluated the effects of high concentrate diets (HCD) on the rumen fermentation and the digestibility of nutrients in different sites of the gastrointestinal tract (GIT) in goats. Four goats were used in a crossover design. The goats were fitted with a ruminal cannula and flexible T-cannulae proximal duodenum and terminal ileum. Treatments were as follows: low concentrate group (LCG) and high concentrate group (HCG). Duodenal flow and forestomach digestibility of starch were significantly higher in the HCG than those in the LCG (p < 0.05); There was no significant difference in ileum flow and digestibility of starch in the small intestine, large intestine and total GIT (p > 0.05). The digestibility of crude protein (CP) in the forestomach was significantly higher in the HCG than in the LCG (p < 0.05); the flow of the duodenum and ileum of CP, and the CP digestibility of the small intestine, large intestine and total GIT were not significantly different between groups (p > 0.05). The duodenal and ileal flow of neutral detergent fiber (NDF), the NDF digestibility of the different segments and total GIT were not significantly different between groups (p > 0.05). Compared to the LCG, the ruminal pH of the HCG was significantly lower (p < 0.05). The HCG concentrations of microbial crude protein, ammonia nitrogen and isovaleric acid were significantly higher (p < 0.05) than the LCG. The foam strength, foam production and viscosity of the rumen fluid in the HCG were higher than the LCG (p < 0.01). These results showed that when the goats were fed with HCD, the digestibility of nutrients was not significantly impaired, but the risk of frothy rumen bloat increased. ImplicationsDue to a serious shortage of high-quality roughage in China, producers commonly used a high-concentrate diet in ruminants, which can improve animal production performance.Gastrointestinal digestive function plays a vital role in the absorption of nutrients and the healthy growth of animals.Therefore, this research evaluated the digestibility of various nutrients in different segments of the gastrointestinal tract (GIT) under HCD feeding by using three-site cannula goats as experimental animals.The results indicated that the GIT of goats could fully digest nutrients such as starch and protein under HCD feeding conditions.

Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is a heterogeneous disorder with complex pathogenesis. Therefore, in the present study, we aimed to assess genome-wide DNA methylation changes associated explicitly with the pathogenesis of UC. METHODS: DNA methylation changes were identified by comparing UC tissues with healthy controls (HCs) from the GEO databases. The candidate genes were obtained and verified in clinical samples. Moreover, the underlying molecular mechanism related to Zbtb7b in the pathogenesis of UC was explored using the dextran sodium sulfate (DSS)-induced colitis model. RESULTS: Bioinformatic analysis from GEO databases confirmed that Zbtb7b, known as Th-inducing POZ-Kruppel factor (ThPOK), was demethylated in UC tissues. Then, we demonstrated that Zbtb7b was in a hypo-methylation pattern through the DSS-induced colitis model (P = 0.0357), whereas the expression of Zbtb7b at the mRNA and protein levels was significantly up-regulated in the inflamed colonic tissues of UC patients (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0079, P < 0.0001) and DSS-induced colitis model (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0045, P = 0.0004). Moreover, the expression of Zbtb7b was positively associated with the degree of UC activity. Mechanically, over-expression of Zbtb7b might activate the maturation of CD4+T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4+CD8+T (DP CD4+CD8+T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-α (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-γ (P = 0.0016, P = 0.0042), in the serum and colonic tissue of DSS-induced colitis model. CONCLUSIONS: Epigenetic DNA hypo-methylation of Zbtb7b activated the maturation of CD4+T cells and repressed the differentiation of DP CD4+CD8+ T cells, resulting in the production of inflammatory cytokines and colonic inflammation in UC. Therefore, Zbtb7b might be a diagnostic and therapeutic biomarker for UC, and hypo-methylation might affect the biological function of Zbtb7b.

New paeonol derivative C302 reduces hypertension in spontaneously hypertensive rats through endothelium-dependent and endothelium-independent vasodilation.

Hypertension is a major risk factor for cardiovascular disease and Chinese herb monomers could provide new structural skeletons for anti-hypertension new drug development. Paeonol is a Chinese herbal monomer extracted from Cortex moutan, exhibited some anti-hypertensive activity. The study focused on the structural optimization of paeonol to provide promising lead compounds for anti-hypertension new drug development. Herein, twelve new paeonol derivatives (PD) were designed and synthesized and their vasodilation activity was evaluated by in vitro vasodilation drug screening platform based on Myograph. Its anti-hypertension activity, PD-C302 (2-hydroxy-4-methoxyvalerophenone) as a representative with the optimal vasodilation activity, was determined by its response to blood pressure in spontaneously hypertensive rats (SHR) in vivo. Moreover, its molecular mechanism was probed by the vasodilation activity of rat superior mesenteric artery rings with or without endothelium pre-contracted by potassium chloride (KCl) or phenylephrine hydrochloride (PE). It was indicated that PD-C302 significantly reduced the blood pressure in SHR, which would involve in PD-C302-induced vasodilation. Furthermore, endothelium-dependent pathways and endothelium-independent pathways both contributed importantly to PD-C302-induced vasodilation at low concentration of PD-C302. Endothelium-independent pathways (vascular smooth muscle cell-mediated vasodilation), were mainly responsible for the PD-C302-induced vasodilation at high concentration of PD-C302, which involved in opening multiple K+ channels to restrain Ca2+ channels, and then triggered vasodilation to reduce blood pressure. PD-C302 has a simple structure and favorable anti-hypertensive activity in vivo, which could be a promising lead compound for anti-hypertension new drug development.

Complex Crystal Structure Determination of Hsp90N-NVP-AUY922 and In Vitro Anti-NSCLC Activity of NVP-AUY922.

New targeted chemotherapy agents greatly improved five-year survival in NSCLC patients, but which were susceptible to drug resistance. NVP-AUY922, terminated in phase II clinical trials, exhibited promising anti-NSCLC (non-small-cell lung cancer) activity targeting to Hsp90N (heat shock protein), which demonstrated advantages in overcoming drug resistance as a broad-spectrum anti-cancer target. It was expected to develop novel anti-NSCLC drugs to overcome drug resistance by the structural optimization of NVP-AUY922. However, the absence of high-resolution complex crystal structure of Hsp90N-NVP-AUY922 blocked the way. Herein, 1.59 Å-resolution complex crystal structure of Hsp90N-NVP-AUY922 (PDB ID 6LTI) was successfully determined by X-ray diffraction. Meanwhile, there was a strong binding capability between NVP-AUY922 and its target Hsp90N verified by TSA (ΔTm, -15.56 ± 1.78°C) and ITC (K d, 5.10 ± 2.10 nM). Results by the complex crystal structure, TSA and ITC verified that NVP-AUY922 well accommodated in the ATP-binding pocket of Hsp90N to disable the molecular chaperone activity of Hsp90. Therefore, NVP-AUY922 exhibited approving inhibitory activity on NSCLC cell line H1299 (IC50, 2.85 ± 0.06 µM) by inhibiting cell proliferation, inducing cell cycle arrest and promoting cell apoptosis. At the basis of the complex crystal structure and molecular interaction analysis, thirty-two new NVP-AUY922 derivatives were further designed, and among which twenty-eight new ones display enhanced binding force with Hsp90N by molecular docking evaluation. The results would promote anti-NSCLC new drug development to overcome drug resistance based on the lead compound NVP-AUY922.

New Insights Into the Epigenetic Regulation of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the colonic mucosa. Environmental factors, genetics, intestinal microbiota, and the immune system are all involved in the pathophysiology of IBD. Lately, accumulating evidence has shown that abnormal epigenetic changes in DNA methylation, histone markers, and non-coding RNA expression greatly contribute to the development of the entire disease. Epigenetics regulates many functions, such as maintaining the homeostasis of the intestinal epithelium and regulating the immune system of the immune cells. In the present study, we systematically summarized the latest advances in epigenetic modification of IBD and how epigenetics reveals new mechanisms of IBD. Our present review provided new insights into the pathophysiology of IBD. Moreover, exploring the patterns of DNA methylation and histone modification through epigenetics can not only be used as biomarkers of IBD but also as a new target for therapeutic intervention in IBD patients.

Periostin-a potential molecular marker for early diagnosis of disease / 中国药理学通报

Periostin (POSTN), an evolutionary conserved and secreted extracellular matrix protein, can be easily detected by humoral samples such as blood, urine, interstitial fluid etc., which was firstly found in bone tissues.POSTN is expressed in various tissues and its expression level is closely related to oc¬currence and development of various diseases, which will be a potential molecular marker in early diagnosis of diseases.'Hie paper systematically summarizes the relationship of the expres¬ sion level of POSTN and some diseases including myocardial in¬farction, vascular calcification, diseases related to bone metabo¬lism, chronic nephrosis and various cancers, and explores its function as well as mechanism, which provides scientific basis for the early diagnostic kits or new drug development of diseases based on POSTN.

Atheroprotective Effects and Molecular Mechanism of Berberine.

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Atherosclerosis is the main pathological basis of cardiovascular diseases and it is closely associated with hyperlipidemia, endothelial injury, macrophage-derived foam cells formation, proliferation and migration of vascular smooth muscle cells (VSMCs), platelet aggregation, and altered gut microbiota. Various symptomatic treatments, that are currently used to inhibit atherosclerosis, need to be administered in long term and their adverse effects cannot be ignored. Berberine (BBR) has beneficial effects on atherosclerosis through regulating multiple aspects of its progression. This review highlights the recent advances in understanding the anti-atherosclerosis mechanism of BBR. BBR alleviated atherosclerosis by attenuation of dyslipidemia, correction of endothelial dysfunction, inhibition of macrophage inflammation and foam cell formation, activation of macrophage autophagy, regulation of the proliferation and migration of VSMCs, attenuation of platelet aggregation, and modulation of gut microbiota. This review would provide a modern scientific perspective to further understanding the molecular mechanism of BBR attenuating atherosclerosis and supply new ideas for atherosclerosis management.

Multiple functions of autophagy in vascular calcification.

BACKGROUND: Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. METHODS: In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. RESULTS: Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, ß-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/ß-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA­PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34-beclin-1-related bone mineralization via vascular calcification. CONCLUSION: The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

Comprehensive analysis on the expression profile and prognostic values of Synaptotagmins (SYTs) family members and their methylation levels in gastric cancer.

Synaptotagmins (SYTs), constitute a family of 17 membrane-trafficking protein, palying crucial roles in the development and progression of human cancers. However, only very few studies have investigated the expression profile and prognostic values of SYTs family members in gastric cancer (GC). Therefore, we comprehensively evaluated the expression, methylation, prognosis and immune significance of SYTs family members through bioinformatics analysis from the online databases in GC. The expressions of SYT4, SYT9, and SYT14 were up-regulated, and negatively associated with their methylation levels in GC. Both the over-expression of SYT4, SYT9 and SYT14 and their hypomethylation levels contributed to an unsatisfactory overall survival (OS) and progression-free survival (PFS) in GC. Moreover, the low expressions of several methylation cg sites (cg02795029, cg07581146, cg15149095, cg19922137, cg25371503, cg26158959, cg02269161, cg03226737, cg08185661, cg16437728, cg22723056 and cg24678137) were significantly correlated with an unfavorable OS and PFS in GC. Furthermore, the expression of SYT4, SYT9 and SYT14 played a pivotal role in immune cells infiltration in GC. Collectively, our current finding suggested that SYT4, SYT9 and SYT14 might be potent prognostic indictors and promising immunotherapeutic targets for GC patients.

Scalable Fabrication of Crystalline COF Membranes from Amorphous Polymeric Membranes.

Covalent organic framework (COF) membranes hold potential for widespread applicability, but scalable fabrication is challenging. Here, we demonstrate the disorder-to-order transformation from amorphous polymeric membrane to crystalline COF membrane via monomer exchange. Solution processing is used to prepare amorphous membrane and the replacing monomer is selected based on the chemical and thermodynamical stability of the final framework. Reversible imine bonds allow the extraneous monomers to replace the pristine monomers within amorphous membrane, driving the transformation from disordered network to ordered framework. Incorporation of intramolecular hydrogen bonds enables the crystalline COF to imprint the amorphous membrane morphology. The COF membranes harvest proton conductivity up to 0.53 S cm-1 at 80 °C. Our strategy bridges amorphous polymeric and crystalline COF membranes for large-scale fabrication of COF membranes and affords guidance on materials processing.

Tight Covalent Organic Framework Membranes for Efficient Anion Transport via Molecular Precursor Engineering.

Fabricating covalent organic frameworks (COFs) membranes with tight structure, which can fully utilize well-defined framework structure and thus achieve superior conduction performance, remains a grand challenge. Herein, through molecular precursor engineering of COFs, we reported the fabrication of tight COFs membrane with the ever-reported highest hydroxide ion conductivity over 200 mS cm-1 at 80 °C, 100 % RH. Six quaternary ammonium-functionalized COFs were synthesized by assembling functional hydrazides and different aldehyde precursors. In an organic-aqueous reaction system, the impact of the aldehyde precursors with different size, electrophilicity and hydrophilicity on the reaction-diffusion process for fabricating COFs membranes was elucidated. Particularly, more hydrophilic aldehydes were prone to push the reaction zone from the interface region to the aqueous phase of the reaction system, the tight membranes were thus fabricated via phase-transfer polymerization process, conferring around 4-8 times the anion conductivity over the loose membranes via interfacial polymerization process.

Effectiveness of Virtual Reality in the Rehabilitation of Motor Function of Patients With Subacute Stroke: A Meta-Analysis.

Stroke is a major cause of death and disability in adults. Conventional therapy (CT) has limited effectiveness, and therefore, various virtual reality (VR) rehabilitation programs have been designed. However, their efficacy in regaining motor function in patients with subacute stroke is questionable. Therefore, we conducted this meta-analysis to determine the efficacy of VR, compared to CT, in restoring motor function in this patient population. Up to October 10, 2020, nine electronic databases were searched for relevant articles reporting the effectiveness of VR in regaining motor function in patients with subacute stroke. This search was updated on March 7, 2021, with no additional added articles. The control group included CT, physical therapy, occupational therapy, or a combination of them. Effectiveness is defined as the positive change from baseline values to the last follow-up point. The Cochrane's revised risk-of-bias tool was used to determine the quality of included trials. A metaregression analysis was conducted to determine the effect of "time since last stroke" on reported outcomes. Publication bias and sensitivity analyses were also carried out. A total of 19 studies (17 randomized controlled trials, 1 cohort study, and 1 crossover trial) were included in the qualitative analysis, whereas 16 trials were meta-analyzed. A great improvement in motor function was noted in the VR group, when compared to preintervention values [standardized mean difference (SMD) = 1.14; 95% confidence interval (CI) = 0.77-1.52; I 2 = 82%; P < 0.001]. When compared to CT, VR resulted in mild improvement in motor function (SMD = 0.47; 95% CI = 0.22-0.72; I 2 = 75%; P < 0.001). However, upon trim-and-fill adjustment, this finding was deemed insignificant (SMD = 0.08; 95% CI = -0.16 to 0.33; I 2 = 82.6%; P < 0.001). Ten studies had low risk, five had some concerns, three had high risk, and one had a moderate risk of bias. VR programs can be used jointly with CT for the rehabilitation of the motor function of patients with subacute stroke. However, more studies are still warranted to determine the effectiveness of these interventions in retaining the cognitive function and physical performance of such patients.

Complex Crystal Structure Determination and in vitro Anti-non-small Cell Lung Cancer Activity of Hsp90 N Inhibitor SNX-2112.

SNX-2112, as a promising anticancer lead compound targeting heat shock protein 90 (Hsp90), absence of complex crystal structure of Hsp90 N -SNX-2112 hindered further structural optimization and understanding on molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90 N -SNX-2112 was successfully determined by X-ray diffraction, resolution limit, 2.14 Å, PDB ID 6LTK, and their molecular interaction was analyzed in detail, which suggested that SNX-2112 was well accommodated in the ATP-binding pocket to disable molecular chaperone activity of Hsp90, therefore exhibiting favorable inhibiting activity on three non-small cell lung cancer (NSCLC) cell lines (IC50, 0.50 ± 0.01 µM for A549, 1.14 ± 1.11 µM for H1299, 2.36 ± 0.82 µM for H1975) by inhibited proliferation, induced cell cycle arrest, and aggravated cell apoptosis. SNX-2112 exhibited high affinity and beneficial thermodynamic changes during the binding process with its target Hsp90 N confirmed by thermal shift assay (TSA, ΔTm, and -9.51 ± 1.00°C) and isothermal titration calorimetry (K d , 14.10 ± 1.60 nM). Based on the complex crystal structure and molecular interaction analysis, 32 novel SNX-2112 derivatives were designed, and 25 new ones displayed increased binding force with the target Hsp90 N verified by molecular docking evaluation. The results would provide new references and guides for anti-NSCLC new drug development based on the lead compound SNX-2112.