The novel chalcone analog L2H17 protects retinal ganglion cells from oxidative stress-induced apoptosis

Chalcone is a plant metabolite widely found in fruits,vegetables,spices and tea,and has anti-tumor,anti-inflammation,immunomodulation,antibacterial and anti-oxidation activities,as well as many other pharmacological and biological effects.Our team has shown that its analogs have antioxidant activity,and oxidative stress is a pathological hallmark of retinal ischemia/reperfusion injury that can lead to retinal damage and visual loss.This investigation aims to identify a chalcone that protects retinal ganglion cells in vitro from the effects of oxidative stress and examine its mechanism.Rat retinal ganglion cell-5 cells were pretreated with chalcones and then exposed to tert-butyl hydroperoxide that causes oxidative damage.Controls received dimethyl sulfoxide only or tert-butyl hydroperoxide in dimethyl sulfoxide.Only（E）-3,4-dihydroxy-2′-methylether ketone（L2 H17）,of the five chalcone analogs,markedly increased the survival rate of oxidatively injured RGC-5 cells.Thus,subsequent experiments only analyzed the results of the L2 H17 intervention.Cell viability and apoptosis were measured.Intracellular superoxide dismutase and reactive oxygen species levels were used to assess induced oxidative stress.The mechanism of action by L2 H17 was explored by measuring the ER stress/UPR pathway and the expression and localization of Nrf2.All results demonstrated that L2 H17 could reduce the apoptosis of oxidatively injured cells,inhibit caspase-3 activity,increase Bcl-2 expression,decrease Bad expression,increase the activity of superoxide dismutase,inhibit the production of reactive oxygen species,increase Nrf2 immunoreactivity,and reduce the activating transcription factor 4,phospho-eukaryotic initiation factor 2 and CHOP expression.L2 H17 protects retinal ganglion cells induced by oxidative stress by regulating Nrf2,which indicates that it has the potential to become a drug for retinal ischemia/reperfusion.

Chemo/Dietary prevention of cancer:perspectives in China

Cancer is a major disease worldwide and different approaches are needed for its prevention.Previous laboratory and clinical studies suggest that cancer can be prevented by chemicals,including those from the diet.Furthermore,epidemiological studies have suggested that deficiencies in certain nutrients can increase the risk of some cancers.In this article on chemo/dietary prevention,examples will be given to illustrate the effectiveness of chemopreventive agents in the prevention of breast,colon and prostate cancers in high-risk populations and the possible side effects of these agents.The potential usefulness of dietary approaches in cancer prevention and the reasons for some of the failed trials will be discussed.Lessons learned from these studies can be used to design more relevant research projects and develop effective measures for cancer prevention in the future.The development of effective chemopreventive agents,the use of nutrient supplements in deficient or carcinogen-exposed populations,and the importance of cohort studies will be discussed in the context of the current socioeconomic situation in China.More discussions are needed on how we can influence society to pay more attention to cancer prevention research and measures.

Phase Selectively Soluble Dendritic Derivative of 4-(Dimethylamino)- pyridine: An Easily Recyclable Catalyst for Baylis-Hillman Reactions

A new thermomorphic catalytic system for the Baylis-Hillman coupling of aromatic aldehydes with a, β-unsaturated ketone has been described, in which the alkyl-functionalized dendritic catalyst preferred to dissolve in non-polar organic layer in the thermomorphic biphasic system, leading to easy separation of the catalyst from the polar products by changing the temperature of the system at end of the reaction.

Chemical tools for E3 ubiquitin ligase study

E3 ubiquitin ligases catalyze the final step of ubiquitylation,a crucial post-translational modification involved in almost every process in eukaryotic cells.E3 ubiquitin ligases are key regulators of cellular events,and the investigation into their functions and functioning mechanisms are research areas with great importance.Synthetic or semi-synthetic tools have greatly facilitated the research about the enzyme activity,distribution in different physiological events,and catalytic mechanism of E3 ubiquitin ligase.In this review,we summarize the development of chemical tools for E3 ubiquitin ligases with an emphasis on the synthetic routes.We show the utility of these chemical tools by briefly discussing their applications in biological research.

Visible light cross-linking and bioactive peptides loaded integrated hydrogel with sequential release to accelerate wound healing complicated by bacterial infection

The effective management of bacterial infections that are resistant to multiple drugs remains a substantial clinical challenge.The eradication of drug-resistant bacteria and subsequent promotion of angiogenesis are imperative for the regeneration of the infected wounds.Here,a novel and facile peptide containing injectable hydrogel with sustained antibacterial and angiogenic capabilities is developed.The antibacterial peptide that consists of 11 residues(CM11,WKLFKKILKVL)is loaded onto acrylate-modified gelatin through charge interactions.A vascular endothelial growth factor mimetic peptide KLT(KLTWQELYQLKYKGI)with a GCG(Gly-Cys-Gly)modification at the N-terminal is covalently coupled through a visible light-induced thiol-ene reaction.In this reaction,the acrylate gelatin undergoes cross-linkage within seconds.Based on the physical/chemical double crosslinking strategy,the bioactive peptides achieve sustained and sequential release.The results show that the hydrogel significantly inhibits methicillin-resistant Staphylococcus aureus(MRSA)growth through the rapid release of CM11 peptides at early stage;it forms obvious growth inhibition zones against pathogenic bacterial strains.Moreover,cell counting kit-8 assay and scratch test confirm that the CM11/KLT-functionalized hydrogels promote cell proliferation and migration through the later release of KLT peptides.In a mouse skin wound infected with self-luminous MRSA,the CM11/KLT-functionalized hydrogels enhance wound healing,with rapidly bacterial infection reduction,lower expression of inflammatory factors,and neovascularization promotion.These results suggest that the rationally designed,sustained and sequential release CM11/KLT-functionalized hydrogels have huge potential in promoting the healing of multi-drug resistant bacterial infected wounds.

Thylakoid engineered M2 macrophage for sonodynamic effect promoted cell therapy of early atherosclerosis

Atherosclerosis is the most common cause of cardiovascular diseases that contribute to the major morbidity worldwide,but still lacking of effective treatment strategy.Here,a hybrid cell is constructed for the sonodynamic effect promoted cell therapy of early atherosclerosis by fusing M2 macrophages with thylakoid(TK)membranes.After systemic administration,the obtained TK-M2 actively accumulates in the early atherosclerotic plaques,wherein M2 macrophages relieve the cholesterol accumulation and the inflammation in the foam cells.Meanwhile,the TK membranes decorated on the M2 macrophages exhibit both type I and type II sonodynamic effects under ultrasound(US)activation,inducing the direct apoptosis of foam cells.The cooperation of M2 and TK leads to significant outcome in eliminating atherosclerotic plaques without obvious side-effects,providing a new avenue for atherosclerosis treatment.

Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

Chemical Synthesis of Structurally Defined Phosphorylated Ubiquitins Suggests Impaired Parkin Activation by Phosphorylated Ubiquitins with a Non-Phosphorylated Distal Unit

Mutations in genes encoding PINK1(PTEN-induced kinase 1)and Parkin(E3 ubiquitin ligase)are identified in familial Parkinson’s disease.However,it remains unclear whether the phosphorylated Ub chains activate wild-type Parkin(w-Parkin)or phosphorylated Parkin(p-Parkin),with the consequent expulsion of the damaged mitochondria.

Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases

The NLRP3 inflammasome’s core and most specific protein,NLRP3,has a variety of functions in inflammation-driven diseases.Costunolide(COS)is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity,but the principal mechanism and molecular target of COS remain unclear.Here,we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3,altering the ATPase activity and assembly of NLRP3 inflammasome.We declare COS’s great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation.We also reveal that theα-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation.Taken together,NLRP3 is identified as a direct target of COS for its anti-inflammasome activity.COS,especially theα-methylene-γ-butyrolactone motif in COS structure,might be used to design and produce novel NLRP3 inhibitors as a lead compound.

Rhodium-Catalyzed Transannulation of 1,2,3-Thiazoles with Alkynes for the Direct Synthesis of Thiochromenones

A rhodium-catalyzed denitrogenative carbonylation of 1,2,3-thiadiazole with alkynes to construct(benzo)thiochromenones is developed.Both terminal and internal alkynes were compatible in this[3+2+1]cycloaddition,affording a broad range of poly-substituted thiochromenones.Unsymmetrical alkyne substrates exhibited good regioselectivity.

Exploiting Complex-Type N-Glycan to Improve the in Vivo Stability of Bioactive Peptides

Peptides can be potentmolecules with high efficacy and selectivity in the development of biotherapeutics.However,the poor pharmacokinetic properties of peptides pose major challenges for their broader medicinal applications.Inspired by the proteinstabilizing role of natural N-glycosylation,we design and synthesize a series of parathyroid hormone(PTH)peptides(1-34),bearing either N-GlcNAc or biantennary complex-type N-glycan modification,and evaluate their serum stability and biological activities.The results indicate that an N-Asn-linked complex-type sialylundecasaccharide can increase the serum half-life and in vivo bioactivity of PTH peptides with a broad tolerance of modification sites.Further,hydrogen/deuterium exchange mass spectroscopy indicates that the larger-sized Nglycan can induce enhanced hydration dynamics in its surroundings,which may facilitate an improved resistance for the peptide against enzymatic proteolysis.This sialylundecasaccharide-based peptideengineering strategy has also been applied to glucagon-like peptide-1(7-37),leading to glycopeptides with enhanced hypoglycemic activity and acting time in vivo.Together,these results demonstrate the potential of using sialylated complextype N-glycan as a general engineering strategy for developing long-acting peptide therapeutics.

Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1

As a terpenoids natural product isolated from the plant Thunder God Vine,Celastrol is widely studied for its pharmacological activities,including anti-tumor activities.The clinical application of Celastrol is strictly limited due to its severe side effects,whereas previously revealed targets and mechanism of Celastrol seldom reduce its in vivo toxicity via structural optimization.Target identification has a far-reaching influence on the development of innovative drugs,and omics data has been widely used for unbiased target prediction.However,it is difficult to enrich target of specific phenotype from thousands of genes or proteins,especially for natural products with broad promising activities.Here,we developed a text-mining-based web-server tool to enrich targets from omics data of inquired compounds.Then peroxiredoxin 1(PRDX1)was identified as the ROS-manipulating target protein of Celastrol in colorectal cancer.Our solved high-resolution crystal structure revealed the unique covalent binding mode of Celastrol with PRDX1.New derivative compound 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized based on crystal structure analysis.Both Celastrol and 19-048 effectively suppressed the proliferation of colorectal cancer cells.The anti-tumor efficacy of Celastrol and 19-048 was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells.Several downstream genes of p53 signaling pathway were dramatically up-regulated with Celastrol or 19-048 treatment.Our findings reveal that the side effects of Celastrol could be reduced via structural modification,and PRDX1 inhibition is promising for the treatment of colorectal cancer.

Genetic Encoding of a Photocaged Glutamate for Optical Control of Protein Functions

Genetic encoding of photocaged noncanonical amino acids provides a powerful tool to study protein functions through optical control but is not yet available for acidic amino acids.Herein,we report the first site-specific genetic encoding of a photocaged glutamate,4-methoxy-7-nitroindolinyl caged glutamate(MNI-Glu),into recombinant proteins via an expanded genetic code through evolved EcLeuRS/tRNA pair.Using two enzymes as examples,we demonstrate that substituting the conserved-active-site glutamate of a secreted alkaline phosphatase and a protease HRV3C to MNI-Glu allows photoregulatory control of their enzymatic activities.Our approach is an important addition to the photocaged noncanonical amino-acid toolbox and provides a general method to photocontrol protein activity based on caging a critical glutamate.

TMPRSS2 and SARS-CoV-2 SPIKE interaction assay for uHTS

SARS-CoV-2,the coronavirus that causes the disease COVID-19,has claimed millions of lives over the past 2 years.This demands rapid development of effective therapeutic agents that target various phases of the viral replication cycle.The interaction between host transmembrane serine protease 2(TMPRSS2)and viral SPIKE protein is an important initial step in SARS-CoV-2 infection,offering an opportunity for therapeutic development of viral entry inhibitors.Here,we report the development of a time-resolved fluorescence/Förster resonance energy transfer(TR-FRET)assay for monitoring the TMPRSS2–SPIKE interaction in lysate from cells co-expressing these proteins.The assay was configured in a 384-well-plate format for high-throughput screening with robust assay performance.To enable large-scale compound screening,we further miniaturized the assay into 1536-well ultrahigh-throughput screening(uHTS)format.A pilot screen demonstrated the utilization of the assay for uHTS.Our optimized TR-FRET uHTS assay provides an enabling platform for expanded screening campaigns to discover new classes of small-molecule inhibitors that target the SPIKE and TMPRSS2 protein–protein interaction.

Antimony salt-promoted cyclization facilitating on-DNA syntheses of dihydroquinazolinone derivatives and its applications

DNA-encoded chemical libraries technology has become a novel approach to finding hit compounds in early drug discovery.The chemical space in a DEL would be expanded to realize its full potential,especially when integrating privileged scaffold dihydroquinazoline that has demonstrated a variety of diverse bioactivities.Driven by the requirement of parallel combinatorial synthesis,we here report a facile synthesis of on-DNA dihydroquinazolinone from aldehyde and anthranilamide.This DNA-compatible reaction was promoted by antimony trichloride,which has been proven to accelerate the reaction and improve conversions.Notably,the broad substrate scope of aldehydes and anthranilamides was explored under the mild reaction condition to achieve moderate-to-excellent conversion yields.We further applied the reaction into on-DNA macrocyclization,obtaining macrocycles embedded dihydroquinazolinone scaffold in synthetically useful conversion yields.

螺[4,4]-1,6-壬二烯骨架手性双膦配体的合成

从方便易得的原料出发,以钯催化的烯基三氟甲磺酸酯与二苯基膦氧化物的偶联反应为关键步骤,合成了螺[4,4]-1,6-壬二烯骨架的手性双膦配体1.其中,关键中间体5的拆分是通过半制备手性液相色谱实现的,并通过该化合物的X射线单晶衍射分析确定了其中螺碳原子的绝对构型.配体(S)-1的Rh(I)络合物在α-乙酰氨基肉桂酸的氢化中表现出中等的对映选择性(53%ee).配体(S)-1的Cu(I)络合物能以较好的反应活性实现苯乙酮的不对称氢化,产物的对映体过量可以达到67%.

手性螺[4,4]-1,6-壬二烯骨架双口恶唑啉配体的合成

设计、合成结构多样的手性配体一直是不对称催化领域的核心问题之一.近年来,具有C2-对称性的双口恶唑啉配体在有机金属催化中受到广泛关注．

癌症化学预防在中国--代专辑前言

当前，全球的癌症负担持续增加，是世界范围内对人类健康的主要威胁之一。根据GLOBOCAN2008提供的数据，癌症在发达国家居民死因中占据首位，而在发展中国家居民死因中占第二位。癌症发病率和死亡率在美国及部分国家已经开始下降，但在发展中国家中仍在上升。中国作为最大的人口最多的发展中国家，正面临着更为严峻的来自癌症的挑战。

Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents

Scavenging reactive oxygen species(ROS) by antioxidants is the important therapy to cerebral ischemia-reperfusion injury(CIRI) in stroke. The antioxidant with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through antioxidant pathway activation may be a promising CIRI therapeutic strategy. In our study, a series of chalcone analogues were designed and synthesized, and multiple potential chalcone analogues with dual antioxidant mechanisms were screened. Among these compounds, the most active 33 not only conferred cytoprotection of H2 O2-induced oxidative damage in PC12 cells through scavenging free radicals directly and activating NRF2/ARE antioxidant pathway at the same time, but also played an important role against ischemia/reperfusion-related brain injury in animals. More importantly, in comparison with mono-antioxidant mechanism compounds, 33 exhibited higher cytoprotective and neuroprotective potential in vitro and in vivo. Overall, our findings showed compound 33 couldemerge as a promising anti-ischemic stroke drug candidate and provided novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related diseases treatment.