Complex structure of human Hsp90~N and a novel small inhibitor FS5

Heat shock proteins(Hsps)are a family of abundantly expressed ATP-dependent chaperone proteins.Hsp90 is an eminent member of Hsp family.Thus far,two primary functions have been described for Hsp90:first,as a regulator of conformational change of some protein kinases and nuclear hormone receptors,and the other as an indispensable factor in cellular stress response.Hsp90 has an essential number of interaction proteins since it participates in almost every biological process and its importance is self-evident.Hsp90 has an inextricable relationship in the pathogenesis of cancer,especially in the proliferation and irradiation of cancer cells,thus being a notable cancer target.Since the discovery of geldanamycin,the first inhibitor of Hsp90,from the bacterial species Streptomyces hygroscopicus,even more attention has been focused toward Hsp90.Many structure-based inhibitors of Hsp90 have been designed to develop an innovative method to defeat cancer.However,already designed inhibitors have various deficiencies,such as hepatotoxicity,poor aqueous solubility,instability,and non-ideal oral bioavailability.Based on the aforementioned reasons and to achieve an optimal performance and fewer side effects,we designed a novel inhibitor of Hsp90,called FS5,and resolved the crystal structure of the Hsp90^N-FS5 complex(1.65 A°,PDB code 5XRB).Furthermore,we compared the complexes Hsp90^N,Hsp90^N-GDM,and Hsp90^N-ATP and suggest that the inhibitor FS5 may compete with ATP for binding to Hsp90,which can be regarded as a potential strategy for the development of novel cancer drugs in the future.

Imperatorin alleviates Aβ-induced spatial learning memory impairment and neuroinflam⁃mation in model mice of Alzheimer disease

OBJECTIVE To investigate the effects of imperatorin on the spatial learning memory impairment and neuroinflammation in model mice of Alzheimer disease(AD)induced by intracerebroventricular injection of Aβ1-42.METHODS Mouse model of AD was established by injection of Aβ1-42 into the lateral ventricles.Im⁃peratorin(2.5 and 5.0 mg·kg-1,daily)was inject⁃ed by intraperitoneally 1 h after intracerebroven⁃tricular injection for 13 d.The effect of imperato⁃rin on the spatial learning and memory impair⁃ment was assessed by eight arm maze tests.The levels of cytokines TNF-α,IL-1β,IL-6,IL-18 and chemokines MCP-1 in mouse cortex and hip⁃pocampus were detected by ELISA.The protein expression of NF-κB P65,TLR4,MyD88,p-P38,p-ERK,and p-JNK were detected by Western blotting.RESULTS As compared with the AD model group,imperatorin treatment significantly attenuated Aβ1-42-induced spatial learning and memory impairment assessed by eight arm maze tests.In addition,imperatorin significantly reduced the levels of cytokines TNF-α,IL-1β,IL-6,IL-18 and chemokines MCP-1 in the cerebral cortex and hippocampus.Meanwhile,Western blotting results showed that imperatorin treat⁃ment significantly down-regulated the protein expression of NF-κB P65,TLR4,MyD88,p-P38,p-ERK,and p-JNK.CONCLUSION Imperatorin has neuroprotective effects in the Aβ1-42 induced AD model mice and its mechanism may be partially associated with the inhibition of inflam⁃matory response in the cortex and hippocampus.

Regulation of pathological blood-brain barrier for intracranial enhanced drug delivery and anti-glioblastoma therapeutics

The blood-brain barrier(BBB)is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system(CNS).During the occurrence and development of glioblastoma(GBM),BBB is pathologically destroyed with a marked increase in permeability.Due to the obstruction of the BBB,current strategies for GBM therapeutics still obtain a meager success rate and may lead to systemic toxicity.Moreover,chemotherapy could promote pathological BBB functional restoration,which results in significantly reduced intracerebral transport of therapeutic agents during multiple administrations of GBM and the eventual failure of GBM chemotherapy.The effective delivery of intracerebral drugs still faces severe challenges.However,strategies that regulate the pathological BBB to enhance the transport of therapeutic agents across the barrier may provide new opportunities for the effective and safe treatment of GBM.This article reviews the structure and function of BBB in physiological states,the mechanisms underlying BBB pathological fenestration during the development of GBM,and the therapeutic strategies of GBM based on BBB intervention and medicinal drugs transporting across the BBB.

Growth Hormone Releasing Hormone Receptors Antagonists and Cancers: Do GHRH-R Antagonists Play a Role in the Management of Prostate Cancer?

Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in the progression of various tumors such as those of the prostate. Treatment modalities for prostate cancer in a localized stage or when it is still castration-sensitive yield good results in most patients. However, such treatments are only palliative in the advanced stage. Therefore, new therapeutic targets like growth hormone-releasing hormone receptor (GHRH-R) and its splice variants should be found in order to get effective treatments for more aggressive stages in prostate cancer. This review talks about the GHRH-R and its splice variants, the signaling pathways induced by GHRH to produce cancer, the structure activity relationship of GHRH-R antagonists and the resume of some in vitro and in vivo studies on the role of GHRH-R antagonists in the treatment of prostate cancer.

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Ethanol extract of Cyathulae Radix inhibits osteoclast differentiation and bone loss

Cyathulae Radix,a traditional Chinese medicine and a common vegetable,boasts a history spanning millennia.It enhances bone density,boosts metabolism,and effectively alleviates osteoporosis-induced pain.Despite its historical use,the molecular mechanisms behind Cyathulae Radix’s impact on osteoporosis remain unexplored.In this study,we investigated the effects and mechanisms of Cyathulae Radix ethanol extract(CEE)in inhibiting osteoporosis and osteoclastogenesis.Eight-week-old female mice underwent ovariectomy and were treated with CEE for eight weeks.Micro-computed tomography(micro-CT)assessed histomorphometric parameters,bone tissue staining observed distal femur histomorphology,and three-point bending tests evaluated tibia mechanical properties.Enzyme-linked immunosorbent assay(ELISA)measured serum estradiol(E2),receptor activator for nuclear factor B ligand(RANKL),and osteoprotegerin(OPG)levels.Osteoclastogenesis-related markers were analyzed via Western blotting(WB)and quantitative real-time polymerase chain reaction(qRT-PCR).Additionally,CEE effects on RANKL-induced osteoclast formation and bone resorption were investigated in vitro using tartrate-resistant acid phosphatase(TRAP)staining,qRT-PCR,and WB assay.Compared with the ovariectomy(OVX)group,CEE treatment enhanced trabecular bone density,maximal load-bearing capacity,and various histomorphometric parameters.Serum E2 and OPG levels significantly increased,while Receptor activator of nuclear factor-κB(RANK)decreased in the CEE group.CEE downregulated matrix metallopeptidase 9(MMP-9),Cathepsin K(CTSK),and TRAP gene and protein expression.In bone marrow macrophages(BMMs),CEE reduced mature osteoclasts,bone resorption pit areas,and MMP-9,CTSK,and TRAP expression during osteoclast differentiation.Compared with DMSO treatment,CEE markedly inhibited RANK,TNF receptor associated factor 6(TRAF6),Proto-oncogene c-Fos(c-Fos),Nuclear factor of activated T-cells cytoplasmic 1(NFATc1)expressions,and Extracellular regulated protein kinases(ERK),c-Jun N-terminal kinase(JNK),NF-kappa B-p65(p65)phosphorylation in osteoclasts.In conclusion,CEE significantly inhibits OVX-induced osteoporosis and RANKL-induced osteoclastogenesis,potentially through modulating the Estrogen Receptor(ER)/RANK/NFATc1 signaling pathway.

Photocatalyst-controlled and visible light-enabled selective oxidation of pyridinium salts

This study proposes two different methods of photocatalytic-controlled and visible light-induced selective oxidation of pyridiniums with air as the terminal oxidant.The key to these transformations is to choose the appropriate light source and photocatalyst.Pyridiniums are successfully converted into pyrroles through oxygen-mediated cycloaddition,proton-coupled electron transfer(PCET),pyridine ring opening,and recyclization.The other route is that pyridiniums selectively form 4-carbonyl pyridines through free radical rearrangement/aerobic oxidation under the catalysis of cobalt(Ⅱ).

Visible-light induced transition-metal and photosensitizer-free conversion of aldehydes to acyl fluorides under mild conditions

Acyl fluorides are powerful synthons for acylation with wide application in the synthesis of valued compounds,especially peptides.Herein,a practical and catalyst-free method for the synthesis of acyl fluorides from aldehydes via C(sp^(2))-H fluorination is reported.This method enables the conversion of both aliphatic and aromatic aldehydes into acyl fluorides in good to excellent yields by visible-light under mild conditions in the absence of transition-metal and external photosensitizer.A variety of functional groups were well tolerated for this transformation.This green method provides a practical pathway to synthesize acyl fluorides under mild conditions.

A step-by-step multiple stimuli-responsive metal-phenolic network prodrug nanoparticles for chemotherapy

Currently,chemotherapy is the main clinical therapy of tumors.Depressingly,most chemotherapeutic drugs such as doxorubicin and paclitaxel(PTX)have poor water solubility,leading to low bioavailability and serious side effects.Till now,although a variety of nanoparticulate drug delivery systems have been designed to ameliorate the above disadvantage of chemotherapy drugs,their application is still severely limited due to the complex preparation,poor stability,low drug loading,and premature drug release.Herein,a metal phenolic network-based drug delivery system with superior stability,satisfactory drug loading capacity,good biocompatibility,reduced undesired premature release,and excellent anti-tumor ability has been established for achieving step-by-step multiple stimuli-responsive drug delivery.Firstly,the redox-responsive dimeric paclitaxel(diPTX)prodrug was synthesized.Then diPTX@Fe&tannic acid(diPTX@Fe&TA)complex nanoparticles with satisfactory PTX loading capacity were obtained by deposition of Fe&TA network complex on the nanocore of diPTX rapidly with a simple method.The diPTX@Fe&TA nanoparticles have a hydrodynamic diameter of 152.6±1.2 nm,long-term colloidal stability,and high PTX loading content of 24.7%.Besides,diPTX@Fe&TA could expose to the acidic lysosomal environment and the reduction cytoplasmic environment continuously,resulting in the sequential release of diPTX and PTX when it was phagocytosed by tumor cells.Meanwhile,PTX showed almost no release under physiological condition(pH 7.4),which effectively inhibited the undesirable premature release of PTX.More importantly,diPTX@Fe&TA could suppress the growth of tumor effectively in vivo,along with negligible toxicity for organs.This work developed a simple and novel approach for the construction of a stepwise multiple stimuli-responsive drug delivery system with superior stability and satisfactory drug loading capacity to inhibit tumor growth effectively.