The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan

The drugs extending healthspan in clinic have always been searched.Nitazoxanide is an FDA-approved clinical antiprotozoal drug.Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo.Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK,oral nitazoxanide protects against experimental hyperlipidemia,hepatic steatosis,and atherosclerosis.Here,we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 pathway.Additionally,both nitazoxanide and tizoxanide improve high glucose-induced shortening of C.elegans lifespan.Nitazoxanide has been a clinical drug with a good safety profile,we suggest that it is a novel anti-aging drug.

Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition

Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.

Broad-spectrum ginsentides are principal bioactives in unraveling the cure-all effects of ginseng

Stress and illness connection is complex and involves multiple physiological systems.Panax ginsengs,reputed for their broad-spectrum“cure-all”effect,are widely prescribed to treat stress and related illnesses.However,the identity of ginseng’s“cure-all”medicinal compounds that relieve stress remains unresolved.Here,we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress.Ginsentides are disulfide-rich,cell-penetrating and proteolytic-stable microproteins.Using affinity-enrichment mass spectrometry target identification together with in vitro,ex vivo and in vivo validations,we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway,alleviate a1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta,decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation.Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation,to prevent collagen and adrenalineinduced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice.Together,these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra-and intra-cellular proteins to reverse stress-induced damages.

Biomimetic“Gemini nanoimmunoregulators”orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy.Here,a new type of spatiotemporal biomimetic“Gemini nanoimmunoregulators”was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death(ICD),tumor-associated macrophages(TAMs)phenotype reprogramming and programmed cell death ligand 1(PD-L1)degradation.The“Gemini nanoimmunoregulators”PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine(mPDA)as nanovectors to deliver metformin(Met)and toll-like receptor 7/8 agonist resiquimod(R848)to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane(RM)inlaid with T7or M2 peptides.mPDA/Met@RM-T7(abbreviated as PM@RM-T7)was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity.Meanwhile,PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion.Subsequently,mPDA/R848@RM-M2(abbreviated as PR@RM-M2)specifically recognized TAMs and reset the phenotype from M2 to M1 state,thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes.This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity,which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis.This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

There are only eight approved small molecule antiviral drugs for treating COVID-19.Among them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous studies.Thus there is a dearth of new treatment options for SARS-CoV-2.In this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity.One compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern.Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro.In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice.Overall,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

The role of N-glycosylation in cancer

Despite advances in understanding the development and progression of cancer in recent years,there remains a lack of comprehensive characterization of the cancer glycoproteome.Glycoproteins play an important role in medicine and are involved in various human disease conditions including cancer.Glycan-moieties participate in fundamental cancer processes like cell signaling,invasion,angiogenesis,and metastasis.Aberrant N-glycosylation significantly impacts cancer processes and targeted therapies in clinic.Therefore,understanding N-glycosylation in a tumor is essential for comprehending disease progression and discovering anti-cancer targets and biomarkers for therapy monitoring and diagnosis.This review presents the fundamental process of protein N-glycosylation and summarizes glycosylation changes in tumor cells,including increased terminal sialylation,N-glycan branching,and corefucosylation.Also,the role of N-glycosylation in tumor signaling pathways,migration,and metabolism are discussed.Glycoproteins and glycopeptides as potential biomarkers for early detection of cancer based on site specificity have been introduced.Collectively,understanding and exploring the cancer glycoproteome,along with its role in medicine,implication in cancer and other human diseases,highlights the significance of N-glycosylation in tumor processes,necessitating further research for potential anticancer targets and biomarkers.

HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor via intranasal administration

The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant protein,heptad repeat(HR)121,as a variant-proof vaccine.Here,we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants.Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike(S)2 subunit to block virus-cell fusion.Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH,highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route.Importantly,HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells,as well as block authentic SARSCoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells.After intranasal administration to Syrian golden hamsters,it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection.Together,our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.

Announcing 2022 Impact Factor for Acta Pharmaceutica Sinica B

Acta Pharmaceutica Sinica B(APSB)is delighted to announce that the 2022 Impact Factor(IF)of the journal is now 14.5(13.8 without self-citations)according to the latest Clarivate Journal Citation Reports released on Jun 28th,2023.APSB ranks No.5(Q1 quartile)of the 277 journals in the Pharmacology and Pharmacy category.

Announcing 2022 Impact Factor for Acta Pharmaceutica Sinica B

Acta Pharmaceutica Sinica B(APSB)is delighted to announce that the 2022 Impact Factor(IF)of the journal is now 14.5(13.8 without self-citations)according to the latest Clarivate Journal Citation Reports released on Jun 28th,2023.APSB ranks No.5(Q1 quartile)of the 277 journals in the Pharmacology and Pharmacy category.

Characterization of the depsidone gene cluster reveals etherification,decarboxylation and multiple halogenations as tailoring steps in depsidone assembly

Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities and structural diversity.Previous structure-activity relationships indicated that triple halogenated depsidones display the best anti-pathogenic activity.However,the gene cluster and the tailoring steps responsible for halogenated depsidone nornidulin(3)remain enigmatic.In this study,we disclosed the complete biosynthetic pathway of the halogenated depsidone through in vivo gene disruption,heterologous expression and in vitro biochemical experiments.We demonstrated an unusual depside skeleton biosynthesis process mediated by both highly-reducing polyketide synthase and nonreducing polyketide synthase,which is distinct from the common depside skeleton biosynthesis.This skeleton was subsequently modified by two in-cluster enzymes DepG and DepF for the ether bond formation and decarboxylation,respectively.In addition,the decarboxylase DepF exhibited substrate promiscuity for different scaffold substrates.Finally,and interestingly,we discovered a halogenase encoded remotely from the biosynthetic gene cluster,which catalyzes triple-halogenation to produce the active end product nornidulin(3).These discoveries provide new insights for further understanding the biosynthesis of depsidones and their derivatives.

Nanoplateletsomes restrain metastatic tumor formation through decoy and active targeting in a preclinical mouse model

Platelets buoy up cancer metastasis via arresting cancer cells, enhancing their adhesion, and facilitating their extravasation through the vasculature. When deprived of intracellular and granular contents, platelet decoys could prevent metastatic tumor formation. Inspired by these, we developed nanoplatesomes by fusing platelet membranes with lipid membranes(P-Lipo) to restrain metastatic tumor formation more efficiently. It was shown nanoplateletsomes bound with circulating tumor cells(CTC)efficiently, interfered with CTC arrest by vessel endothelial cells, CTC extravasation through endothelial layers, and epithelial-mesenchymal transition of tumor cells as nanodecoys. More importantly, in the mouse breast tumor metastasis model, nanoplateletsomes could decrease CTC survival in the blood and counteract metastatic tumor growth efficiently by inhibiting the inflammation and suppressing CTC escape. Therefore, nanoplatelesomes might usher in a new avenue to suppress lung metastasis.

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells(DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals(around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4 T1 cell adhesion to mesenchymal stem cells(MSCs)/preosteoblasts(pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4 T1 cells and MSCs/pre-OBs.The chemotactic migration of 4 T1 cells toward osteogenic cells was blocked by arsenic in mimic 3 D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4 T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.

Antibody-drug conjugates:Recent advances in linker chemistry

Antibody-drug conjugates(ADCs)are gradually revolutionizing clinical cancer therapy.The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects,and so has a major influence on the fate of ADCs.An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor.However,existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity.This defect is becoming an increasingly important factor that restricts the development of ADCs.The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers.The present review summarizes the advance of the chemical trigger,linker-antibody attachment and linker-payload attachment over the last 5 years,and describes the ADMET properties of ADCs.This work also helps clarify future developmental directions for the linkers.

A pentapeptide enabled AL3810 liposome-based glioma-targeted therapy with immune opsonic effect attenuated

AL3810,a molecular dual inhibitor of the vascular endothelial growth factor receptor(VEGFR)and fibroblast growth factor receptor(FGFR),has earned the permission of phase II clinical trial for tumor treatment by China FDA.As a reversible ATP-competitive inhibitor,AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR,whereas,AL3810 lacking interplay with extracellular region of receptors rendered deficient bloodebrain tumor barrier(BBTB)recognition,poor brain penetration and unsatisfactory anti-glioma efficacy.Integrin avb3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma.The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia,activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3 b and C5 b-9,and experienced complement-dependent opsonization.We newly proposed a pentapeptide mn with superb avb3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation,targeting ability,and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly.Stemming from attenuated immunogenicity,peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.

Intracellular aggregation of peptide-reprogrammed small molecule nanoassemblies enhances cancer chemotherapy and combinatorial immunotherapy

The intracellular retention of nanotherapeutics is essential for their therapeutic activity.The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors.However,strategies for the intracellular immobilization of nanoparticles are limited.Herein,a cisplatin prodrug was synthesized and utilized as a glutathione(GSH)-activated linker to induce aggregation of the cisplatin prodrug/IR820/docetaxel nanoassembly.The nanoassembly has been reprogrammed with peptidecontaining moieties for tumor-targeting and PD-1/PD-L1 blockade.The aggregation of the nanoassemblies is dependent on GSH concentration.Evaluations in vitro and in vivo revealed that GSH-induced intracellular aggregation of the nanoassemblies enhances therapeutic activity in primary tumors by enhancing the accumulation and prolonging the retention of the chemotherapeutics in the tumor site and inducing reactive oxygen species(ROS)generation and immunogenic cell death.Moreover,the nanoassemblies reinvigorate the immunocytes,especially the systemic immunocytes,and thereby alleviate pulmonary metastasis,even though the population of immunocytes in the primary tumor site is suppressed due to the enhanced accumulation of chemotherapeutics.This strategy provides a promising option for the intracellular immobilization of nanoparticles in vitro and in vivo.

Gasdermin D in pyroptosis

Pyroptosis is the process of inflammatory cell death.The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection.Excessive pyroptosis,however,leads to several inflammatory diseases,including sepsis and autoimmune disorders.Pyroptosis can be canonical or noncanonical.Upon microbe infection,the canonical pathway responds to pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs),while the noncanonical pathway responds to intracellular lipopolysaccharides(LPS) of Gram-negative bacteria.The last step of pyroptosis requires the cleavage of gasdermin D(GsdmD) at D275(numbering after human GSDMD) into N-and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11(caspase 4/5 in humans,caspase 11 in mice) in the noncanonical pathway.Upon cleavage,the N-terminus of GsdmD(GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water,eventually resulting in strong inflammation and cell death.Since GsdmD is the effector of pyroptosis,promising inhibitors of GsdmD have been developed for inflammatory diseases.This review will focus on the roles of GsdmD during pyroptosis and in diseases.

A facile and universal method to achieve liposomal remote loading of non-ionizable drugs with outstanding safety profiles and therapeutic effect

Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents,thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy.In this study,a series of weak acid drug derivatives were designed by a simplistic one step synthesis,which could be remotely loaded into liposomes by p H gradient method.Cabazitaxel(CTX)weak acid derivatives were selected to evaluate regarding its safety profiles,pharmacodynamics,and pharmacokinetics.CTX weak acid derivative liposomes were superior to Jevtanaa in terms of safety profiles,including systemic toxicity,hematological toxicity,and potential central nerve toxicity.Specifically,it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons.Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.

Nature-derived compounds modulating Wnt/β-catenin pathway:a preventive and therapeutic opportunity in neoplastic diseases

The Wnt/β-catenin signaling is a conserved pathway that has a crucial role in embryonic and adult life.Dysregulation of the Wnt/β-catenin pathway has been associated with diseases including cancer,and components of the sisnaling have been proposed as innovative therapeutic targets,mainly for cancer therapy.The attention of the worldwide researchers paid to this issue is increasing,also in view of the therapeutic potential of these agents in diseases,such as Parkinson’s disease(PD),for which no cure is existing today.Much evidence indicates that abnormal Wnt/β-catenin signaling is involved in tumor immunology and the targeting of Wnt/β-catenin pathway has been also proposed as an attractive strategy to potentiate cancer immunotherapy.During the last decade,several products,including naturally occurring dietary agents as well as a wide variety of products from plant sources,including curcumin,quercetin,berberin,and ginsenosides,have been identified as potent modulators of the Wnt/β-catenin signaling and have gained interest as promising candidates for the development of chemopreventive or therapeutic drugs for cancer.In this review we make an overview of the nature-derived compounds reported to have antitumor activity by modulating the Wnt/β-catenin signaling,also focusing on extraction methods,chemical features,and bio-activity assays used for the screening of these compounds.

Selective phytochemicals targeting pancreatic stellate cells as new anti-fibrotic agents for chronic pancreatitis and pancreatic cancer

Activated pancreatic stellate cells(PSCs)have been widely accepted as a key precursor of excessive pancreatic fibrosis,which is a crucial hallmark of chronic pancreatitis(CP)and its formidable associated disease,pancreatic cancer(PC).Hence,anti-fibrotic therapy has been identified as a novel therapeutic strategy for treating CP and PC by targeting PSCs.Most of the anti-fibrotic agents have been limited to phaseⅠ/Ⅱclinical trials involving vitamin analogs,which are abundant in medicinal plants and have proved to be promising for clinical application.The use of phytomedicines,as new anti-fibrotic agents,has been applied to a variety of complementary and alternative approaches.The aim of this review was to present a focused update on the selective new potential anti-fibrotic agents,including curcumin,resveratrol,rhein,emodin,green tea catechin derivatives,metformin,eruberin A,and ellagic acid,in combating PSC in CP and PC models.It aimed to describe the mechanism(s)of the phytochemicals used,either alone or in combination,and the associated molecular targets.Most of them were tested in PC models with similar mechanism of actions,and curcumin was tested intensively.Future research may explore the issues of bioavailability,drug design,and nano-formulation,in order to achieve successful clinical outcomes with promising activity and tolerability.

PXR:a center of transcriptional regulation in cancer

Pregnane X receptor(PXR,NR 112)is a prototypical member of the nuclear receptor superfamily.PXR can be activated by both endobiotics and xenobiotics.As a key xenobiotic receptor,the cellular function of PXR is mostly exerted by its binding to the regulatory gene sequences in a liganddependent manner.Classical downstream target genes of PXR participate in xenobiotic responses,such as detoxification,metabolism and inflammation.Emerging evidence also implicates PXR signaling in the processes of apoptosis,cell cycle arrest,proliferation,angiogenesis and oxidative stress,which are closely related to cancer.Here,we discussed,in addition to the characterization of PXR per se,the biological function and regulatory mechanism of PXR signaling in cancer,and its potential for the targeted prevention and therapeutics.