State Key Laboratory of Natural Medicine

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Nitrogen heterocycles belong to a highly important class of compounds which are found in various natural products, biologically active structures, and medicinally relevant compounds. Therefore, there is continuing interest in the development of novel synthetic methods for the construction of nitrogen containing heterocycles. Recently, radical insertion reactions into isonitriles have emerged as an efficient and powerful strategy for the construction of nitrogen heterocycles, such as phenanthridines, indoles, quinolines, quinoxalines, and isoquinolines. This review highlights recent advances in this fast growing research area and also includes important pioneering studies in this area.

Abstract Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U 13 C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.

Significance: Hydrogen sulfide (H 2 S) has been recognized as the third gaseous transmitter alongside nitric oxide and carbon monoxide. In the past decade, numerous studies have demonstrated an active role of H 2 S in the context of cancer biology. Recent Advances: The three H 2 S-producing enzymes, namely cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3MST), have been found to be highly expressed in numerous types of cancer. Moreover, inhibition of CBS has shown anti-tumor activity, particularly in colon cancer, ovarian cancer, and breast cancer, whereas the consequence of CSE or 3MST inhibition remains largely unexplored in cancer cells. Intriguingly, H 2 S donation at high amounts or a long time duration has also been observed to induce cancer cell apoptosis in vitro and in vivo while sparing noncancerous fibroblast cells. Therefore, a bell-shaped model has been proposed to explain the role of H 2 S in cancer development. Specifically, endogenous H 2 S or a relatively low level of exogenous H 2 S may exhibit a pro-cancer effect, whereas exposure to H 2 S at a higher amount or for a long period may lead to cancer cell death. This indicates that inhibition of H 2 S biosynthesis and H 2 S supplementation serve as two distinct ways for cancer treatment. This paradoxical role of H 2 S has stimulated the enthusiasm for the development of novel CBS inhibitors, H 2 S donors, and H 2 S-releasing hybrids. Critical Issues: A clear relationship between H 2 S level and cancer progression remains lacking. The possibility that the altered levels of these byproducts have influenced the cell viability of cancer cells has not been excluded in previous studies when modulating H 2 S producing enzymes. Future Directions: The consequence of CSE or 3MST inhibition in cancer cells need to be examined in the future. Better portrayal of the crosstalk among these gaseous transmitters may not only lead to an in-depth understanding of cancer progression but also shed light on novel strategies for cancer therapy.

The increasing understanding of the role of nitric oxide (NO) in cancer biology has generated significant progress in the use of NO donor-based therapy to fight cancer. These advances strongly suggest the potential adoption of NO donor-based therapy in clinical practice, and this has been supported by several clinical studies in the past decade. In this review, we first highlight several types of important NO donors, including recently developed NO donors bearing a dinitroazetidine skeleton, represented by RRx-001, with potential utility in cancer therapy. Special emphasis is then given to the combination of NO donor(s) with other therapies to achieve synergy and to the hybridization of NO donor(s) with an anticancer drug/agent/fragment to enhance the activity or specificity or to reduce toxicity. In addition, we briefly describe inducible NO synthase gene therapy and nanotechnology, which have recently entered the field of NO donor therapy.

Cancer-associated stimuli-responsive nanosystems have been increasingly considered for the delivery of anticancer drugs, which primarily target the tumor microenvironment and/or intracellular elements to enhance intratumoral accumulation and promote drug release at the target site. The signals facilitating drug delivery include tumor and endocytic acidities, hypoxia, enzyme overexpression, as well as high levels of intracellular glutathione, reactive oxygen species, and adenosine-5′-triphosphate. This article reviews the current techniques and ongoing developments in anticancer drug delivery using these signals. In particular, the focus is placed on design strategies and methods of formulating novel nanoscaled materials. The merits and drawbacks of recent strategies, as well as potential future developments, are discussed.

Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.

A bioinspired cocoon-like anticancer drug delivery system consisting of a deoxyribonuclease (DNase)-degradable DNA nanoclew (NCl) embedded with an acid-responsive DNase I nanocapsule (NCa) was developed for targeted cancer treatment. The NCl was assembled from a long-chain single-stranded DNA synthesized by rolling-circle amplification (RCA). Multiple GC-pair sequences were integrated into the NCl for enhanced loading capacity of the anticancer drug doxorubicin (DOX). Meanwhile, negatively charged DNase I was encapsulated in a positively charged acid-degradable polymeric nanogel to facilitate decoration of DNase I into the NCl by electrostatic interactions. In an acidic environment, the activity of DNase I was activated through the acid-triggered shedding of the polymeric shell of the NCa, resulting in the cocoon-like self-degradation of the NCl and promoting the release of DOX for enhanced therapeutic efficacy.

Each major step leading to the classical yellow, orange and red constituents of <italic>Monascus</italic> azaphilone pigments was defined.

Photodynamic therapy (PDT) combined with oxygenating strategies is widely employed in cancer treatment; however, oxygen-boosted PDT has failed to achieve an ideal effect due to the complexity, heterogeneity, and irreversible hypoxic environment generated by tumor tissues. With the emergence of Fe-dependent ferroptosis boasting reactive oxygen species (ROS) cytotoxicity as well, such a chemodynamic approach to cancer therapy has drawn extensive attention. In this study, hemoglobin (Hb) is connected with the photosensitizer chlorin e6 (Ce6) to construct a 2-in-1 nanoplatform (SRF@Hb-Ce6) with Sorafenib (SRF, ferroptosis promotor) loaded, combining oxygen-boosted PDT and potent ferroptosis. Benefiting from the intrinsic presence of Fe capable of binding oxygen, hemoglobin concurrently furnishes oxygen for oxygen-dependent PDT and Fe for Fe-dependent ferroptosis. Furthermore, amphiphilic MMP2-responsive peptide is incorporated into the skeleton of the nanoplatform to ensure drug-release specificity for safety improvement. Correlative measurements demonstrate the potentiation of PDT and ferroptosis with SRF@Hb-Ce6. More importantly, PDT strengthens ferroptosis by recruiting immune cells to secrete IFN-γ, which can sensitize the tumor to ferroptosis in our findings. The therapeutic effect of synergistic treatment with SRF@Hb-Ce6 in vitro and in vivo was proven significant, revealing the promising prospects of combined PDT and ferroptosis therapy with the 2-in-1 nanoplatform.

Quercetin, a typical flavonoid, possesses diverse biochemical and physiological actions, including antiplatelet, estrogenic, and anti-inflammatory properties. This review mainly centers on recent ten years findings with respect to intervening diabetes and its complications with the well-known flavonoid quercetin. After a short introduction of quercetin, major in vitro and in vivo findings are summarized showing that quercetin is a promising molecule for the treatment of these diseases. Finally, we contemplate future development and application prospects of quercetin. Despite the wealth of in animal research results suggesting the anti-diabetic and its complications potential of quercetin, its efficacy in diabetic human subjects is yet to be explored. The problem may become an important direction in the future research.

Biocatalytic reactions in living cells involve complex transformations in the spatially confined microenvironments. Inspired by biological transformation processes, we demonstrate effective biocatalytic cascade driven photodynamic therapy in tumor-bearing mice by the integration of an artificial enzyme (ultrasmall Au nanoparticles) with upconversion nanoparticles (NaYF4@NaYb0.92F4:Er0.08@NaYF4)zirconium/iron porphyrin metal–organic framework core–shell nanoparticles (UMOF NPs) which act as biocatalysts and nanoreactors. The construction of core–shell UMOF NPs are realized by using a unique “solvent-assisted self-assembly” method. The integration of ultrasmall AuNPs on the UMOFs matrix leads to glucose depletion, providing Au-mediated cancer therapy via glucose oxidase like catalytic activity. Meanwhile, the UMOF matrix acts as a near-infrared (NIR) light photon-activated singlet oxygen generator through a continuous supply of oxygen via hydrogen peroxide decomposition upon irradiation. Such kinds of biocatalysts offer exciting opportunities for biomedical, catalytical ,and energy applications.

Topical administration of anticancer drugs provides a potential chemotherapeutic modality with high patient compliance for cutaneous melanoma. However, the drug delivery efficiency is highly limited by physiological barriers from the skin to the tumor, which cannot acquire desired therapeutic efficacy. Herein, we propose a paintable oligopeptide hydrogel containing paclitaxel (PTX)-encapsulated cell-penetrating-peptide (CPP)-modified transfersomes (PTX-CTs) to enhance transdermal PTX delivery for topical melanoma treatment. After being plastered on the skin above the melanoma tumor, the PTX-CTs-embedded hydrogel (PTX-CTs/Gel) as a patch provided prolonged retention capacity of the PTX-CTs on the skin. The PTX-CTs with superior deformability could efficiently squeeze through the channels in the stratum coreum, and the surfactant components improved the fluidity of the lipid molecules in the stratum corneum to further enhance the skin permeation. Moreover, the CPP modification rendered the PTX-CT-enhanced penetration in the skin and tumor stroma as well as efficient transportation in the tumor cells. The PTX-CTs were shown to effectively slow the tumor growth in combination with the systemic chemotherapy using Taxol, the commercial PTX formulation on the xenograft B10F16 melanoma mouse model.

In humans, oxidative stress and antioxidant defenses are the sum of a complicated network of enzymatic and non-enzymatic processes. Depending on the stage and severity of diseases, a patient's antioxidant armamentarium may increase as an appropriate response to an oxidant challenge, whereas others may decrease as an indication of unbalanced consumption. In some cases, the formation of reactive oxygen species is a requisite and healthy event. In fact, free radicals can affect intracellular signal transduction and gene regulation, resulting in cytokine production essential to the inflammatory process. In many other cases, especially liver diseases, excessive oxidative stress undoubtedly contributes to the progression and pathological findings of disease and serves as a prognostic indicator. Reactive oxygen species are highly reactive molecules that are naturally generated in small amounts through metabolism and could damage cellular molecules such as lipids, proteins or DNA. Oxidative stress plays a major role in many liver diseases. In this review, we summarize the biological character of free radicals and some antioxidants, and the related methods of analysis. Then, we discusses the association of oxidative stress to many types of liver diseases.

Mitophagy is a type of selective macroautophagy/autophagy that degrades dysfunctional or excessive mitochondria. Regulation of this process is critical for maintaining cellular homeostasis and has been closely implicated in acquired drug resistance. However, the regulatory mechanisms and influences of mitophagy in cancer are still unclear. Here, we reported that inhibition of CDK9 blocked PINK1-PRKN-mediated mitophagy in HCC (hepatocellular carcinoma) by interrupting mitophagy initiation. We demonstrated that CDK9 inhibitors promoted dephosphorylation of SIRT1 and promoted FOXO3 protein degradation, which was regulated by its acetylation, leading to the transcriptional repression of FOXO3-driven BNIP3 and impairing the BNIP3-mediated stability of the PINK1 protein. Lysosomal degradation inhibitors could not rescue mitophagy flux blocked by CDK9 inhibitors. Thus, CDK9 inhibitors inactivated the SIRT1-FOXO3-BNIP3 axis and PINK1-PRKN pathway to subsequently block mitophagy initiation. Moreover, CDK9 inhibitors facilitated mitochondrial dysfunction. The dual effects of CDK9 inhibitors resulted in the destruction of mitochondrial homeostasis and cell death in HCC. Importantly, a novel CDK9 inhibitor, oroxylin A (OA), from Scutellaria baicalensis was investigated, and it showed strong therapeutic potential against HCC and a striking capacity to overcome drug resistance by downregulating PINK1-PRKN-mediated mitophagy. Additionally, because of the moderate and controlled inhibition of CDK9, OA not led to extreme repression of general transcription and appeared to overcome the inconsistent anti-HCC efficacy and high normal tissue toxicity that was associated with existing CDK9 inhibitors. All of the findings reveal that mitophagy disruption is a promising strategy for HCC treatment and OA is a potential candidate for the development of mitophagy inhibitors.Abbreviations: BNIP3: BCL2 interacting protein 3; CCCP: carbonyl cyanide p-trichloromethoxy-phenylhydrazone; CDK9: cyclin dependent kinase 9; CHX: cycloheximide; CQ, chloroquine; DFP: deferiprone; DOX: doxorubicin; EBSS: Earle’s balanced salt solution; E64d: aloxistatin; FOXO3: forkhead box O3; HCC: hepatocellular carcinoma; HepG2/ADR: adriamycin-resistant HepG2 cells; MMP: mitochondrial membrane potential; mito-Keima: mitochondria-targeted and pH-sensitive fluorescent protein; MitoSOX: mitochondrial reactive oxygen species; OA: oroxylin A; PB: phosphate buffer; PDX: patient-derived tumor xenograft; PINK1: PTEN induced kinase 1; POLR2A: RNA polymerase II subunit A; p-POLR2A-S2: Ser2 phosphorylation of RNA polymerase II subunit A; PRKN: parkin RBR E3 ubiquitin protein ligase; SIRT1: sirtuin 1.

Nanozyme is a collection of nanomaterials with enzyme-like activity but higher environmental tolerance and long-term stability than their natural counterparts. Improving the catalytic activity and expanding the category of nanozymes are prerequisites to complement or even supersede enzymes. However, the development of hydrolytic nanozymes is still challenged by diverse hydrolytic substrates and following complicated mechanisms. Here, two strategies are informed by data to screen and predict catalytic active sites of MOF (metal-organic framework) based hydrolytic nanozymes: (1) to increase the intrinsic activity by finely tuned Lewis acidity of the metal clusters; (2) to improve the density of active sites by shortening the length of ligands. Finally, as-obtained Ce-FMA-MOF-based hydrolytic nanozyme is capable of cleaving phosphate bonds, amide bonds, glycosidic bonds, and even their mixture, biofilms. This work provides a rational methodology to design hydrolytic nanozyme, enriches the diversity of nanozymes, and potentially sheds light on future evolution of enzyme engineering.

Integrins are transmembrane receptors that have been implicated in the biology of various human physiological and pathological processes. These molecules facilitate cell-extracellular matrix and cell-cell interactions, and they have been implicated in fibrosis, inflammation, thrombosis, and tumor metastasis. The role of integrins in tumor progression makes them promising targets for cancer treatment, and certain integrin antagonists, such as antibodies and synthetic peptides, have been effectively utilized in the clinic for cancer therapy. Here, we discuss the evidence and knowledge on the contribution of integrins to cancer biology. Furthermore, we summarize the clinical attempts targeting this family in anti-cancer therapy development.

A cellular protease (furin)-mediated graphene-based nanosystem is developed for co-delivery of a membrane-associated cytokine (tumor-necrosis-factor-related apoptosis-inducing ligand, TRAIL) and an intracellular-acting small-molecule drug (Doxorubicin, DOX). TRAIL and DOX can be sequentially released toward the plasma membrane and nucleus, respectively.

Abstract Chemotherapy suffers numbers of limitations including poor drug solubility, nonspecific biodistribution, and inevitable adverse effects on normal tissues. Tumor‐targeted delivery and intratumoral stimuli‐responsive release of drugs by nanomedicines are considered to be highly promising in solving these problems. Compared with traditional chemotherapeutic drugs, high concentration of nitric oxide (NO) exhibits unique anticancer effects. The development of tumor‐targeting and intratumoral microenvironment‐responsive NO‐releasing nanomedicines is highly desired. Here a novel kind of organic–inorganic composite nanomedicine (QM‐NPQ@PDHNs) is presented by encapsulating a glutathione S ‐transferases π (GSTπ)‐responsive drug O 2 ‐(2,4‐dinitro‐5‐{[2‐(β‐ d ‐galactopyranosyl olean‐12‐en‐28‐oate‐3‐yl)‐oxy‐2‐oxoethyl] piperazine‐1‐yl} phenyl) 1‐(methylethanolamino)diazen‐1‐ium‐1,2‐dilate (NPQ) as NO donor and an aggregation‐induced‐emission (AIE) red fluorogen QM‐2 into the cores of the hybrid nanomicelles (PEGylated disulfide‐doped hybrid nanocarriers (PDHNs)) with glutathione (GSH)‐responsive shells. The QM‐NPQ@PDHN nanomedicine is able to respond to the intratumoral over‐expressed GSH and GSTπ, resulting in the responsive biodegradation of the protective organosilica shell and NPQ release, and subsequent NO release within the tumor, respectively, and thus normal organs remain unaffected. This work demonstrates a paradigm of dual intratumoral redox/enzyme‐responsive NO‐release nanomedicine for tumor‐specific and high‐efficacy cancer therapy.

Herein we disclose a scalable organocatalytic direct arylation approach for the regio- and atroposelective synthesis of non-C2-symmetric 2,2'-dihydroxy-1,1'-binaphthalenes (BINOLs). In the presence of catalytic amounts of axially chiral phosphoric acids, phenols and naphthols are coupled with iminoquinones via a cascade process that involves sequential aminal formation, sigmatropic rearrangement, and rearomatization to afford enantiomerically enriched BINOL derivatives in good to excellent yields. Our studies suggest that the (local) symmetry of the initially formed aminal intermediate has a dramatic impact on the level of enantioinduction in the final product. Aminals with a plane of symmetry give rise to BINOL derivatives with significantly lower enantiomeric excess than unsymmetrical ones featuring a stereogenic center. Presumably asymmetric induction in the sigmatropic rearrangement step is significantly more challenging than during aminal formation. Sigmatropic rearrangement of the enantiomerically enriched aminal and subsequent rearomatization transfers the central chirality into axial chirality with high fidelity.