From immune checkpoints to therapies: understanding immune checkpoint regulation and the influence of natural products and traditional medicine on immune checkpoint and immunotherapy in lung cancer.

Lung cancer is a disease of global concern, and immunotherapy has brought lung cancer therapy to a new era. Besides promising effects in the clinical use of immune checkpoint inhibitors, immune-related adverse events (irAEs) and low response rates are problems unsolved. Natural products and traditional medicine with an immune-modulating nature have the property to influence immune checkpoint expression and can improve immunotherapy's effect with relatively low toxicity.

Efficacy of Yisui granule on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/β-catenin signaling pathway.

Objective: To unmask the underlying mechanisms of Yisui granule (, YSG) for the treatment of Myelodysplastic syndromes (MDS).

Methods: Our study used an SKM-1 mouse xenograft model of MDS to explore the anti-tumor potential of YSG and its safety, assess its effect on overall survival (OS), and evaluate whether its mechanism is associated with the demethylation of the secreted frizzled related protein 5 (sFRP5) gene and suppressing Wnt/β-catenin pathway. Bisulfite amplicon sequencing was applied to detect the level of methylation of the sFRP5 gene; western blotting, immunofluorescence staining, and real-time Polymerase Chain Reaction were performed to detect DNA methyltransferase 1 (DNMT1), sFRP5, and other Wnt/β-catenin pathway-related mRNA and protein expression.

Promotion of quality standard of Chinese herbal medicine by the integrated and efficacy-oriented quality marker of Effect-constituent Index.

Background: Multiple constituents have been applied currently as markers to control the quality of Chinese herbal medicine (CHM). However, those constituents are isolated from each other, failed to present their contribution differences to the bioeffect of CHM. Besides, a CHM for different clinic uses is often controlled by the same quality marker (Q-marker), which cannot correlate its efficacies differentially.

Tylophorine Analogs Allosterically Regulates Heat Shock Cognate Protein 70 And Inhibits Hepatitis C Virus Replication.

Tylophorine analogs have been shown to exhibit diverse activities against cancer, inflammation, arthritis, and lupus in vivo. In this study, we demonstrated that two tylophorine analogs, DCB-3503 and rac-cryptopleurine, exhibit potent inhibitory activity against hepatitis C virus (HCV) replication in genotype 1b Con 1 isolate. The inhibition of HCV replication is at least partially mediated through cellular heat shock cognate protein 70 (Hsc70).

Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug.

Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.

Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors.

Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.

Correction: Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library.

Correction for 'Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library' by Dik-Lung Ma et al., Chem. Commun.

Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library.

Amentoflavone has been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library. In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo. Molecular modeling and kinetic experiments suggested that the analogues may function as Type II inhibitors of JAK2.

Cryptopleurine analogs with modification of e ring exhibit different mechanism to rac-cryptopleurine and tylophorine.

Tylophorine analogs exhibit a broad range of pharmacological activities, including anti-cancer, anti-inflammatory, anti-autoimmune, and anti-virus effects. Structure-activity relationship study of different structure tylophorine analogs can provide further understanding of their biological activity. Modifications on the E ring of the quinolizidine moiety of cryptopleurine analogs changed the potency and the selective inhibitory effect on NF-κB, AP-1, and CRE signaling pathways.

Antitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino-4'-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents.

Two conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino-4'-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT-derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation.

Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI.

The synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal served as a glycosyl donor. Electrophilic glycosidation between and the silylated nucleobases (-acetylcytosine, -benzoyladenine and -acetyl--diphenylcarbamoylguanine) was carried out in the presence of -iodosuccinimide (NIS) leading to the exclusive formation of the desired β-anomers and . Anti-HIV studies demonstrated that these 4'-thio nucleosides were less cytotoxic to T-lymphocyte (i.

Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique.

Endogenous ribonucleotides and deoxyribonucleotides play a critical role in cell function, and determination of their levels is of fundamental importance in understanding key cellular processes involved in energy metabolism and molecular and biochemical signaling pathways. In this study, we determined the respective ribonucleotide and deoxyribonucleotide pool sizes in different human cell lines using a simple sample preparation method and LC/MS/MS. This assay was used to determine alterations in deoxyribonucleotide pools in human pancreatic PANC1 cells in response to hypoxia and to treatment with either hydroxyurea or aphidicolin.

The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity.

PHY906, a four-herb Chinese medicine formula first described 1800 years ago, decreases gastrointestinal toxicity induced by the chemotherapeutic drug CPT-11 (irinotecan), as shown in a phase I/II clinical study. Similarly, in a murine colon 38 allograft model, PHY906 increased the antitumor activity of CPT-11 while decreasing animal weight loss caused by CPT-11. Here, we have further examined the effect of PHY906 on the intestinal toxicity caused by CPT-11 in mice.

Discovery of a synthetic dual inhibitor of HIV and HCV infection based on a tetrabutoxy-calix[4]arene scaffold.

A potential anti-HIV and HCV drug candidate is highly desirable as coinfection has become a worldwide public health challenge. A potent compound based on a tetrabutoxy-calix[4]arene scaffold that possesses dual inhibition for both HIV and HCV is described. Structural activity relationship studies demonstrate the effects of lower-rim alkylation in maintaining cone conformation and upper-rim interacting head groups on the calix[4]arene play key roles for its potent dual antiviral activities.

A novel class of meso-tetrakis-porphyrin derivatives exhibits potent activities against hepatitis C virus genotype 1b replicons in vitro.

Recent years have seen the rapid advancement of new therapeutic agents against hepatitis C virus (HCV) in response to the need for treatment that is unmet by interferon (IFN)-based therapies. Most antiviral drugs discovered to date are small molecules that modulate viral enzyme activities. In the search for highly selective protein-binding molecules capable of disrupting the viral life cycle, we have identified a class of anionic tetraphenylporphyrins as potent and specific inhibitors of the HCV replicons.

Butyrate mediates nucleotide-binding and oligomerisation domain (NOD) 2-dependent mucosal immune responses against peptidoglycan.

The interaction between digestive tract microbiological flora and food has an important influence on human health. Butyrate is produced during the fermentation of dietary fibres by intestinal bacteria and plays an important role in the regulation of mucosal immunity. In this report, we studied the impact of butyrate on the defence mechanism against the bacterial membrane component peptidoglycan (PGN).

Synthesis and anti-HIV activity of 4'-C-ethynyl-2'-deoxy-4'-thio-nucleosides.

Synthesis of 4'-C-ethynyl-2'-deoxy-4'-thionucleosides was carried out based on electrophilic glycosidation using 4-C-ethynyl-4-thiofuranoid glycal. The glycal 15 was prepared as follows: oxidative cleavage of 6 with Pb(OAc)(4) forming the aldehyde 7, aldol reaction of 7 and subsequent silylation to furnish 8, conversion of the formyl group of 8 into an ethynyl group, and finally beta-elimination of the resulting 14 with t-BuLi. The glycosyl donor 16 was prepared by silyl-protection of 15.

Impacts of baicalein analogs with modification of the 6th position of A ring on the activity toward NF-kappaB-, AP-1-, or CREB-mediated transcription.

The water extract of Scutellariae baicalensis Georgi (S. baicalensis) has potential anti-tumor and anti-inflammatory activities. A major flavonoid isolated from S.

Synthesis and anti-HIV activity of 4'-substituted 4'-thiothymidines: a new entry based on nucleophilic substitution of the 4'-acetoxy group.

Diacetoxylation of 1-(2,5-dideoxy-beta-L-glycero-pent-4-eno-4-thiofuranosyl)thymine (13) with Pb(OAc) 4 allowed introduction of an acetoxy leaving group to the 4'-position. Nucleophilic substitution of the resulting 4'-acetoxy derivative (14) with silicon reagents enabled us to prepare the 4'-phenylthio (17a), 4'-azido (18a), 4'-methoxy (20a), and 4'-allyl (21a) analogues of 4'-thiothymidine. 4'-Cyano ( 25a) and 4'-ethynyl (31) nucleosides were also synthesized from 3',5'-bis-O-TBDMS derivative (24).

Structural analogs of tylophora alkaloids may not be functional analogs.

Phenanthroindolizidine-based tylophora alkaloids have been reported to have potential antitumor, anti-immuno and, anti-inflammatory activity. The structure-activity relationships of a series of tylophora alkaloids were studied to guide future drug design. Our results indicate that although these compounds are structural analogs, their potency of cytotoxicity, selectivity against NF-kappaB signaling pathway, and their inhibitory effects against protein and nucleic acid synthesis are different.

Structure-activity studies of phenanthroindolizidine alkaloids as potential antitumor agents.

Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofolliculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the structure-activity relationships (SAR) of this class of compounds. We demonstrated that DCB-3503 and tylophorinidine (PA-7) were among the most active compounds against tumor growth both in vitro and in vivo.

9-{[3-fluoro-2-(hydroxymethyl)cyclopropylidene]methyl}adenines and -guanines. Synthesis and antiviral activity of all stereoisomers1.

All stereoisomers of adenine and guanine methylene-3-fluoromethylenecyclopropane analogues of nucleosides 9a, 9b, 10a, 10b, 11a, 11b, 12a, and 12b were synthesized and their antiviral activities were evaluated. A highly convergent approach permitted the synthesis of all these analogues using a single intermediate 15. Reaction of aldehyde 13 with fluorotrichloromethane and tri-n-butylphosphine gave fluoroalkenes 14a+14b (83:17).

Phosphoralaninate pronucleotides of pyrimidine methylenecyclopropane analogues of nucleosides: synthesis and antiviral activity.

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N4-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b.

Synthesis, antiviral, and antitumor activity of 2-substituted purine methylenecyclopropane analogues of nucleosides.

The Z- and E-2-fluoro- and 2-chloropurine methylenecyclopropanes 9a,b and 10a,b as well as enantiomeric Z-isoguanine methylenecyclopropanes 11a,b and their phenyl phosphoralaninate pronucleotides 11c,d were synthesized and their antiviral activity against several viruses was evaluated. Fluoro analogues 9a and 10a were active against human cytomegalovirus but they were cytotoxic at approximately the same concentrations. Chloro derivatives 9b and 10b were non-cytotoxic and effective against Epstein-Barr virus in Daudi cells.

Inhibition of hepatitis B virus gene expression and replication by helioxanthin and its derivative.

Chronic hepatitis B virus (HBV) infection continues to be an important worldwide cause of morbidity and mortality. All the currently approved therapeutic drugs have their limitations: interferon-alpha (IFN-alpha) has limited efficacy and a high incidence of adverse effects; nucleoside analogues are very efficient HBV DNA inhibitors, but resistance occurs eventually. Therefore, it is important to develop new non-nucleoside/nucleotide agents with different modes of action that can be used for antiviral combination therapy.