Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling.

Cyclic adenosine diphosphate (ADP)-ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD+) hydrolysis. We show that v-cADPR (2'cADPR) and v2-cADPR (3'cADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2'cADPR-producing TIR domains reveal conformational changes that lead to an active assembly that resembles those of Toll-like receptor adaptor TIR domains. Mutagenesis reveals a conserved tryptophan that is essential for cyclization. We show that 3'cADPR is an activator of ThsA effector proteins from the bacterial antiphage defense system termed Thoeris and a suppressor of plant immunity when produced by the effector HopAM1. Collectively, our results reveal the molecular basis of cADPR isomer production and establish 3'cADPR in bacteria as an antiviral and plant immunity-suppressing signaling molecule.

Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.

The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD+) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD+ mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1.

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration.

Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+ and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise.

Significance of LL-37 on Immunomodulation and Disease Outcome.

LL-37, also called cathelicidin, is an important part of the human immune system, which can resist various pathogens. A plethora of experiments have demonstrated that it has the multifunctional effects of immune regulation, in addition to antimicrobial activity. Recently, there have been increasing interest in its immune function. It was found that LL-37 can have two distinct functions in different tissues and different microenvironments. Thus, it is necessary to investigate LL-37 immune functions from the two sides of the same coin. On the one side, LL-37 promotes inflammation and immune response and exerts its anti-infective and antitumor effects; on the other side, it has the ability to inhibit inflammation and promote carcinogenesis. This review presents a brief summary of its expression, structure, and immunomodulatory effects as well as brief discussions on the role of this small peptide as a key factor in the development and treatment of various inflammation-related diseases and cancers.

Therapeutic Effects of Ten Commonly Used Chinese Herbs and Their Bioactive Compounds on Cancers.

Effective cancer therapy is one of the biggest global challenges. Conventional cancer therapies have been at the forefront of combating cancers, but more evidence showed considerable side effects, limiting their use. There are various new therapies in development, but combined approaches for treating cancer are much expected. Natural herbs had been traditionally in use for cancer therapy in most parts of the world. In this review, we have examined ten commonly used Chinese herbs that have, for centuries, shown effectiveness in treating cancers. They demonstrated the abilities to promote the apoptosis of cancer cells, inhibit their metastasis, activate the patient's anticancer immunity, and synergistically increase the efficacy of conventional chemotherapy and radiation therapy when used in combination. Clinical experiences had proved that these herbs and their bioactive compounds were effective against a plethora of cancers through a variety of mechanisms, effectively improving patients' quality of life without significant side effects. These advantages indicate that there are huge potentials in the development of Chinese herbs into cancer medicine as part of a promising, holistic cancer treatment modality.

Carbohydrate-based nanocarriers and their application to target macrophages and deliver antimicrobial agents.

Many deadly infections are produced by microorganisms capable of sustained survival in macrophages. This reduces exposure to chemadrotherapy, prevents immune detection, and is akin to criminals hiding in police stations. Therefore, the use of glyco-nanoparticles (GNPs) as carriers of therapeutic agents is a burgeoning field. Such an approach can enhance the penetration of drugs into macrophages with specific carbohydrate targeting molecules on the nanocarrier to interact with macrophage lectins. Carbohydrates are natural biological molecules and the key constituents in a large variety of biological events such as cellular communication, infection, inflammation, enzyme trafficking, cellular migration, cancer metastasis and immune functions. The prominent characteristics of carbohydrates including biodegradability, biocompatibility, hydrophilicity and the highly specific interaction of targeting cell-surface receptors support their potential application to drug delivery systems (DDS). This review presents the 21st century development of carbohydrate-based nanocarriers for drug targeting of therapeutic agents for diseases localized in macrophages. The significance of natural carbohydrate-derived nanoparticles (GNPs) as anti-microbial drug carriers is highlighted in several areas of treatment including tuberculosis, salmonellosis, leishmaniasis, candidiasis, and HIV/AIDS.

A Simple Glycolipid Mimic of the Phosphatidylinositol Mannoside Core from Mycobacterium tuberculosis Inhibits Macrophage Cytokine Production.

Glycolipids from Mycobacterium tuberculosis have a profound impact on the innate immune response of the host. Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor that has been shown to bind trehalose dimycolate (TDM) from the mycobacterium and instigate intracellular signalling in the immune cell. There are structural similarities between the structures of TDM and phosphatidyl inositol mannoside (PIM). We thus hypothesized that these latter structures might also modulate an immune response in a similar manner. To test this, we synthesized a series of new mannose derivatives modified with fatty esters at the 6-position and assessed the release of inflammatory cytokines in human U937 macrophages under the induction of lipopolysaccharides (LPS) after glycolipid treatment. The results showed that the amount of two major cytokines-tumour necrosis factor (TNF)-α and interleukin (IL)-6-released from LPS-stimulated U937 cells decreased significantly when compared to a control upon treatment with the prepared glycolipids, thus indicating a reduction in cytokine production by the macrophages.

Temperature and pH-tunable fluorescence nanoplatform with graphene oxide and BODIPY-conjugated polymer for cell imaging and therapy.

This paper demonstrates the development of pH and thermo-responsive fluorescent nanoparticles, which are composed of graphene oxide (GO) with BODIPY conjugated PEG, to trigger the detection of cancer cells through imaging based on intracellular accommodation. Responsiveness to pH is studied using atomic force microscopy and apparent thickness differences are seen with changes in pH. Confocal images of the nanoparticles (NPs) exhibit remarkably bright fluorescence at lysosomal pH, while no fluorescence is observed under a physiological environment, making the NPs a novel fluorescent probe. The NPs are able to accumulate the hydrophobic anticancer drug DOX due to the hydrophobic surface of GO and show excellent drug release behavior. Therefore, the NPs developed are novel candidates for a fluorescent probe to identify cancer cells and a drug carrier for cancer therapy.

Recyclable and stable silver deposited magnetic nanoparticles with poly (vinyl pyrrolidone)-catechol coated iron oxide for antimicrobial activity.

This paper introduces a facile method to make highly stable and recyclable antimicrobial magnetic nanoparticles (NPs). Initially, magnetic iron oxide nanoparticles (IONPs) were coated with poly (vinyl pyrrolidone) conjugated catechol (PVP-CCDP). Afterward, silver nanoparticles (Ag(0)) were deposited onto PVP-CCDP coated IONPs using remain catechol. The prepared nanoparticles showed long term (~4 weeks) colloidal stability and redispersibility, respectively, against external magnetic field and over a broad range of pH (4-12). The NPs were characterized by UV-vis, SEM, XPS, and XRD measurements. TEM and DLS analyses showed that the mean particle size of PVP-CCDP coated IONPs/Ag(0) were about 72 nm. The recyclable magnetic NPs possessed a high antibacterial effect against the model microbes Staphylococcus aureus and Escherichia coli and could be separated easily using magnet following antibacterial test for repeated uses and maintained 100% antibacterial efficiency during three cycles. In MTT assay, the magnetic nanoparticles possessed no measureable cytotoxicity to live cells.

Evaluation of antinociceptive and antihyperglycemic activities in methanol extracts of whole plants of Alternanthera philoxeroides (Mart.) Griseb. (Amaranthaceae) in mice.

The present study evaluated the antinociceptive and antihyperglycemic effects of crude methanol extract of whole plants of Alternanthera philoxeroides (Mart.) Griseb. (Amaranthaceae) in Swiss albino mice. Antin(o)Ciceptive activity was evaluated by attenuation of the number of constrictions in acetic acid-induced gastric pain, while antihyperglycemic activity was evaluated through oral glucose tolerance tests in glucose-loaded mice. Dose-dependent and significant inhibitions in the number of constrictions were seen in mice administered with extract at doses of 50, 100, 200 and 400 mg per kg body weight. At these concentrations, the numbers of constrictions were reduced, respectively, by 31.0, 32.7, 37.9 and 44.8%. In comparison, a standard antinociceptive drug, aspirin reduced the number of constrictions by 37.9 and 67.2%, when administered at doses, respectively, of 200 and 400 mg per kg body weight. The extract also exhibited dose-dependent and significant antihyperglycemic activity when administered to mice at the afore-mentioned four doses. Serum glucose concentrations were reduced, respectively, by 36.3, 58.6, 65.0 and 65.6% at the four doses administered. The results compare favorably with a standard antihyperglycemic drug, glibenclamide, which when administered at a dose of 10 mg per kg body weight reduced serum glucose level by 42.7%. Taken together, the results obtained indicate that the extract merit further scientific studies towards discovery of components, which may prove beneficial in ameliorating pain, as well as high sugar levels of diabetic patients.