Structural characterization of Russula griseocarnosa polysaccharide and its improvement on hematopoietic function.

The hematopoietic function of a polysaccharide derived from Russula griseocarnosa was demonstrated in K562 cells, and subsequently purified through chromatography to obtain RGP1. RGP1 is a galactan composed of 1,6-α-D-Galp as the main chain, with partial substitutions. A -CH3 substitution was detected at O-3 of 1,6-α-D-Galp. The possible branches at O-2 of 1,6-α-D-Galp was α-L-Fucp. In mice with cyclophosphamide (CTX)-induced hematopoietic dysfunction, RGP1 alleviated bone marrow damage and multinucleated giant cell infiltration of the spleen, increased the number of long-term hematopoietic stem cells, and regulated the levels of myeloid cells in the peripheral blood. Furthermore, RGP1 promoted the differentiation of activated T cells and CD4+ T cells without affecting natural killer cells and B cells. Proteomic analysis, detection of cytokines, and western blotting revealed that RGP1 could alleviate hematopoietic dysfunction by promoting the activation of CD4+ T cells and the Janus kinase/ signal transducer and activator of transcription 3 pathway. The present study provides experimental evidence to support the application of RGP1 in CTX-induced hematopoietic dysfunction.

Huoxiang Zhengqi alleviates azoxymethane/dextran sulfate sodium-induced colitis-associated cancer by regulating Nrf2/NF-κB/NLRP3 signaling.

Colitis-associated cancer (CAC) is a subtype of inflammatory bowel disease (IBD)-associated colorectal cancer. Huoxiang Zhengqi (HXZQ) is a classical Chinese herbal medicine and has been used to treat intestinal disorders, however, anti-CAC effects and underlying mechanisms of HXZQ have not been reported. An azoxymethane/dextran sulfate sodium-induced CAC mice model was used to investigate the anti-CAC effect of HXZQ. HXZQ significantly reduced colonic inflammation, suppressed the size and number of tumors, and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-1α, IL-1ß, IL-6, IL-17A, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and tumor necrosis factor-α) and oxidative stress markers (reactive oxygen species and malondialdehyde), and increased the levels of anti-inflammatory cytokines (IL-10 and IL-27) in CAC mice. Intestinal microbiota and serum metabolomics analyses indicated that HXZQ altered the gut microbial composition and the abundance of 29 serum metabolites in CAC mice. Additionally, HXZQ activated the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) signaling pathway and increased the levels of antioxidants such as catalase (CAT), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductases-1 (NQO-1), and superoxide dismutase-1 (SOD-1). HXZQ inhibited the activation of the nuclear factor kappa-B (NF-κB) signaling pathway and decreased the expression of NLR family pyrin domain containing 3 (NLRP3) by inhibiting the phosphorylation of inhibitor of nuclear factor kappa-B (IκB), inhibitor of nuclear factor kappa-B kinase (IKK), and NF-κB. In conclusion, HXZQ alleviated CAC in mice by modulating the intestinal microbiota and metabolism, activating Nrf2-mediated antioxidant response, and inhibiting NF-κB-mediated NLRP3 inflammasome activation against inflammation. The present data provide a reference for the use of HXZQ as a therapeutic or combination agent for clinical CAC treatment.

Anti-Gouty Arthritis and Anti-Hyperuricemia Properties of Sanghuangporus vaninii and Inonotus hispidus in Rodent Models.

Acute inflammation and hyperuricemia are associated with gouty arthritis. As an edible and therapeutic mushroom, Sanghuangporus vaninii (SV) has an inhibitory effect on tumorigenesis, and Inonotus hispidus (IH) exhibits anti-tumor, anti-inflammatory, and antioxidant properties. In this study, uric acid (UA) and xanthine oxidase (XOD) levels in hyperuricemic mice were examined to determine the regulatory effects of SV and IH. SV and IH reversed the pathogenic state of elevated UA levels in the serum and reduced levels of XOD in the serum and liver of mice with hyperuricemia. SV and IH affected the inflammatory response in rats with acute gouty arthritis. Compared to vehicle-treated rats, monosodium urate crystals (MSU) increased the swelling ratio of the right ankle joints. SV and IH administration significantly reduced swelling and inflammatory cell infiltration. SV reduced the levels of interleukin-8 (IL-8) and chemokine ligand-2 (CCL-2), whereas IH reduced the levels of matrix metalloproteinase-9 (MMP-9), CCL-2, and tumor necrosis factor-α (TNF-α), which were confirmed in articular soft tissues by immunohistochemistry. In summary, our data provide experimental evidence for the applicability of SV and IH in gouty arthritis and hyperuricemia treatment.

Carnosic Acid Suppresses the Development of Oral Squamous Cell Carcinoma via Mitochondrial-Mediated Apoptosis.

Oral squamous cell carcinoma (OSCC) predominantly consists of squamous cells and is the tumor with the highest incidence of the head and neck. Carnosic acid (CA), a natural monomer drug obtained from rosemary and salvia, shows various pharmacological effects, including of tumor development. This study aimed to assess for an effect of CA on the development of OSCC and the underlying mechanisms. In CAL27 and SCC9 cells, CA inhibited cell proliferation and migration, increased intracellular levels of reactive oxygen species (ROS) and Ca2+, decreased the mitochondrial membrane potential (MMP), and promoted apoptosis. In CAL27- and SCC9-xenotransplanted BALB/c nude mice, CA inhibited the tumor growth without affecting the body weight and tissue morphology. CA upregulated Bax, Bad, cleaved Caspase-3 and -9 levels, and the cleaved PARP1/PARP1 ratio but downregulated Bcl-2 in CA-treated OSCC cells and OSCC cells-xenotransplanted BALB/c nude mice. These results indicate that CA suppresses OSCC at least via the mitochondrial apoptotic pathway and offers this natural compound as a potential therapeutic against OSCC.

Transferrin-conjugated liposomes loaded with carnosic acid inhibit liver cancer growth by inducing mitochondria-mediated apoptosis.

Our previous studies have proven that carnosic acid (CA) induces apoptosis of liver cancer cells. However, the poor chemical properties of CA limit its in vivo anti-cancer effects. In this study, CA was loaded into liposomes (LP-CA), and LP-CA was further conjugated with transferrin (Tf-LP-CA) to overcome the shortcomings of poor solubility and absorption at the lesion site. In HepG2 and SMMC-7721 cells, compared with CA and LP-CA, more Tf-LP-CA was absorbed by liver cancer cells, which induced higher levels of apoptosis and reduced the mitochondrial membrane potential more effectively. In HepG2- and SMMC-7721-xenotransplanted mice, Tf-LP-CA inhibited tumor growth with no cytotoxicity to the liver, spleen, or kidney. Furthermore, compared with CA and LP-CA, Tf-LP-CA targeted the tumor site more effectively, enhanced the expressions of cleaved poly(ADP-ribose) polymerase, and Caspase-3 and -9, and regulated the expression levels of B-cell lymphoma 2 (Bcl2) family members in the tumor tissues. Tf-LP-CA was taken up by tumor cells and targeted at tumor tissues, ensuring the precise delivery of CA, which further promoted mitochondria-mediated intrinsic apoptosis in the liver cancer cells. These results provide evidence for the clinical application of the Tf-LP-based CA drug delivery system for liver cancer.

Brain-Computer Interface with Inhibitory Neurons Reveals Subtype-Specific Strategies.

Brain-computer interfaces have seen an increase in popularity due to their potential for direct neuroprosthetic applications for amputees and disabled individuals. Supporting this promise, animals-including humans-can learn even arbitrary mapping between the activity of cortical neurons and movement of prosthetic devices [1-4]. However, the performance of neuroprosthetic device control has been nowhere near that of limb control in healthy individuals, presenting a dire need to improve the performance. One potential limitation is the fact that previous work has not distinguished diverse cell types in the neocortex, even though different cell types possess distinct functions in cortical computations [5-7] and likely distinct capacities to control brain-computer interfaces. Here, we made a first step in addressing this issue by tracking the plastic changes of three major types of cortical inhibitory neurons (INs) during a neuron-pair operant conditioning task using two-photon imaging of IN subtypes expressing GCaMP6f. Mice were rewarded when the activity of the positive target neuron (N+) exceeded that of the negative target neuron (N-) beyond a set threshold. Mice improved performance with all subtypes, but the strategies were subtype specific. When parvalbumin (PV)-expressing INs were targeted, the activity of N- decreased. However, targeting of somatostatin (SOM)- and vasoactive intestinal peptide (VIP)-expressing INs led to an increase of the N+ activity. These results demonstrate that INs can be individually modulated in a subtype-specific manner and highlight the versatility of neural circuits in adapting to new demands by using cell-type-specific strategies.