Antiaging Effects of Human Fecal Transplants with Different Combinations of Bifidobacterium bifidum LTBB21J1 and Lactobacillus casei LTL1361 in d-Galactose-Induced Mice.

The feces of healthy middle-aged and old people were first transplanted into d-galactose-induced aging mice to construct humanized aging mice with gut microbiota (FMTC) to confirm the antiaging effect of probiotics produced from centenarians. The mouse model was then treated with centenarian-derived Bifidobacterium bifidum (FMTL), Lactobacillus casei (FMTB), and their mixtures (FMTM), and young mice were used as the control. Compared with the FMTC group, the results demonstrated that the probiotics and their combinations alleviated neuronal damage, increased antioxidant capacity, decreased inflammation, and enhanced cognitive and memory functions in aging mice. In the gut microbiota, the relative abundance of Lactobacillus, Ligilactobacillus, and Akkermansia increased and that of Desulfovibrio and Colidextribacter decreased in the FMTM group compared with that in the FMTC group. The three probiotic groups displayed significant changes in 15 metabolites compared with the FMTC group, with 4 metabolites showing increased expression and 11 metabolites showing decreased expression. The groups were graded as Control > FMTM > FMTB > FMTL > FMTC using a newly developed comprehensive quantitative scoring system that thoroughly analyzed the various indicators of this study. The beneficial antiaging effects of probiotics derived from centenarians were quantitatively described using a novel perspective in this study; it is confirmed that both probiotics and their combinations exert antiaging effects, with the probiotic complex group exhibiting a larger effect.

Self-Immolated Nanoadjuvant for In Situ Vaccination Immunotherapy of Colorectal Cancer.

Vaccination immunotherapy has revolutionized cancer treatment modalities. Although the immunomodulatory adjuvant generally employs for potentiating vaccine response, systemic administration may drive immune-related side effects, even immune tolerance. Therefore, tunable immunoadjuvants are highly desirable to simultaneously stimulate the immune response and mitigate systemic toxicity. Self-immolated nanoadjuvants are herein reported to potentiate vaccination immunotherapy of cancer. The nanoadjuvants are engineered by co-assembling an intracellular acidity-ionizable polymeric agonist of toll-like receptor 7/8 resiquimod (R848) and polymeric photosensitizer pyropheophorbide a (PPa). The resultant nanoadjuvants specifically accumulate at the tumor site via passive targeting and are dissociated in the acidic endosome versicles to activate PPa via protonation of the polymer backbone. Upon 671 nm laser irradiation, PPa performed photodynamic therapy to induce immunogenic cell death of tumor cells and subsequently releases R848 in a customized manner, which synergistically activates dendritic cells (DCs), promotes antigen cross-presentation, and eventually recruits cytotoxic T lymphocytes for tumor regression. Furthermore, the synergistic in situ vaccination immunotherapy with immune checkpoint blockade induce sustained immunological memory to suppress tumor recurrence in the rechallenged colorectal tumor model.

Two-dimensional metal-organic frameworks: from synthesis to bioapplications.

As a typical class of crystalline porous materials, metal-organic framework possesses unique features including versatile functionality, structural and compositional tunability. After being reduced to two-dimension, ultrathin metal-organic framework layers possess more external excellent properties favoring various technological applications. In this review article, the unique structural properties of the ultrathin metal-organic framework nanosheets benefiting from the planar topography were highlighted, involving light transmittance, and electrical conductivity. Moreover, the design strategy and versatile fabrication methodology were summarized covering discussions on their applicability and accessibility, especially for porphyritic metal-organic framework nanosheet. The current achievements in the bioapplications of two-dimensional metal-organic frameworks were presented comprising biocatalysis, biosensor, and theranostic, with an emphasis on reactive oxygen species-based nanomedicine for oncology treatment. Furthermore, current challenges confronting the utilization of two-dimensional metal-organic frameworks and future opportunities in emerging research frontiers were presented.

Photoactivatable nanogenerators of reactive species for cancer therapy.

In recent years, reactive species-based cancer therapies have attracted tremendous attention due to their simplicity, controllability, and effectiveness. Herein, we overviewed the state-of-art advance for photo-controlled generation of highly reactive radical species with nanomaterials for cancer therapy. First, we summarized the most widely explored reactive species, such as singlet oxygen, superoxide radical anion (O2 ●-), nitric oxide (●NO), carbon monoxide, alkyl radicals, and their corresponding secondary reactive species generated by interaction with other biological molecules. Then, we discussed the generating mechanisms of these highly reactive species stimulated by light irradiation, followed by their anticancer effect, and the synergetic principles with other therapeutic modalities. This review might unveil the advantages of reactive species-based therapeutic methodology and encourage the pre-clinical exploration of reactive species-mediated cancer treatments.

Nanoscale Covalent Organic Frameworks with Donor-Acceptor Structure for Enhanced Photothermal Ablation of Tumors.

Covalent organic frameworks (COFs) have shown great potential in catalysis and the biomedical fields, but monodisperse COFs with tunable sizes are hard to obtain. Herein, we successfully developed a series of COFs based on electron donor-acceptor strategy in mild conditions. The synthetic COFs exhibit excellent colloidal stability with uniform spherical morphology. The sizes can be flexibly adjusted by the amount of catalyst, and the absorption spectra also vary with the sizes. By changing the electron-donating ability of the monomers, the corresponding COFs possess a wide range of absorption spectra, which can be even extended to the second near-infrared biowindow. The obtained COFs possess potent photothermal activity under laser irradiation, and could inhibit the growth of tumors effectively. This work provides a strategy for the synthesis of monodisperse COFs with variable absorption for their potential applications.

Merocyanine-paclitaxel conjugates for photothermal induced chemotherapy.

Small molecular nanomedicines that integrate the flexibility of self-assembly strategies and the advantages of a precise molecular structure, a high drug content and controlled drug release are effective diagnostic and therapeutic modalities. Herein, merocyanine-paclitaxel conjugates (MC-PTX) were developed and fabricated by using the degradable ester bonds as the linker. The as-prepared MC-PTX could self-assemble into nanoparticles (MC-PTX NPs) using the non-covalent molecular interaction via the nanoprecipitation method. MC-PTX NPs possess a favorable biological stability and can efficiently release the paclitaxel (PTX) activated by the heat of the photoactive material merocyanine under light illumination, as monitored using dynamic light scattering. The obtained MC-PTX NPs could be endocytosed into cancer cells and release PTX under laser irradiation in the cytoplasm, thus eliciting a satisfactory anticancer effect. Photothermal triggered degradation upon light illumination could enhance the chemotherapeutic efficacy of paclitaxel. The fluorescent nature of the NPs could visualize the internalization process. We believe that this robust nanomedicine offers a novel strategy to facilitate clinical translation for use as a small molecular chemotherapy nanomedicine.

Highly efficient near-infrared BODIPY phototherapeutic nanoparticles for cancer treatment.

BODIPYs are highly potential photoactive agents for cancer theragnostics. The rational design of BODIPY-based photoactive nanodrugs with high efficiency and near-infrared (NIR) absorption is imperative. Herein, we developed a donor-acceptor-donor (D-A-D) organic photosensitizer (PS) (BODIPY, named NBB), which possessed strong absorption in the NIR region due to the multi-intersection of intramolecular charge transfer (ICT), photoinduced electron transfer (PET), and heavy atom effects. Through a nanoprecipitation method, NBB nanoparticles (NPs) were facilely prepared. The as-prepared NBB NPs exhibited favorable water-stability and photostability. In particular, the outstanding photon absorption capacity endows the NPs with high photothermal conversion efficiency (η = 53.8%) and active singlet oxygen (1O2) generation ability upon 808 nm laser irradiation, and promotes their tumour inhibition efficiency via the combination of photothermal/photodynamic therapy (half-maximal inhibitory concentration IC50 = 8.11 and 7.77 µM for HeLa and HepG2 cells, respectively). Together with the favorable synthetic yield and excellent antitumour effect, we envision that this exploration can provide beneficial guidance for the clinical translation of BODIPY-based PSs for phototherapy.

Integration of metal-organic framework with a photoactive porous-organic polymer for interface enhanced phototherapy.

Porphyrin-based porous organic polymers are highly potential candidates for cancer theranostics. However, un-controllable particle size and unclear photoactive mechanisms have been deemed to be "Achilles' heels" for their biomedical application. Herein, a facile self-template strategy has been applied to integrate two types of porous materials to build the MOF@POP-PEG nanocomposite (named HUC-PEG). As-synthesized HUC-PEG exhibited controllable particle shape and size, good biocompatibility, and better colloidal stability. Importantly, synergy "0 + 1 > 1" interface effects have been demonstrated to simultaneously enhance both the generation of more singlet oxygen (1O2) for photodynamic therapy (PDT) and local hyperthermia for photothermal therapy (PTT), thus to achieve favorable proliferation inhibition of tumor cell both in vitro and in vivo. Moreover, the strong X-ray attenuating ability of Hf element and excellent photothermal conversion efficacy endow this nanocomposite with computed tomography (CT)/photothermal imaging functions. We believe that our ingenious design may open a new horizon for the preparation of nanoscale POP-based therapeutic agents and also realize a paradigm shift in the understanding of photoactive mechanism in porous materials.

Exercise effects on γ3-AMPK activity, phosphorylation of Akt2 and AS160, and insulin-stimulated glucose uptake in insulin-resistant rat skeletal muscle.

One exercise session can increase subsequent insulin-stimulated glucose uptake (ISGU) by skeletal muscle. Prior research on healthy muscle suggests that enhanced postexercise ISGU depends on elevated γ3-AMPK activity leading to greater phosphorylation of Akt substrate of 160 kDa (pAS160) on an AMPK-phosphomotif (Ser704). Phosphorylation of AS160Ser704, in turn, may favor greater insulin-stimulated pAS160 on an Akt-phosphomotif (Thr642) that regulates ISGU. Accordingly, we tested if exercise-induced increases in γ3-AMPK activity and pAS160 on key regulatory sites accompany improved ISGU at 3 h postexercise (3hPEX) in insulin-resistant muscle. Rats fed a high-fat diet (HFD; 2-wk) that induces insulin resistance either performed acute swim-exercise (2 h) or were sedentary (SED). SED rats fed a low-fat diet (LFD; 2 wk) served as healthy controls. Isolated epitrochlearis muscles from 3hPEX and SED rats were analyzed for ISGU, pAS160, pAkt2 (Akt-isoform that phosphorylates pAS160Thr642), and γ1-AMPK and γ3-AMPK activity. ISGU was lower in HFD-SED muscles versus LFD-SED, but this decrement was eliminated in the HFD-3hPEX group. γ3-AMPK activity, but not γ1-AMPK activity, was elevated in HFD-3hPEX muscles versus both SED controls. Furthermore, insulin-stimulated pAS160Thr642, pAS160Ser704, and pAkt2Ser474 in HFD-3hPEX muscles were elevated above HFD-SED and equal to values in LFD-SED muscles, but insulin-independent pAS160Ser704 was unaltered at 3hPEX. These results demonstrated, for the first time in an insulin-resistant model, that the postexercise increase in ISGU was accompanied by sustained enhancement of γ3-AMPK activation and greater pAkt2Ser474. Our working hypothesis is that these changes along with enhanced insulin-stimulated pAS160 increase ISGU of insulin-resistant muscles to values equaling insulin-sensitive sedentary controls.NEW & NOTEWORTHY Earlier research focusing on signaling events linked to increased insulin sensitivity in muscle has rarely evaluated insulin resistant muscle after exercise. We assessed insulin resistant muscle after an exercise protocol that improved insulin-stimulated glucose uptake. Prior exercise also amplified several signaling steps expected to favor enhanced insulin-stimulated glucose uptake: increased γ3-AMP-activated protein kinase activity, greater insulin-stimulated Akt2 phosphorylation on Ser474, and elevated insulin-stimulated Akt substrate of 160 kDa phosphorylation on Ser588, Thr642, and Ser704.

Red fluorescent pyrazoline-BODIPY nanoparticles for ultrafast and long-term bioimaging.

Fluorescence bioimaging is very significant in studying biological processes. Fluorescent nanoparticles (NPs) manufactured from aggregation-induced emission (AIE) materials, as promising candidates, have attracted more attention. However, it is still a challenge to explore suitable AIE NPs for bioimaging. Herein, we synthesized pyrazoline-BODIPY (PZL-BDP) with a donor and acceptor (D-A) structure by a condensation reaction, cultured its single crystal, and studied its twisted intramolecular charge transfer (TICT) and AIE effects. PZL-BDP could self-assemble to form red fluorescent nanoparticles (PZL-BDP NPs) which showed a good fluorescence quantum yield of 15.8% in water. PZL-BDP NPs with excellent stability and biocompatibility exhibited a large Stokes shift (Δλ = 111 nm) which resulted in the reduction of external interference and enhancement of the fluorescence contrast. Furthermore, these nanoparticles could be readily internalized by HeLa cells and they stain the cells in just five seconds, indicating an ultrafast bioimaging protocol. Moreover, long-term tracking fluorescence signals in vivo for about 12 days were obtained. The bright red fluorescence, ultrafast cell staining ability, and long-term in vivo tracking competence outline the great potential of rational design nanomaterials with AIE characteristics for monitoring biological processes.

LKB1 suppresses androgen synthesis in a mouse model of hyperandrogenism via IGF-1 signaling.

Polycystic ovary syndrome (PCOS) is a major cause of anovulatory sterility in women, and most PCOS patients exhibit hyperandrogenism (HA). Liver kinase b1 (LKB1) is a tumor suppressor that has recently been reported to be involved in PCOS. However, the mechanism by which LKB1 affects HA has not previously been elucidated. We report here that ovarian LKB1 levels are significantly decreased in a female mouse model of HA. Moreover, we report that LKB1 expression is inhibited by elevated androgens via activation of androgen receptors. In addition, LKB1 treatment was observed to suppress androgen synthesis in theca cells and promote estrogen production in granulosa cells by regulating steroidogenic enzyme expression. As expected, LKB1 knockdown inhibited estrogen levels and enhanced androgen levels, and LKB1-transgenic mice were protected against HA. The effect of LKB1 appears to be mediated via IGF-1 signaling. In summary, we describe here a key role for LKB1 in controlling sex hormone levels.

Cynanchum bungei Decne and its two related species for "Baishouwu": A review on traditional uses, phytochemistry, and pharmacological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum bungei Decne. (CB) (Asclepiadaceae) and its two related species Cynanchum auriculatum Royle ex Wight. (CA) and Cynanchum wilfordii (Maxim.) Hemsl. (CW) are well known Chinese herbal medicines known by the name Baishouwu. Among them, CB has long been used for nourishing the kidney and liver, strengthening the bones and muscles, and regulating stomachache. However, to date, no comprehensive review on Baishouwu has been published. AIM OF THE REVIEW: This review aims to provide a comprehensive summary on traditional uses, phytochemistry, pharmacology, and toxicology of the three herbal components of Baishouwu with the ultimate objective of providing a guide for future scientific and therapeutic potential use of Baishouwu. MATERIAL AND METHODS: A literature search was undertaken on CB, CA and CW by analyzing the information from scientific databases (SciFinder, Pubmed, Elsevier, Google Scholar, Web of Science, and Baidu Scholar). Information was also gathered from local classic herbal literatures and conference papers on ethnopharmacology and the information provided in this review has been obtained from peer-reviewed papers. RESULTS: Comparative analysis of literature search indicate that ethnopharmacological use of CB was recorded in China, however, CA and CW have been used in China, Korea and Japan. To date, 151 chemical compounds have been isolated from these species, and the major chemical constituents have been revealed to be acetophenones, C21-steroids, terpenoids, and alkaloids. These compounds and extracts have been proven to exhibit significant pharmacological activities, including anti-tumor, anti-inflammatory, immunomodulatory, hypolipidemic, anti-obesity, hepatoprotective, antifungal, antiviral, anti-depressant, vasodilating and estrogenic activities. CONCLUSIONS: CB, CA and CW collectively known as Baishouwu are valuable medicinal herbs with multiple pharmacological activities. The traditional use for nourishing liver is closely associated with the hepatoprotective activity. The available literature performs that various of the activity of Baishouwu can be attributed to acetophenones and C21-steroids. It is high time that more efforts should be focused on the underlying mechanisms of their beneficial bioactivities and the structure activity relationship of the constituents, as well as their potential synergistic and antagonistic effects. The proper toxicology evaluation is crucial to guarantee the safety, efficacy, and eligibility for medical use. Further research on the comprehensive evaluation of medicinal quality and the understanding of multi-target network pharmacology of Baishouwu is in great request.

A Review: The Bioactivities and Pharmacological Applications of Phellinus linteus.

Phellinus linteus is a popular medicinal mushroom that is widely used in China, Korea, Japan, and other Asian countries. P. linteus comprises various bioactive components, such as polysaccharides, triterpenoids, phenylpropanoids, and furans, and has proven to be an effective therapeutic agent in traditional Chinese medicine for the treatment and the prevention of various diseases. A number of studies have reported that P. linteus possesses many biological activities useful for pharmacological applications, including anticancer, anti-inflammatory, immunomodulatory, antioxidative, and antifungal activities, as well as antidiabetic, hepatoprotective, and neuroprotective effects. This review article briefly presents the recent progress made in understanding the bioactive components, biological activities, pharmacological applications, safety, and prospects of P. linteus, and provides helpful references and promising directions for further studies of P. linteus.

Whole body glucoregulation and tissue-specific glucose uptake in a novel Akt substrate of 160 kDa knockout rat model.

Akt substrate of 160 kDa (also called AS160 or TBC1D4) is a Rab GTPase activating protein and key regulator of insulin-stimulated glucose uptake which is expressed by multiple tissues, including skeletal muscle, white adipose tissue (WAT) and the heart. This study introduces a novel rat AS160-knockout (AS160-KO) model that was created using CRISPR/Cas9 technology. We compared male AS160-KO versus wildtype (WT) rats for numerous metabolism-related endpoints. Body mass, body composition, energy expenditure and physical activity did not differ between genotypes. Oral glucose intolerance was detected in AS160-KO versus WT rats (P<0.005). A hyperinsulinemic-euglycemic clamp (HEC) revealed insulin resistance for glucose infusion rate (P<0.05) with unaltered hepatic glucose production in AS160-KO versus WT rats. Genotype-effects on glucose uptake during the HEC: 1) was significantly lower in epitrochlearis (P<0.01) and extensor digitorum longus (P<0.05) of AS160-KO versus WT rats, and tended to be lower for AS160-KO versus WT rats in the soleus (P<0.06) and gastrocnemius (P<0.08); 2) tended to be greater for AS160-KO versus WT rats in white adipose tissue (P = 0.09); and 3) was significantly greater in the heart (P<0.005) of AS160-KO versus WT rats. GLUT4 protein abundance was significantly lower for AS160-KO versus WT rats in each tissue analyzed (P<0.01-0.001) except the gastrocnemius. Ex vivo insulin-stimulated glucose uptake was significantly lower (P<0.001) for AS160-KO versus WT rats in isolated epitrochlearis or soleus. Insulin-stimulated Akt phosphorylation (in vivo or ex vivo) did not differ between genotypes for any tissue tested. Ex vivo AICAR-stimulated glucose uptake by isolated epitrochlearis was significantly lower for AS160-KO versus WT rats (P<0.01) without genotype-induced alteration in AMP-activated protein phosphorylation. This unique AS160-KO rat model, which elucidated striking genotype-related modifications in glucoregulation, will enable future research aimed at understanding AS160's roles in numerous physiological processes in response to various interventions (e.g., diet and/or exercise).