Tunable optical activities in chiral transition metal oxide nanoparticles.

Chiral transition metal oxides (TMOs) are widely used in various optoelectronic devices. However, the currently poor understanding of how the optical activities of TMOs can be regulated considerably hinders their applications. We have synthesized a series of chiral TMO nanoparticles (NPs), i.e., MoOx (x = 2, 2.4 and 2.5) and Co3O4. Compared with TMO NPs with L-/D-cysteine molecules as the capping ligand, L-/D-histidine-capped TMO NPs possess larger anisotropic factors (gabs), which are as high as ∼0.01 and ∼0.02 for L-/D-histidine-capped MoO2.5 and Co3O4 NPs, respectively. A nondegenerate coupled oscillator (NDCO) theoretical calculation confirms that L-/D-histidine molecules can generate a smaller electric dipole moment and thus induce higher optical activity than L-/D-cysteine molecules. Impressively, the chiral NPs exhibit broadband second harmonic generation. This work indicates that chiral TMO NPs have potential for application in nonlinear optical devices.

Peimine ameliorates pulmonary fibrosis via the inhibition of M2-type macrophage polarization through the suppression of P38/Akt/STAT6 signals.

Peimine, a bioactive substance isolated from Chinese medicine Fritillaria, can potentially suppress pulmonary fibrosis (PF); however, its therapeutic mechanism remains unclear. Recent evidence suggests the participation of M2-type macrophages in the pathogenesis of PF. The present study aimed to investigate the effect of peimine on a bleomycin (BLM)-induced PF rat model and the underlying mechanism of this effect. After BLM administration, peimine was administered to rats from day 29 to day 42, with pirfenidone (PFD) as a positive control. H&E and Masson's trichrome stain were used to analyze histological changes. Q-PCR and western blotting were used to measure mRNA levels and protein levels, respectively. High-throughput RNA sequencing (RNA-seq) technology detected the differentially expressed genes (DEGs) regulated by peimine. Our results revealed that peimine treatment significantly ameliorated BLM-induced PF by suppressing histological changes and collagen deposition. In addition, peimine decreased the number of M2 macrophages and the expression of profibrotic factors. RNA-seq results showed that DEGs regulated by peimine in IL-4-induced macrophages were mainly associated with immune system processes, the PI3K/Akt pathway, and the MAPKs pathway. Then, immunofluorescence assay and western blot results demonstrated that peimine treatment suppressed the expression of p-p38 MAPK and p-Akt (s473) and also inhibited the nuclear translocation of p-STAT6. In conclusion, the present study demonstrated that peimine has a protective effect on PF through the suppression of M2 polarization of macrophages by inhibiting the STAT6, p38 MAPK, and Akt signals.

Effective-compound combination inhibits the M2-like polarization of macrophages and attenuates the development of pulmonary fibrosis by increasing autophagy through mTOR signaling.

BACKGROUND AND PURPOSE: The M2 polarization of macrophages substantially contributes to the progression of pulmonary fibrosis (PF). Effective-compound combination (ECC), which is composed of isoliquiritigenin, icariin, nobiletin, peimine, and paeoniflorin, ameliorated bleomycin-induced PF in rats. Hence, we investigated the anti-PF mechanism of ECC with a focus on the suppression of M2 polarization in macrophages in vivo and in vitro. METHODS: The PF rat model was generated via the intratracheal instillation of bleomycin. Histological changes, M2 macrophages, and profibrotic mediators were detected. The M2 polarization model was generated by incubating macrophages with IL-4. Quantitative PCR and Western blotting were used to measure mRNA and protein levels, respectively. RESULTS: ECC attenuated bleomycin-induced PF in rats, which might be associated with reduced macrophage infiltration, M2 polarization, and profibrotic mediator expression. Furthermore, ECC significantly suppressed M2 polarization in IL-4-treated macrophages, which was accompanied by the upregulation of autophagy. An autophagy inhibitor abrogated the inhibitory effect of ECC on M2 polarization. In addition, ECC decreased the levels of p-p70S6K/p-4EBP and p-AKT473/p-GSK3ß, which are critical regulators of autophagy. CONCLUSION: ECC can ameliorate PF, which might be associated with the inhibition of M2 polarization through the promotion of autophagy via mTOR signaling suppression.

m6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity.

N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism, but its role in innate immunity-driven non-alcoholic fatty liver disease (NAFLD) and obesity is not known. Here, we show that myeloid lineage-restricted deletion of the m6A "writer" protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Mechanistically, loss of METTL3 results in the differential expression of multiple mRNA transcripts marked with m6A, with a notable increase of DNA Damage Inducible Transcript 4 (DDIT4) mRNA level. In METTL3-deficient macrophages, there is a significant downregulation of mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathway activity in response to cellular stress and cytokine stimulation, which can be restored by knockdown of DDIT4. Taken together, our findings identify the contribution of METTL3-mediated m6A modification of Ddit4 mRNA to macrophage metabolic reprogramming in NAFLD and obesity.

Bufei Jianpi Formula Improves Mitochondrial Function and Suppresses Mitophagy in Skeletal Muscle via the Adenosine Monophosphate-Activated Protein Kinase Pathway in Chronic Obstructive Pulmonary Disease.

Skeletal muscle dysfunction, a striking systemic comorbidity of chronic obstructive pulmonary disease (COPD), is associated with declines in activities of daily living, reductions in health status and prognosis, and increases in mortality. Bufei Jianpi formula (BJF), a traditional Chinese herbal formulation, has been shown to improve skeletal muscle tension and tolerance via inhibition of cellular apoptosis in COPD rat models. This study aimed to investigate the mechanisms by which BJF regulates the adenosine monophosphate-activated protein kinase (AMPK) pathway to improve mitochondrial function and to suppress mitophagy in skeletal muscle cells. Our study showed that BJF repaired lung function and ameliorated pathological impairment in rat lung and skeletal muscle tissues. BJF also improved mitochondrial function and reduced mitophagy via the AMPK signaling pathway in rat skeletal muscle tissue. In vitro, BJF significantly improved cigarette smoke extract-induced mitochondrial functional impairment in L6 skeletal muscle cells through effects on mitochondrial membrane potential, mitochondrial permeability transition pores, adenosine triphosphate production, and mitochondrial respiration. In addition, BJF led to upregulated expression of mitochondrial biogenesis markers, including AMPK-α, PGC-1α, and TFAM and downregulation of mitophagy markers, including LC3B, ULK1, PINK1, and Parkin, with increased expression of downstream markers of the AMPK pathway, including mTOR, PPARγ, and SIRT1. In conclusion, BJF significantly improved skeletal muscle and mitochondrial function in COPD rats and L6 cells by promoting mitochondrial biogenesis and suppressing mitophagy via the AMPK pathway. This study suggests that BJF may have therapeutic potential for prophylaxis and treatment of skeletal muscle dysfunction in patients with COPD.

Water-soluble chiral CdSe/CdS dot/rod nanocrystals for two-photon fluorescence lifetime imaging and photodynamic therapy.

Compared with traditional organic contrast agents, semiconductor nanocrystals (NCs) have unique optical properties that are vital for biological applications with ultrahigh sensitivities, such as long fluorescence lifetime and large multiphoton absorption (MPA). However, the MPA properties and biological applications of chiral-ligand-stabilized semiconductor NCs have scarcely been reported, which seriously hinders their relevant applications. In this work, we report the aqueous phase transfer of CdSe/CdS dot/rod NCs with the use of cysteine molecules, after which the NCs preserve their high fluorescence quantum yield, long lifetime, and efficient circular dichroism. More importantly, the investigated dot/rod NCs show extremely large two- and three-photon absorption action cross-sections in the first and second biological windows, with maximum values of ∼21 000 GM at 800 nm and ∼4.6 × 10-78 cm6 s2 per photon2 at 1300 nm, which are among the largest values reported for water-soluble fluorescent nanoparticles. Interestingly, the dot/rod NCs exhibit a high singlet oxygen generation efficiency of 35%. In addition, for the first time, two-photon fluorescence lifetime imaging and photodynamic therapy of the dot/rod NCs were successfully demonstrated. The performed investigation of the optical properties of these water-soluble CdSe/CdS dot/rod NCs indicates that they are promising candidates for nonlinear biological imaging applications.

Strong multiphoton absorption in chiral CdSe/CdS dot/rod nanocrystal-doped poly(vinyl alcohol) films.

Cysteine-capped cadmium selenide/cadmium sulfide (CdSe/CdS) dot/rod nanocrystals (NCs) were synthesized and then doped in poly(vinyl alcohol) (PVA) films. Compared with an L-/D-cysteine-capped NC solution (10-4), the anisotropic factors of the circular dichroism and circular polarized luminescence in the doped PVA films increased by one order of magnitude, probably because of the enhanced anisotropy degree, crystal orientations, and ordered morphologies. The two- and three-photon absorption coefficients of the doped PVA films were determined as 0.58 cm/GW at 800 nm and 2.3×10-4 cm3/GW2 at 1300 nm, respectively. The chiral NC-doped PVA films are promising for applications in chirality-related nonlinear photonic devices.

Water-soluble chiral tetrazine derivatives: towards the application of circularly polarized luminescence from upper-excited states to photodynamic therapy.

A new family of water-soluble chiral tetrazine derivatives 1 and 2 is reported. Spectroscopic studies reveal that the derivatives violate Kasha's rule and emit from their upper-excited states (S n , n > 1). The transition assignments are supported by time-dependent density functional theory calculations. More importantly, both chromophores exhibit anisotropy factors on the order of ∼10-3 to 10-4 for circular dichroism and circularly polarized luminescence (CPL) from upper-excited states. Additionally, the nonplanar geometry of the derivatives induces a significant yield of triplet excited states. Transient absorption spectroscopic measurements reveal high triplet quantum yields of ∼86% for 1 and ∼81% for 2. Through in vitro studies, we demonstrate that the derivatives can be used as photodynamic therapy (PDT) agents, providing a highly efficient form of cancer therapy. This study is the first demonstration of simple organic molecules with CPL from upper-excited states and efficient PDT.

Chiral CdSe nanoplatelets as an ultrasensitive probe for lead ion sensing.

As opposed to traditional photoluminescence and ultra-violet based optical sensing, we present here a sensing system based on resolved optically active polarization with promising applications. It is based on the ultrathin CdSe nanoplatelets (NPLs) when modified with either l or d-cysteine molecules (l/d-cys) as bio-to-nano ligands. The chiral ligand transfers its chiroptical activity to the achiral nanoplatelets with an anisotropy factor of ∼10-4, which unlocks the chiral excitonic transitions and allows lead ion detection with a limit of detection (LOD) as low as 4.9 nM. Simulations and modelling based on time-dependent density functional theory (TD-DFT) reveal the chiral mechanism of l/d-cys capped CdSe NPLs. The presented CD-based sensing system illustrates an alternative possibility of using chiral CdSe NPLs as competitive chiral sensors for heavy metal ion detection.

Bufei Jianpi Granules Reduce Quadriceps Muscular Cell Apoptosis by Improving Mitochondrial Function in Rats with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Cell apoptosis is an important mechanism underlying skeletal muscle dysfunction in chronic obstructive pulmonary disease (COPD) patients, and mitochondrial dysfunction is recognized as a central aspect contributing to skeletal muscle deterioration. Bufei Jianpi granules have been confirmed effective for improving motor function in COPD patients, but the specific mechanism for this improved function remains unknown. This study explored the mechanisms by which Bufei Jianpi granules improve cell apoptosis and mitochondrial dysfunction in COPD. METHODS: Sprague-Dawley rats were randomized into control, model, Bufei Jianpi, and aminophylline groups. A stable COPD rat model was induced with respective repeated cigarette smoke inhalation and intragastric bacterial infection, and rats were sacrificed after 20 weeks; the quadriceps muscle was harvested from each rat. Skeletal muscle mitochondria were extracted for measurements of mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore openings (mPTPs). ATP levels were determined with a firefly luciferase-based ATP assay kit. The rates of cell apoptosis were determined by the transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) method. Cyto C and caspase-3 mRNA and protein levels were measured by qPCR and western blotting. RESULTS: ATP, MMP, and mPTPs were markedly decreased in COPD rats, while cell apoptosis, caspase-3, and Cyto C were increased (P<0.01). All aforementioned parameters were improved in treatment groups (P<0.05). ATP, MMP, and mPTPs were significantly higher in the Bufei Jianpi group than in the aminophylline group, while cell apoptosis, caspase-3, and Cyto C were lower (P<0.05). CONCLUSIONS: Bufei Jianpi granules can inhibit mitochondrial dysfunction and cell apoptosis in peripheral muscles, which might be the mechanism involved in improving skeletal muscle function in COPD patients.

Optically Active CdSe-Dot/CdS-Rod Nanocrystals with Induced Chirality and Circularly Polarized Luminescence.

Ligand-induced chirality in semiconductor nanocrystals (NCs) has attracted attention because of the tunable optical properties of the NCs. Induced circular dichroism (CD) has been observed in CdX (X = S, Se, Te) NCs and their hybrids, but circularly polarized luminescence (CPL) in these fluorescent nanomaterials has been seldom reported. Herein, we describe the successful preparation of l- and d-cysteine-capped CdSe-dot/CdS-rods (DRs) with tunable CD and CPL behaviors and a maximum anisotropic factor ( glum) of 4.66 × 10-4. The observed CD and CPL activities are sensitive to the relative absorption ratio of the CdS shell to the CdSe core, suggesting that the anisotropic g-factors in both CD and CPL increase to some extent for a smaller shell-to-core absorption ratio. In addition, the molar ratio of chiral cysteine to the DRs is investigated. Instead of enhancing the chiral interactions between the chiral molecules and DRs, an excess of cysteine molecules in aqueous solution inhibits both the CD and CPL activities. Such chiral and emissive NCs provide an ideal platform for the rational design of semiconductor nanomaterials with chiroptical properties.

Restoring Th17/Treg balance via modulation of STAT3 and STAT5 activation contributes to the amelioration of chronic obstructive pulmonary disease by Bufei Yishen formula.

ETHNOPHARMACOLOGY RELEVANCE: Bufei Yishen formula (BYF), a Traditional Chinese Medicine (TCM), has been extensively applied in clinical treatment of chronic obstructive pulmonary disease (COPD) and provides an effective treatment strategy for the syndrome of lung-kidney qi deficiency in COPD patients. Here, we investigated its anti-COPD mechanism in COPD rats in relation to the balance between T helper (Th) 17 cells and regulatory T (Treg) cells. METHODS: Rat model of cigarette smoke- and bacterial infection-induced COPD was established, and orally treated with BYF for 12 consecutive weeks. Then, the rats were sacrificed, their lung tissues were removed for histological analysis, and spleens and mesenteric lymph nodes (MLNs) were collected to evaluate the Th17 and Treg cells. RESULTS: Oral treatment of BYF markedly suppressed the disease progression and alleviated the pathological changes of COPD. It also decreased the bronchoalveolar lavage fluid (BALF) levels of pro-inflammatory cytokines, including IL-1ß, IL-6, TNF-α and Th17-related IL-17A, and induced a significant increase in Treg-related IL-10. Furthermore, BYF treatment obviously decreased the proportion of CD4+RORγt+ T (Th17) cell and increased the proportion of CD4+CD25+Foxp3+ T (Treg) cell, leading to restore the Th17/Treg balance. BYF treated groups also decreased RORγt and increased Foxp3 expression in the spleens and MLNs. BYF further inhibited the phosphorylation of signal transducer and activator of transcription-3 (STAT3) and boosted the phosphorylation of STAT5, that were critical transcription factors for TH17 and Treg differentiation. CONCLUSION: these results demonstrated that BYF exerted its anti-COPD efficacy by restoring Th17/Treg balance via reciprocally modulating the activities of STAT3 and STAT5 in COPD rats, which may help to elucidate the underlying immunomodulatory mode of BYF on COPD treatment.

Long-Term Effects of TCM Yangqing Kangxian Formula on Bleomycin-Induced Pulmonary Fibrosis in Rats via Regulating Nuclear Factor-κB Signaling.

OBJECTIVE: We aimed to evaluate the therapeutic effects and long-term effects of YKF and dissect the potential mechanisms. MATERIALS AND METHODS: IPF rats were given YKF, prednisone, or pirfenidone, respectively, from day 1 to day 42, followed by a 28-day nonintervention interval through day 70. Forced vital capacity (FVC), histopathology, hydroxyproline (HYP) contents, lung coefficient, blood inflammatory cell populations, inflammatory cytokine levels of the lung tissues, and the expression of proteins involved in nuclear factor- (NF-) κB signaling pathway were evaluated on days 7, 14, 28, 42, and 70. RESULTS: HYP contents, Ashcroft scores, lung coefficient, and pulmonary fibrosis blood cell populations increased significantly in IPF rats, while FVC declined. All the above-mentioned parameters were improved in treatment groups from day 7 up to day 70, especially in YKF group. The mRNA and protein expressions of tumor necrosis factor- (TNF-) α significantly decreased, while interferon- (IFN-) γ significantly increased, and phosphorylations of cytoplasm inhibitor of nuclear factor kappa-B kinase ß (IKKß), inhibitor of nuclear factor kappa-B α (IκBα), and NF-κB were obviously downregulated in YKF group from day 7 to day 70. CONCLUSION: YKF has beneficial protective and long-term effects on pulmonary fibrosis by anti-inflammatory response and alleviating fibrosis.