An enzyme-responsive and NIR-triggered lipid-polymer hybrid nanoplatform for synergistic photothermal/chemo cancer therapy.

A combination of photothermal therapy (PTT) and chemotherapy is an emerging therapeutic strategy with promising clinical prospects in cancer treatment. Despite the huge progress achieved in the past years, a number of obstacles still hamper the therapeutic efficacy of this synergistic modality such as uneven heat distribution, lack of targetability of anti-cancer agents and dosage-related side effects. Thus, developing a nanoplatform for targeted drug delivery against cancer is of great necessity. Herein, a lipid-polymer hybrid nanosystem (LP/ID) based on polyethyleneimine (PEI)-lecithin-polyethylene glycol (PEG) was fabricated to co-load indocyanine green (ICG) and dichloroacetate (DCA) for combined photothermal/chemotherapy. DCA and ICG were linked to the PEI backbone to form a dense hydrophobic core through amide bonds and electrostatic interactions, which increased the payload of DCA and ICG as well as achieved enzyme-responsive drug release because of the overexpressed amidase in tumor cells. Lecithin and DSPE-PEG2000 self-assembled around the hydrophobic complexes to obtain prolonged blood circulation and attenuated systemic toxicity of the hybrid nanosystem. The prepared LP/ID exhibited favourable stability in a physiological environment, good tumor imaging properties, and satisfactory photothermal/chemotherapeutic performance. Moreover, LP/ID could also enhance the cellular uptake and tumor retention capacity in comparison with free drug administration. Notably, by co-loading two therapeutic agents with different anti-cancer mechanisms, an obvious inhibitory effect on tumor growth was observed with negligible damage to normal tissues and organs because of the synergistic photothermal/chemotherapy effect, indicating the great potential of LP/ID as a robust nanoplatform for cancer treatment.

Aurantio-obtusin induces hepatotoxicity through activation of NLRP3 inflammasome signaling.

Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-α (Tnf-α) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-α and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1ß, IL-1ß and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B p65 (NF-κB p65), in the female mouse livers. In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-κB inhibition.

Regulatory B cells induced by ultraviolet B through toll-like receptor 4 signalling contribute to the suppression of contact hypersensitivity responses in mice.

BACKGROUND: Ultraviolet (UV) B irradiation is known to suppress contact hypersensitivity (CHS) responses in mouse models by suppressing immune responses. However, the cellular mechanisms responsible for UVB-induced systemic suppression remain unclear. Regulatory B cells have been reported to play an inhibitory role during CHS. It is presently unknown whether regulatory B cells contribute to the effect of UVB phototherapy. OBJECTIVE: To investigate the inductive effect of UVB on regulatory B cells and the underlying mechanisms by using a CHS mouse model. METHODS: CHS was induced with oxazolone, and evaluated by histopathology, flow cytometry, and quantitative real-time polymerase chain reaction. RESULT: We found that UVB irradiation induced regulatory B cell expansion and ameliorated CHS. UVB-induced regulatory B cells contribute to systemic immunosuppression by inhibiting the proliferation of T cells. Moreover, we determined that toll-like receptor (TLR) 4, the expression of which was upregulated in B cells after UVB exposure, played an essential role in the induction of regulatory B cells. CONCLUSION: Our data identified regulatory B cells as regulators of UVB-induced immunosuppression in CHS, and suggest the importance of the UVB-TLR4 axis in the generation of regulatory B cells.

Chronic trimethyltin chloride exposure and the development of kidney stones in rats.

We recently reported that occupational exposure to trimethyltin (TMT) is a risk factor for developing kidney stones. To further examine the association between TMT exposure and the formation of kidney stones, we conducted a 180-day animal study and exposed the randomly grouped Sprague-Dawley (SD) rats to TMT in the drinking water at doses of 0, 8.2, 32.8 and 131.3 µg kg(-1) day(-1). Transient behavioral changes were observed in the high-dose group during the first 2 weeks of exposure. TMT exposure led to a significant dose-dependent inhibition of renal H(+)/K(+)-ATPase and an increase in urinary pH. In comparison to no kidney stones being identified in the control and the lowest dose group, 1 rat in the 32.8 µg kg(-1) day(-1) dose group and 3 out of 9 rats in the 131.3 µg kg(-1) day(-1) dose group were found to have stones in the kidney/urinary tract. Pathological analysis showed that more wide spread calcium disposition was observed in kidneys of rats with TMT exposure compared with the rats in the control group. However, X-ray diffraction (XRD) analysis found that the kidney stones were mainly composed of struvite with the formula: NH4MgPO4 6H2O, while calcium-containing components were also detected. Together, this study further demonstrates through animal studies that chronic exposure to a relatively low level of TMT induces nephrotoxicity and increases the risk for developing kidney stones.