Transient Mild Photothermia Improves Therapeutic Performance of Oral Nanomedicines with Enhanced Accumulation in the Colitis Mucosa.

The treatment outcomes of oral medications against ulcerative colitis (UC) have long been restricted by low drug accumulation in the colitis mucosa and subsequent unsatisfactory therapeutic efficacy. Here, high-performance pluronic F127 (P127)-modified gold shell (AuS)-polymeric core nanotherapeutics loading with curcumin (CUR) is constructed. Under near-infrared irradiation, the resultant P127-AuS@CURs generate transient mild photothermia (TMP; ≈42 °C, 10 min), which facilitates their penetration through colonic mucus and favors multiple cellular processes, including cell internalization, lysosomal escape, and controlled CUR release. This strategy relieves intracellular oxidative stress, improves wound healing, and reduces immune responses by polarizing the proinflammatory M1-type macrophages to the anti-inflammatory M2-type. Upon oral administration of hydrogel-encapsulating P127-AuS@CURs plus intestinal intralumen TMP, their therapeutic effects against acute and chronic UC are demonstrated to be superior to those of a widely used clinical drug, dexamethasone. The treatment of P127-AuS@CURs (+ TMP) elevates the proportions of beneficial bacteria (e.g., Lactobacillus and Lachnospiraceae), whose metabolites can also mitigate colitis symptoms by regulating genes associated with antioxidation, anti-inflammation, and wound healing. Overall, the intestinal intralumen TMP offers a promising approach to enhance the therapeutic outcomes of noninvasive medicines against UC.

[Strategy and challenge of innovative drug research and development from clinically effective ingredients of traditional Chinese medicine].

Novel drug discovery from the active ingredients of traditional Chinese medicine is the most distinctive feature and advantageous field of China, which has provided an unprecedented opportunity. However, there are still problems such as unclear functional substance basis, action targets and mechanism, which greatly hinder the clinical transformation of active ingredients in traditional Chinese medicine. Based on the analysis of the current status and progress of innovative drug research and development in China, this paper aimed to explore the prospect and difficulties of the development of natural active ingredients from traditional Chinese medicine, and to explore the efficient discovery of trace active ingredients in traditional Chinese medicine, and obtain drug candidates with novel chemical structure, unique target/mechanism and independent intellectual property rights, in order to provide a new strategy and a new model for the development of natural medicine with Chinese characteristics.

Camphor Attenuates Hyperalgesia in Neuropathic Pain Models in Mice.

Background: The treatment of neuropathic pain is still a major troublesome clinical problem. The existing therapeutic drugs have limited analgesic effect and obvious adverse reactions, which presents opportunities and challenges for the development of new analgesic drugs. Camphor, a kind of monoterpene, has been shown anti-inflammatory and analgesic effects in traditional Chinese medicine. But we know little about its effect in neuropathic pain. In this article, We have verified the reliable analgesic effect of camphor in the neuropathic pain model caused by different predispositions. Methods: The nociceptive response of mice was induced by transient receptor potential A1 (TRPA1) agonist to verify the effect of camphor on the nociceptive response. Multiple paclitaxel (PTX) injection models, Single oxaliplatin (OXA) injection models, Chronic constriction injury (CCI) models and Streptozotocin-induced (STZ) diabetic neuropathic pain models were used in this study. We verified the analgesic effect of camphor in mice by acetone test and conditioned place aversion test. At the same time, comparing the adverse reaction of nervous system between camphor and pregabalin at equivalent dose in locomotor activity test and rotarod test. Using patch clamp to verify the effect of camphor on dorsal root ganglion (DRG) excitability. Results: In behavioral test, compared with vehicle group, camphor significantly reduced the spontaneous nociception caused by TRPA1 agonist-formalina and allyl isothiocyanate (AITC). Compared with vehicle group, camphor significantly reduced the flinching and licking time in neuropathic pain model mice, including PTX, OXA, STZ and CCI induced peripheral neuralgia models. Compared with vehicle group, pregabalin significantly increased the resting time and reduced the average speed without resting and distance in locomotor activity test, reduced the time stayed on rotarod in rotarod test. In patch clamp test, compared with vehicle group, camphor significantly reduced the action potential (AP) firing frequency of DRG. Conclusion: Camphor can alleviate the symptoms of hyperalgesia in various neuropathic pain models, and has no obvious adverse reactions compared with pregabalin. This effect is related to the down-regulation of DRG neuron excitability.

Dual drugs decorated bacteria irradiate deep hypoxic tumor and arouse strong immune responses.

Intratumoral environment as a hypoxic, non-inflamed "cold" state is difficult for many agents to accumulate and activate the immune system. Intrinsically, facultative anaerobic Salmonella VNP20009 target the tumor hypoxic areas, invade into tumor cells and exhibit an immune effect. Here we engineer the bacteria by decorating their surface with newly synthesized heptamethine cyanine dyes NHS-N782 and JQ-1 derivatives to obtain the biohybrid agent N-V-J, leading to the deep tumor targeted photothermal therapy and magnified immunotherapy. Due to the mitochondrial targeting capacity of NHS-N782, N-V-J becomes susceptive to the temperature rise when reaching tumors. This synergistic strategy promotes the systemic immunity by creating an inflamed "hot" tumor state from three different dimensions, which include the inherent immunogenicity of bacteria, the near-infrared laser triggered tumor antigens and the downregulation of PD-L1 expression. All these approaches result in effective and long-lasting T cell immune responses to prevent local and distant tumors for extended time. Leveraging the attenuated bacteria to transport dual drugs to the tumor tissues for self-synthetic vaccines provides a novel paradigm to enhance the bacteria-mediated cancer immunotherapy.

Multi-responsive nanotheranostics with enhanced tumor penetration and oxygen self-producing capacities for multimodal synergistic cancer therapy.

Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin (DOX)-loaded silk fibroin-based nanoparticles (NPs) with surface functionalization by photosensitizer (N770). The obtained nanotheranostics (N770-DOX@NPs) had desirable particle size (157 nm) and negative surface charge (-25 mV). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli (acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared (NIR) fluorescence imaging, photothermal imaging, and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumor retardation effect among all treatment groups based on tumor-bearing mouse models and a patient-derived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imaging-guided mitochondrial phototherapy (photothermal therapy and photodynamic therapy) and chemotherapy. Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.

Multi-responsive nanococktails with programmable targeting capacity for imaging-guided mitochondrial phototherapy combined with chemotherapy.

The integration of multimodal functions into one nanoplatform holds great promise for enhancing anticancer drug action and mitigating adverse effects. Herein, we prepared hyaluronic acid-functionalized regenerated silk fibroin-based nanoparticles (NPs) loading with photosensitizer (NIR770) and doxorubicin (DOX). The resultant HNDNPs had a desirable diameter of 161.0 nm and a negative zeta-potential of -30.5 mV. Interestingly, they showed excellent responses when triggered with various stimuli (acidity, reactive oxygen species, glutathione, hyaluronidase, or hyperthermia). Cell experiments revealed that HNDNPs could be specifically internalized by A549 cells, and efficiently released the payloads into the cytoplasm. Moreover, NIR770 was preferentially retained in mitochondria due to its lipophilic and cationic properties, which exhibited highly efficient photothermal therapy and photodynamic therapy upon near infrared (NIR) irradiation. Meanwhile, DOX molecules were mainly accumulated in the nucleus. Intravenous injection of HNDNPs into mice followed by NIR irradiation provided excellent multimodal imaging (NIR, photothermal, and photoacoustic imaging), almost eliminated the entire tumor, and greatly prolonged mice survival time with no side effects. Our study demonstrates that this HNDNP, which integrates the functions of tumor targeting, on-demand drug release, multimodal imaging, mitochondrial phototherapy, and chemotherapy, can be exploited as a promising nanococktail for imaging-guided synergistic treatment of cancer.

CO as a therapeutic agent: discovery and delivery forms.

Carbon monoxide (CO) as one of the three important endogenously produced signaling molecules, termed as "gasotransmitter," has emerged as a promising therapeutic agent for treating various inflammation and cellular-stress related diseases. In this review, we discussed CO's evolution from a well-recognized toxic gas to a signaling molecule, and the effort to develop different approaches to deliver it for therapeutic application. We also summarize recently reported chemistry towards different CO delivery forms.

HCN1 Channels Contribute to the Effects of Amnesia and Hypnosis but not Immobility of Volatile Anesthetics.

BACKGROUND: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) subtype 1 (HCN1) channels have been identified as targets of ketamine to produce hypnosis. Volatile anesthetics also inhibit HCN1 channels. However, the effects of HCN1 channels on volatile anesthetics in vivo are still elusive. This study uses global and conditional HCN1 knockout mice to evaluate how HCN1 channels affect the actions of volatile anesthetics. METHODS: Minimum alveolar concentrations (MACs) of isoflurane and sevoflurane that induced immobility (MAC of immobility) and/or hypnosis (MAC of hypnosis) were determined in wild-type mice, global HCN1 knockout (HCN1) mice, HCN1 channel gene with 2 lox-P sites flanking a region of the fourth exon of HCN1 (HCN1) mice, and forebrain-selective HCN1 knockout (HCN1: cre) mice. Immobility of mice was defined as no purposeful reactions to tail-clamping stimulus, and hypnosis was defined as loss of righting reflex. The amnestic effects of isoflurane and sevoflurane were evaluated by fear-potentiated startle in these 4 strains of mice. RESULTS: All MAC values were expressed as mean ± SEM. For MAC of immobility of isoflurane, no significant difference was found among wild-type, HCN1, HCN1, and HCN1: cre mice (all ~1.24%-1.29% isoflurane). For both HCN1 and HCN1: cre mice, the MAC of hypnosis for isoflurane (each ~1.05% isoflurane) was significantly increased over their nonknockout controls: HCN1 versus wild-type (0.86% ± 0.03%, P < 0.001) and HCN1: cre versus HCN1 mice (0.84% ± 0.03%, P < 0.001); no significant difference was found between HCN1 and HCN1: cre mice. For MAC of immobility of sevoflurane, no significant difference was found among wild-type, HCN1, HCN1, and HCN1: cre mice (all ~2.6%-2.7% sevoflurane). For both HCN1 and HCN1: cre mice, the MAC of hypnosis for sevoflurane (each ~1.90% sevoflurane) was significantly increased over their nonknockout controls: HCN1 versus wild-type (1.58% ± 0.05%, P < 0.001) and HCN1: cre versus HCN1 mice (1.56% ± 0.05%, P < 0.001). No significant difference was found between HCN1 and HCN1: cre mice. By fear-potentiated startle experiments, amnestic effects of isoflurane and sevoflurane were significantly attenuated in HCN1 and HCN1: cre mice (both P < 0.002 versus wild-type or HCN1 mice). No significant difference was found between HCN1 and HCN1: cre mice. CONCLUSIONS: Forebrain HCN1 channels contribute to hypnotic and amnestic effects of volatile anesthetics, but HCN1 channels are not involved in the immobilizing actions of volatile anesthetics.