Although a plethora of nonviral gene vectors have been developed for potential gene therapy, imageable gemini surfactants with stimuli-responsiveness and high transfection efficiency are still scarce for gene delivery. Herein, three gemini amphiphiles (DEDPP-4/8/12) consisting of an aggregation-induced emission (AIE) central fluorophore: 5,6-diphenylpyrazine-2,3-diester (DEDPP), decorated with triazole-[12]­aneN3 as the hydrophilic moiety and alkyl chains of various lengths as the hydrophobic moiety, were designed and synthesized for trackable gene delivery via optical imaging. All three amphiphiles exhibited ultralow critical micelle concentrations (CMCs) (up to 3.40 × 10–6 M), prominent two-photon absorption properties, and solvatochromic fluorescence. Gel electrophoresis assays demonstrated that the migration of plasmid DNA was completely retarded after condensation with these gemini amphiphiles at low concentrations (up to 10 μM). In addition, the ester bond in these amphiphiles may facilitate vector degradation and DNA release, in response to esterase and the acidic environment inside cells. Upon self-assembly with DOPE to form liposomes, DEDPP-8/DOPE achieved the best transfection efficiency in four cell lines, and the transfection efficiency of DEDPP-8/DOPE in HeLa cell lines was 23.5-fold higher than that of Lipo2000, which is unusually high for small organic molecule-based nonviral vectors. Furthermore, excellent transfection efficiency of DEDPP-8/DOPE was obtained in the presence of serum, and the red fluorescence protein (RFP) gene was successfully transfected in zebrafish embryos. Both one- and two-photon fluorescence imaging clearly demonstrated the delivery process of plasmid DNA. This study demonstrated that gemini-type amphiphiles composed of a two-photon fluorophore core conjugated with triazole-[12]­aneN3 via an ester bond afforded an unprecedentedly high transfection efficiency with excellent biocompatibility, which may provide new insights for the design and development of multifunctional nonviral gene vectors for imageable gene delivery.

Three nonviral gene vectors, TPA-BI-A/B/C, have been designed and synthesized by the combination of one or two hydrophilic [12]­aneN3 moieties and two-photon fluorescent triphenylamine-benzylideneimidazolone (TPA-BI) units through different ester linkage. Spectroscopic characterization demonstrated that TPA-BI-A/B/C had strong aggregation-induced emissions (AIE), large Stokes shifts (230, 284, and 263 nm), and large two-photon absorption cross sections (δ2PA) (67, 592, and 80 GM). Gel electrophoresis indicated that the three compounds completely condensed DNA at 15 μM in the presence of DOPE, and showed the lipase- and pH-triggered reversible release of DNA and the fluorescent recognition of the different lengths of ssDNA and dsDNA. The optimal TPA-BI-C/DOPE-mediated luciferase and GFP activity was 146% and 290% higher than those of Lipo2000. The transfection process of DNA could be traced clearly through one- and two-photon fluorescence spectra, and displayed in a 3D-video. TPA-BI-C/DOPE successfully transfected the GFP gene into zebrafish, which was superior to Lipo2000 (192%). In conclusion, TPA-BI-C/DOPE is the first nonviral gene vector with the abilities of pH/lipase enzyme responsiveness, one/two-photon fluorescent tracking of intracellular delivery of DNA, and successful transfection in vivo and in vitro, even better than Lipo2000.

Background: Clinical trials have proven that indigo naturalis is a candidate drug for treating ulcerative colitis (UC), but its therapeutic mechanism is still unclear.Purpose: This study aimed to evaluate the protective effect and mechanism of indigo naturalis to treat mice with dextran sulfate sodium (DSS)-induced UC.Methods: DSS-induced UC mice were treated with indigo naturalis (200 mg/kg), indigo (4.76 mg/kg), and indirubin (0.78 mg/kg) for 1 week. The anti-UC mechanism of indigo naturalis was studied by pathological section, inflammatory factor, western blot, and 16S rRNA sequencing.Results: According to body weight change, disease activity index, and colon length, indigo naturalis had the strongest anti DSS-induced UC effect, followed by indirubin and indigo. Pathological section showed that indigo naturalis, indigo, and indirubin could reduce the infiltration of inflammatory cells, increase the secretion of intestinal mucus, and repair the intestinal mucosa. Indigo naturalis, indigo, and indirubin could reduce IL-1β,IL-6, and TNF-α by inhibiting TLR4/MyD88/NF-κB signal transduction. Indigo naturalis and indigo could also reduce IgA and IgG both in serum and colon tissue. In addition, indigo naturalis, indigo, and indirubin could adjust the gut microbiota structure of DSS-induced UC mice, reducing the ratio of Firmicutes/Bacteroidetes and increasing the abundance of probiotics.Conclusion: Indigo and indirubin are one of the main anti-UC components of indigo naturalis. INN could regulate intestinal flora, reduce inflammation, repair intestinal mucosa, and improve the physiological status of DSS-induced UC mice and its anti-UC mechanism may be involved in inhibiting TLR4/MyD88/NF-κB signal transduction.

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Novel coronavirus (COVID-19) pneumonia has become a major threat to worldwide public health, having rapidly spread to more than 180 countries and infecting over 1.6 billion people. Fever, cough, and fatigue are the most common initial symptoms of COVID-19, while some patients experience diarrhea rather than fever in the early stage. Many herbal medicine and Chinese patent medicine can significantly improve these symptoms, cure the patients experiencing a mild 22form of the illness, reduce the rate of transition from mild to severe disease, and reduce mortality. Therefore, this paper summarizes the physiopathological mechanisms of fever, cough, fatigue and diarrhea, and introduces Chinese herbal medicines (Ephedrae Herba, Gypsum Fibrosum, Glycyrrhizae Radix et Rhizoma, Asteris Radix et Rhizoma, Ginseng Radix et Rhizoma, Codonopsis Radix, Atractylodis Rhizoma, etc.) and Chinese patent medicines (Shuang-huang-lian, Ma-xinggan-shi-tang, etc.) with their corresponding therapeutic effects. Emphasis was placed on their material basis, mechanism of action, and clinical research. Most of these medicines possess the pharmacological activities of anti-inflammatory, antioxidant, antiviral, and immunity-enhancement, and may be promising medicines for the treatment or adjuvant treatment of COVID-19 patients.