Citrate serves as a signal molecule to modulate carbon metabolism and iron homeostasis in Staphylococcus aureus.

Pathogenic bacteria's metabolic adaptation for survival and proliferation within hosts is a crucial aspect of bacterial pathogenesis. Here, we demonstrate that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, plays a key role as a regulator of gene expression in Staphylococcus aureus. We show that citrate activates the transcriptional regulator CcpE and thus modulates the expression of numerous genes involved in key cellular pathways such as central carbon metabolism, iron uptake and the synthesis and export of virulence factors. Citrate can also suppress the transcriptional regulatory activity of ferric uptake regulator. Moreover, we determined that accumulated intracellular citrate, partly through the activation of CcpE, decreases the pathogenic potential of S. aureus in animal infection models. Therefore, citrate plays a pivotal role in coordinating carbon metabolism, iron homeostasis, and bacterial pathogenicity at the transcriptional level in S. aureus, going beyond its established role as a TCA cycle intermediate.

Enhancing oral delivery and anticancer efficacy of 7-ethyl-10-hydroxycamptothecin through self-assembled micelles of deoxycholic acid grafted N'-nonyl-trimethyl chitosan.

Irinotecan (CPT-11) is used as a first or second-line chemotherapy drug for the treatment and management of colorectal cancers. In vitro studies have shown that 7-ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, displays promising anticancer efficacy. However, its poor aqueous solubility and hydrolytic degradation result in its lower oral bioavailability and impracticable clinical application. To overcome these limitations, a novel amphiphilic chitosan derivative, deoxycholic acid decorated N'-nonyl-trimethyl chitosan, was synthesized. Nano-micelles loaded with SN38 were subsequently prepared to enhance the bioavailability and anti-tumor efficacy of the drug through oral administration. The nano-micelles demonstrated improved dilution stability, enhanced greater mucosal adherence, significant P-gp efflux inhibition, and increased drug transport in the intestine by paracellular and transcellular pathways. Consequently, both the in vivo pharmacokinetic profile and therapeutic efficacy of SN38 against cancer were substantially improved via the micellar system. Thus, the developed polymeric micelles can potentially enhance the SN38 oral absorption for cancer therapy, offering prospective avenues for further exploration.

Oral delivery of pectin-chitosan hydrogels entrapping macrophage-targeted curcumin-loaded liposomes for the treatment of ulcerative colitis.

The oral delivery of anti-inflammatory drugs has been a promising strategy for enhancing the clinical efficacy of ulcerative colitis (UC) treatment strategies. However, achieving site specific drug delivery to colon tissues and target cells is a challenging task for formulation scientists. In this study, macrophages-targeted liposome-loaded pectin-chitosan hydrogels were developed for UC treatment via oral administration. Folate-functionalized cholesterol was synthesized as lipid membrane materials for the liposomes containing curcumin (CUR). The incorporation of the liposomal CUR within pectin-chitosan hydrogels resulted in a matrix that exhibited considerable sensitivity to colonic enzymes during in vitro release. The targeted delivery of hybrids was able to effectively reach macrophages. They also showed enhanced capability to downregulate TNF-α, IL-6, and IL-1ß in the lipopolysaccharide-induced Raw 264.7 cells model. DSS-induced mice modelshowed improved anti-UC effects, including accelerated mucosal repair and decreased inflammation and modulate the immune balance in the intestinal tissue of mice with colitis, which may be attributable to increased drug accumulation in the colonic lumen and improved internalization to target cells. Therefore, the incorporation of folate-modified liposomes containing CUR and pectin-chitosan physical hydrogels could potentially serve as a favorable approach for treating UC through an oral colon-targeted drug delivery system.

Efficiency of a novel thermosensitive enema in situ hydrogel carrying Periplaneta americana extracts for the treatment of ulcerative colitis.

Objective: The aim of this study was to develop a thermosensitive in situ gel (TISG) as an effective rectal delivery platform for delivering Periplaneta americana extracts (PA) to alleviate ulcerative colitis (UC) and explore the underlying molecular mechanism. Materials and methods: Thermosensitive (poloxamer 407) and adhesive polymers (chondroitin sulfate modified carboxymethyl chitosan, CCMTS) were used to construct the in situ gel. CCMTS and aldehyde poloxamer 407 (P407-CHO) were synthesized and chemically cross-linked by Schiff base reaction to formulate thermosensitive in situ gel, which carried Periplaneta americana extracts (PA/CCMTS-P). The cytotoxicity and cellular uptake of CCMTS-P were investigated in lipopolysaccharide (LPS) -induced macrophages by CCK-8 assay. The anti-inflammatory effects of PA/CCMTS-P were studied in lipopolysaccharide-induced RAW264.7 cells and dextran sulfate sodium (DSS)-induced ulcerative colitis mouse models. In addition, the ability of PA/CCMTS-P to restore the intestinal mucosal barrier after rectal administration was evaluated by immunohistochemical analysis (IHC). Results: PA/CCMTS-P was prepared and characterized as gel with a phase-transition temperature of 32.9°C. The results of the in vitro experiments indicated that the hydrogels promoted the cellular uptake of Periplaneta americana extracts without causing any toxicity as compared to the free gel. PA/CCMTS-P showed superior anti-inflammatory activity both in vitro and in vivo, which restored the damaged intestinal mucosal barrier associated by inhibiting necroptosis in dextran sulfate sodium-induced ulcerative colitis models. Conclusion: The findings from our study show that the rectal administration of PA/CCMTS-P holds a promising potential for the treatment of ulcerative colitis.

Prdm14 promotes mouse ESC self-renewal and PGCLC specification through enhancement of Stat3 activity.

Prdm14 plays an important role in the maintenance of mouse embryonic stem cell (mESC) pluripotency and the specification of primordial germ cells (PGCs). However, the mechanism downstream of Prdm14 is still not fully understood. Here, using high-throughput sequencing, chromatin immunoprecipitation, and luciferase reporter assays, we show that Prdm14 directly binds to the promoter of Socs3 and represses its transcription to increase the phosphorylation level of Stat3 protein, a critical downstream effector of LIF. Therefore, ectopic expression of Socs3 is able to decrease the ability of Prdm14 to promote mouse mESC self-renewal and PGC-like cell generation. As expected, similar phenotypes were observed in Prdm14-transfected mESCs after knockdown of Stat3 transcripts or treatment with a pan-inhibitor of JAKs, positive modulators of the LIF/Stat3 signaling pathway. These data will facilitate a better understanding of the regulatory network governing ESC identity and germ cell development.

Chaotropic Effect Stabilized Radical-Containing Supramolecular Organic Frameworks for Photothermal Therapy.

Radical-containing frameworks (RCFs) have emerged as promising functional materials in various fields due to the combination of the highly ordered frame structure and the fascinating property of organic radicals. Here, the first example of radical-containing supramolecular organic frameworks (SOFs) fabricated by the chaotropic effect between closo-dodecaborate cluster (B12 H122- ) and 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT3+ ) is presented. The SOFs can be easily synthesized by stirring the B12 H122- and the TPT3+ in aqueous solution through self-assembly. Upon 435 nm light irradiation, the SOFs exhibits photochromic behavior from slight yellow (SOF-1) to dark purple (SOF-2). Electron paramagnetic resonance spectroscopy also reveals that stable radicals are generated in situ after light irradiation. Powder X-ray diffraction demonstrates the SOFs maintain their structural stabilities upon light irradiation. More interestingly, the radical-containing SOFs exhibit efficient photothermal effect under 660 nm light irradiation, which can be applied as photothermal agent for antibacterial application both in vitro and in vivo. This work highlights the construction of RCFs through supramolecular self-assembly, which may arouse applications in energy, catalysis, photoluminescence, and biomedical fields.

Efficient Ambient Electrocatalytic Ammonia Synthesis by Nanogold Triggered via Boron Clusters Combined with Carbon Nanotubes.

Currently, the development of stable electrochemical nitrogen reduction reaction (ENRR) catalysts with high N2 conversion activity and low cost to instead of the traditional Haber-Bosch ammonia production process of high-energy consumption remains a great challenge for researchers. Here, we have immobilized reductive closo-[B12H11]- boron clusters on a carbon nanotubes (CNT) surface and have successfully prepared a novel Au-CNT catalyst with extraordinary ENRR activity after adding HAuCl4 to the CNT-[B12H11]- precursor. The excellent properties of ammonia yield (57.7 µg h-1 cm-2) and Faradaic efficiency (11.97%) make it possible to achieve using this Au-CNT catalyst in large-scale industrial production of ammonia. Furthermore, its outstanding cyclic stability and long-term tolerability performance make it one of the most cost-effective catalysts to date. Here, by means of density functional theory we disclose the associative mechanism of N2-to-NH3 conversion on the Au(111) surface, providing visual theoretical support for the experimental results.

BCN-Encapsulated Nano-nickel Synergistically Promotes Ambient Electrochemical Dinitrogen Reduction.

The electricity provided by solar or wind power can drive nitrogen in the atmosphere, combining with ubiquitous water to form ammonia, and distributed production methods can alleviate the irreversible damage to the environment caused by the energy-intensive Haber-Bosch process. Here, we have designed a novel Ni-doped BCN heterojunction (S/M-BOPs-1) as a catalyst for the electrochemical nitrogen reduction reaction (NRR). The ammonia yield rate and Faraday efficiency in NRR driven by S/M-BOPs-1 reach up to 16.72 µg-1 h-1 cm-2 and 13.06%, respectively. Moreover, S/M-BOPs-1 still maintains high NRR activity and excellent stability after recycling for eight times and long-time operation of 12 h. Using density functional theory calculations, we reveal a possible NRR path for N2 to NH3 on Ni, BCN, and the S/M-BOPs-1 composite surfaces. The interaction between the BCN matrix and Ni nanoparticles promotes a synergetic effect for the electrochemical NRR efficiency due to the partial electron transfer from the Ni particles to BCN that inhibits hydrogen evolution reaction and decreases the rate-determining step on Ni surfaces toward NRR by ∼1.5 times. Therefore, efficient NRR performance can be achieved by tuning the electronic properties of non-noble metals via the formation of a heterointerface.