Anhui University of Chinese Medicine

Ulcerative colitis (UC) is a chronic and easy-to-relapse intestinal disease characterized by colon inflammation and microbial dysbiosis. Candida albicans is the most common fungal resident in the human gut. Overgrowth of C. albicans has been linked to the aggravation of UC. Previously, we demonstrated that miR-32-5p was the most differentially expressed microRNA in DSS-induced colitis model supplemented with C. albicans and might be a potential target in the treatment of Candida colitis. However, the underlying pathogenic and therapeutic mechanisms remain unclear. Here, we firstly used the ITS technique to analyse intestinal mycobiota. The miR-32-5p adenovirus in company with extracted Candida cell wall β-glucan were then employed to monitor the impacts of miR-32-5p and fungal β-glucan on the severity of Candida colitis. Subsequently, gene silencing together with inhibitors of reactive oxygen species (ROS) and apoptosis was used to survey the modulation of miR-32-5p on macrophage polarization. According to these results, C. albicans became the dominant intestinal fungal species in Candida colitis model. Candida β-glucan could instruct miR-32-5p expression to affect the severity of Candida colitis in a concentration-dependent manner. Interestingly, high fungal β-glucan with pro-inflammatory effects hindered further increases in gut inflammation. Further analysis showed that overexpression of miR-32-5p could effectively inhibit inflammation and apoptosis and enhance phagocytosis and ROS production through Dectin-1 signalling in macrophages. A panel of representative gene expressions verified the polarization of the M2-like phenotype induced by miR-32-5p. Mechanistically, our results reveal the therapeutic potential of miR-32-5p in the amelioration of Candida colitis.

Acute lung injury (ALI) is a lung disease characterized by pulmonary edema caused by an excessive inflammatory response within the lungs and disruption of the alveolar capillary barrier, with a high morbidity and mortality rate in critically ill patients. Dry powder inhalers (DPI) are an effective way of administering medication to improve efficacy, and inhalation administration not only improves efficacy but also increases the bioavailability of the drug. Synephrine, a natural ingredient derived from the fruit of the citrus plant in the Brassicaceae family, has anti-inflammatory and antioxidant properties. In the present study, we prepared a synephrine dry powder inhaler (SYN-DPI) by anti-solvent precipitation method and evaluated it in vivo and in vitro. The in vitro results show that SYN-DPI has low hygroscopicity and good aerodynamic properties. The in vitro and in vivo efficacy results showed that SYN-DPI not only had low toxicity but also possessed good anti-inflammatory and antioxidant capacity, which could significantly reduce inflammation, oxidative stress, and lung injury. Pharmacokinetic results showed that inhalation administration significantly increased SYN bioavailability. In conclusion, this study provides inhalation administration of synephrine as an inhalable formulation that can be used to improve ALI.

The mitochondrial anchoring protein Num1 directly affects mitochondrial redox function, cell division, and growth in unicellular fungi. However, the functional characterization of Num11, its Candida albicans homolog, remains elusive. Our investigation revealed that Num11 deletion in C. albicans caused profound cellular defects: (1) Disrupted cell cycle progression and mitochondrial dysfunction manifesting as mitochondrial morphological aggregation, ATP depletion, membrane potential collapse, and ROS overproduction; (2) Hypersensitivity to cell wall-perturbing agents accompanied by thicker cell walls and increased surface exposure of β-glucan/chitin; (3) Enhanced macrophage phagocytosis and proinflammatory cytokine release. These cellular alterations translated to significantly attenuated virulence in both Galleria mellonella and systematic mice infection models. Mechanistically, transcriptome profiling and protein interaction analyses demonstrated Num11 deficiency hyperactivates the Cdc42-Cek1 MAPK cascade (phospho-Cek1 increased), driving cell wall remodeling. Our findings establish Num11's dual closely connected regulatory roles in C. albicans pathogenesis: as a mitochondrial scaffold maintaining bioenergetic homeostasis to attenuate growth and as a negative regulator of the Cdc42-Cek1 axis controlling cell wall architecture through affection on mitochondria. These coordinated actions collectively underscore Num11's critical role in mediating host-pathogen interactions during invasive candidiasis.