Mycobacterium vaccae alleviates allergic airway inflammation and airway hyper-responsiveness in asthmatic mice by altering intestinal microbiota.

Host immunity can influence the composition of the gut microbiota and consequently affect disease progression. Previously, we reported that a Mycobacterium vaccae vaccine could ameliorate allergic inflammation in asthmatic mice by regulating inflammatory immune processes. Here, we investigated the anti-inflammatory effects of M. vaccae on allergic asthma via gut microbiota modulation. An ovalbumin (OVA)-induced asthmatic murine model was established and treated with M. vaccae. Gut microbiota profiles were determined in 18 BALB/c mice using 16S rDNA gene sequencing and metabolomic profiling was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Mycobacterium vaccae alleviated airway hyper-reactivity and inflammatory infiltration in mice with OVA-induced allergic asthma. The microbiota of asthmatic mice is disrupted and that this can be reversed with M. vaccae. Additionally, a total of 24 differential metabolites were screened, and the abundance of PI(14:1(9Z)/18:0), a glycerophospholipid, was found to be correlated with macrophage numbers (r = 0.52, p = 0.039). These metabolites may affect chemokine (such as macrophage chemoattractant protein-1) concentrations in the serum, and ultimately affect pulmonary macrophage recruitment. Our data demonstrated that M. vaccae might alleviate airway inflammation and hyper-responsiveness in asthmatic mice by reversing imbalances in gut microbiota. These novel mechanistic insights are expected to pave the way for novel asthma therapeutic strategies.

Sulforaphane triggers iron overload-mediated ferroptosis in gastric carcinoma cells by activating the PI3K/IRP2/DMT1 pathway.

OBJECTIVE: Increasing evidence indicates that prolonged exposure to sulforaphane (SFN) can improve malignancies. However, the role of iron in SFN-triggered death in gastric carcinoma cells and the underlying molecular mechanisms remain unclear. Thus, the current study explored the effects of SFN on iron overload-mediated ferroptosis and the PI3K/IRP2/DMT1 pathway in gastric carcinoma cells. METHODS: We utilized the MGC-803 cell line to assess whether SFN affected iron metabolism and whether this effect contributed to cell death. Pharmacological inhibition of iron metabolism also was performed to determine the molecular mechanism underlying SFN-triggered iron overload and the disturbance in iron metabolism. RESULTS: Our data revealed that SFN treatment altered iron homeostasis and led to iron overload in vitro. Interestingly, SFN-stimulated cell death resulted from ferroptosis, a recently identified iron-dependent form of regulated cell death. Furthermore, an iron chelator, deferiprone, ameliorated the SFN-triggered mitochondrial dysfunction and reduced the iron overload. In addition, we found that the SFN-triggered iron overload was regulated by the PI3K/IRP2/DMT1 signaling pathway. CONCLUSION: We discovered that disturbance in iron metabolism might be involved in the SFN-triggered cell death in gastric carcinoma cells. Blockade of the PI3K/IRP2/DMT1 axis could provide a feedback effect on SFN-induced ferroptosis to protect tumor cells from growth.

Selexipag Improves Lipopolysaccharide-Induced ARDS on C57BL/6 Mice by Modulating the cAMP/PKA and cAMP/Epac1 Signaling Pathways.

Selexipag, a long-acting and selective prostacyclin (PGI2) IP receptor agonist, has in aged rats with stroke revealed effects of inhibiting inflammation, ameliorating damage to the blood-brain barrier, and alleviating oxidative stress. However, in the case of acute respiratory distress syndrome (ARDS) characterized by diffuse alveolar damage and lung capillary endothelial injury, its effects yet remain unknown. In this study, we investigated effects of the prophylaxis by Selexipag on a mouse model of ARDS established by the lipopolysaccharide (LPS) challenge and potential mechanism. Compared to the LPS-challenged mice, the LPS-challenged mice with the prophylaxis by 0.5 or 1 mg/kg of Selexipag exhibited significantly alleviated lung histological manifestations, reduced protein leakage, decreased levels of interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein-1 (MCP-1), diminished expressions of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) mRNA, noticeably increased expressions of zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) protein, escalated lung cAMP levels, and raised levels of lung relative phosphorylated-protein kinase A catalytic subunit (p-PKA C) at Thr197 and exchange protein activated by cAMP 1 (Epac1) protein. These results suggest that, through suppressing inflammation and reducing vascular endothelial damage, Selexipag can effectively ameliorate the LPS-induced ARDS on mice. The lung cAMP and its downstream signaling modules, PKA and Epac1, possibly constitute the main regulative molecular mechanism. Selexipag appears to hold promise to become a new potential therapeutic option for ARDS.

Elevated levels of von Willebrand factor and high mobility group box 1 (HMGB1) are associated with disease severity and clinical outcome of scrub typhus.

OBJECTIVES: This study aimed to investigate whether von Willebrand factor (vWF) and high mobility group box 1 (HMGB1) are associated with the severity and clinical outcome of scrub typhus and to seek novel biomarkers for surveillance and prediction of the prognosis of this infection. METHODS: Serum concentrations of vWF and HMGB1 were measured twice by ELISA for scrub typhus patients (n=103), once prior to doxycycline therapy and then on day 7 of doxycycline therapy; concentrations were measured once for healthy controls (n=32). RESULTS: Among the total 103 patients enrolled, 38 had disease complicated by multiple organ dysfunction syndrome (MODS). Serum concentrations of vWF and HMGB1 were significantly higher in all the patients than in the healthy controls, both prior to doxycycline treatment and on day 7 of doxycycline treatment (p<0.01). Furthermore, serum levels of vWF, HMGB1, and creatinine (SCr) in the patients with MODS increased distinctly, while the platelet (PLT) count diminished markedly compared to the levels in patients without MODS (p<0.01). The concentration of vWF was positively correlated with that of HMGB1 (r=0.764, p<0.001) and SCr (r=0.528, p<0.001), but negatively correlated with the PLT count (r=-0.632, p<0.001). Both HMGB1 and vWF were significantly associated with mortality in scrub typhus (area under the curve (AUC)=0.864, p=0.001, and AUC=0.862, p=0.001, respectively). CONCLUSIONS: Elevated levels of vWF and HMGB1 are associated with the severity and clinical outcome of scrub typhus. These represent possible new biomarkers for use in the assessment and prognostic prediction of this infection.

Treatment with growth hormone, somatostatin, and insulin in combination with hypocaloric parenteral nutrition in gastrointestinal cancer patients after surgery.

OBJECTIVE: The metabolic response to gastrointestinal cancer in patients undergoing surgery is associated with hypermetabolism and insulin resistance. The potential use of synergetic anabolic hormones in conjunction with hypocaloric parenteral nutrition (HPN) has become a significant area of investigation. The presented study was performed to determine the clinical efficiency and safety of hormone therapy combined with HPN in patients with gastrointestinal cancer. METHODS: One hundred patients with a Nutrition Risk Screening score of 3 or 4 undergoing surgery for gastrointestinal cancer were randomized into two groups. The patients in the control group received standard total parenteral nutrition and systemic insulin. The patients in the study group received HPN and systemic insulin in addition to pretreatment with recombinant human growth hormone and octreotide. Clinical efficiency and safety were evaluated by the measurement of hormones and protein metabolites, immune function, clinical outcome, and adverse events. Follow-ups were performed to determine the influence on prognosis. RESULTS: Treatment with recombinant human growth hormone, octreotide, and insulin in combination with HPN significantly increased protein synthesis, immune function, and metabolic tolerance, decreased infectious complications, and shortened postoperative hospital stays, but did not increase the risk of tumor development and recurrence in the study group compared with the control group. CONCLUSION: The proper short-term perioperative administration of growth hormone, somatostatin, and insulin in combination with HPN can overcome the postoperative stress response through the increase of protein synthesis to improve immune function in patients with gastrointestinal cancer after surgery.