High-fiber diet mitigates maternal obesity-induced cognitive and social dysfunction in the offspring via gut-brain axis

There is increasing knowledge of AKI and deleterious interorgan crosstalk that arises, at least in part, due to the imbalance of immune, inflammatory, and soluble mediator metabolism that attends severe insults to the kidney. Further studies can build on these new mechanistic observations to develop strategies to improve outcomes in the critically ill patient.

Objective: To investigate the value of initial CT quantitative analysis of ground-glass opacity (GGO), consolidation, and total lesion volume and its relationship with clinical features for assessing the severity of coronavirus disease 2019 (COVID-19). Materials and Methods: A total of 84 patients with COVID-19 were retrospectively reviewed from January 23, 2020 to February 19, 2020. Patients were divided into two groups: severe group (n = 23) and non-severe group (n = 61). Clinical symptoms, laboratory data, and CT findings on admission were analyzed. CT quantitative parameters, including GGO, consolidation, total lesion score, percentage GGO, and percentage consolidation (both relative to total lesion volume) were calculated. Relationships between the CT findings and laboratory data were estimated. Finally, a discrimination model was established to assess the severity of COVID-19. Results: Patients in the severe group had higher baseline neutrophil percentage, increased high-sensitivity C-reactive protein (hs-CRP) and procalcitonin levels, and lower baseline lymphocyte count and lymphocyte percentage (p < 0.001). The severe group also had higher GGO score (p < 0.001), consolidation score (p < 0.001), total lesion score (p < 0.001), and percentage consolidation (p = 0.002), but had a lower percentage GGO (p = 0.008). These CT quantitative parameters were significantly correlated with laboratory inflammatory marker levels, including neutrophil percentage, lymphocyte count, lymphocyte percentage, hs-CRP level, and procalcitonin level (p < 0.05). The total lesion score demonstrated the best performance when the data cutoff was 8.2%. Furthermore, the area under the curve, sensitivity, and specificity were 93.8% (confidence interval [CI]: 86.8-100%), 91.3% (CI: 69.6-100%), and 91.8% (CI: 23.0-98.4%), respectively. Conclusion: CT quantitative parameters showed strong correlations with laboratory inflammatory markers, suggesting that CT quantitative analysis might be an effective and important method for assessing the severity of COVID-19, and may provide additional guidance for planning clinical treatment strategies.

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Summary:Increasing evidence supports a role for oxidative stress, proinflammatory cytokines, and apoptosis in the pathophysiology of focal ischemic stroke. Previous studies have found that the multi-action drug, carvedilol, is a mixed adrenergic antagonist, and that it behaves as an antioxidant and inhibits apoptosis. In the current study, the authors investigated whether carvedilol provides protection in focal cerebral ischemia and whether this protection is associated with reduced apoptosis and the downregulation of the inflammatory cytokines, tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤). Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) by an intraluminal filament technique. Carvedilol (1, 3, and 10 mg/kg) was injected daily subcutaneously 2 or 4 days before the induction of ischemia. Neurologic scores, infarct volumes, TUNEL staining, and mRNA levels of TNF-␣ and IL-1␤ were assessed at 24 hours reperfusion. The effect of carvedilol on microvascular cortical perfusion was studied with continuous laser-Doppler flowmetry. Twenty-four hours after MCAO, carvedilol at all three doses reduced infarct volumes by at least 40% and reduced neurologic deficits on average by 40% compared with vehicle-treated controls when given 2 or 4 days before the induction of ischemia. This protection was not mediated by changes in temperature or blood flow. Treatment with all three dose regimens resulted in fewer TUNEL positive cells compared with controls. At 24 hours reperfusion, carvedilol decreased TNF-␣ and IL-1␤ expression by 40% to 50% in the ipsilateral ischemic cortex compared with the contralateral controls. The results of the current study indicate that carvedilol is neuroprotective in focal cerebral ischemia and may protect the ischemic brain by inhibiting apoptosis and attenuating the expression of TNF-␣ and IL-1␤.

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Scheme 4. Pd-catalyzed enantioselective decarboxylative allylic alkylation. [a] [Pd 2 (dba) 3 ] (3.5 mol %), L2 (8.75 mol %). [b] At 55 8C.Scheme 5. Catalytic enantioselective total synthesis of (À)-aspidospermidine. Reaction conditions: a) HCO 2 H, RT; b) LiAlH 4 , THF, À20 8C, then HCl (2 m); c) K 2 OsO 4 ·2 H 2 O, NMO, THF/H 2 O (1:1), then NaIO 4 ; d) 1,2-ethanedithiol, BF 3 ·Et 2 O, CH 2 Cl 2 ; e) Raney nickel, H 2 , EtOH, 60 8C; f) LiAlH 4 , Et 2 O, reflux; g) Na/NH 3 , THF, À78 8C. NMO = Nmethylmorpholine-N-oxide.

Tyrosine1 and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at kappa receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [D-Ala3]Dyn A(1-11)-NH2 (2) and [Ala3]Dyn A(1-11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central kappa opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1-11)-NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for kappa vs mu and kappa vs delta receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1-11)-NH2 as well as the conformational changes they induce in the message sequence of dynorphin have important effects on potency and selectivity for kappa opioid receptors. To further investigate structure-activity relationships involving the residue at the 3 position of Dyn A(1-11)-NH2, a series of Dyn A analogues with aromatic, charged, and aliphatic side chain substitutions at the 3 position was designed, synthesized, and evaluated for their affinities for kappa, mu, and delta opioid receptors. It was found that analogues with lipophilic amino acids at the 3 position of Dyn A(1-11)-NH2 generally displayed higher affinity but similar selectivities for the kappa receptor than analogues with charged residues at the same position. It is suggested that the structural, configurational, and steric/lipophilic effects of amino acids at position 3 of Dyn A(1-11)-NH2 may play an important role in potency and selectivity for the kappa receptor.