Atg5 deficiency in macrophages protects against kidney fibrosis via the CCR6-CCL20 axis.

BACKGROUND: Autophagy is a lysosome-dependent degradation pathway that regulates macrophage activation, differentiation, and polarization. Autophagy related 5 (Atg5) is a key protein involved in phagocytic membrane elongation in autophagic vesicles that forms a complex with Atg12 and Atg16L1. Alterations in Atg5 are related to both acute and chronic kidney diseases in experimental models. However, the role of macrophage-expressed Atg5 in acute kidney injury remains unclear. METHODS: Using a myeloid cell-specific Atg5 knockout (MΦ atg5-/-) mouse, we established renal ischemia/reperfusion and unilateral ureteral obstruction models to evaluate the role of macrophage Atg5 in renal macrophage migration and fibrosis. RESULTS: Based on changes in the serum urea nitrogen and creatinine levels, Atg5 deletion had a minimal effect on renal function in the early stages after mild injury; however, MΦ atg5-/- mice had reduced renal fibrosis and reduced macrophage recruitment after 4 weeks of ischemia/reperfusion injury and 2 weeks of unilateral ureteral obstruction injury. Atg5 deficiency impaired the CCL20-CCR6 axis after severe ischemic kidneys. Chemotactic responses of bone marrow-derived monocytes (BMDMs) from MΦ atg5-/- mice to CCL20 were significantly attenuated compared with those of wild-type BMDMs, and this might be caused by the inhibition of PI3K, AKT, and ERK1/2 activation. CONCLUSIONS: Our data indicate that Atg5 deficiency decreased macrophage migration by impairing the CCL20-CCR6 axis and inhibited M2 polarization, thereby improving kidney fibrosis.

In Vitro Inhibitory Effects of Polyphenols from Flos sophorae immaturus on α-Glucosidase: Action Mechanism, Isothermal Titration Calorimetry and Molecular Docking Analysis.

Flos sophorae immaturus (FSI) is considered to be a natural hypoglycemic product with the potential for a-glucosidase inhibitory activity. In this work, the polyphenols with α-glucosidase inhibition in FSI were identified, and then their potential mechanisms were investigated by omission assay, interaction, type of inhibition, fluorescence spectroscopy, circular dichroism, isothermal titration calorimetry and molecular docking analysis. The results showed that five polyphenols, namely rutin, quercetin, hyperoside, quercitrin and kaempferol, were identified as a-glucosidase inhibitors with IC50 values of 57, 0.21, 12.77, 25.37 and 0.55 mg/mL, respectively. Quercetin plays a considerable a-glucosidase inhibition role in FSI. Furthermore, the combination of quercetin with kaempferol generated a subadditive effect, and the combination of quercetin with rutin, hyperoside and quercitrin exhibited an interference effect. The results of inhibition kinetics, fluorescence spectroscopy, isothermal titration calorimetry and molecular docking analysis showed that the five polyphenols were mixed inhibitors and significantly burst the fluorescence intensity of α-glucosidase. Moreover, the isothermal titration calorimetry and molecular docking analysis showed that the binding to α-glucosidase was a spontaneous heat-trapping process, with hydrophobic interactions and hydrogen bonding being the key drivers. In general, rutin, quercetin, hyperoside, quercitrin and kaempferol in FSI are potential α-glucosidase inhibitors.

Hydrothermal treatment improves xanthine oxidase inhibitory activity and affects the polyphenol profile of Flos Sophorae Immaturus.

BACKGROUND: Flos Sophorae Immaturus (FSI) is rich in polyphenols and a potential uric acid-lowering food. However, the processing of FSI is greatly restricted due to the heat sensitivity and low solubility of polyphenols. In this study, hydrothermal treatment - an effective strategy - was applied to FSI processing. The variation of xanthine oxidase (XO) inhibitory effect and polyphenol composition of FSI during hydrothermal treatment were recorded. RESULTS: The XO inhibition rate of FSI increased from 32.42% to 89.00% after hydrothermal treatment at 220 °C for 30 min, as well as total polyphenols (from 0.66 to 1.11 mg mL-1 ) and flavonoids (from 1.21 to 1.58 mg mL-1 ). However, high thermal temperature (>160 °C) and extended thermal time (>90 min) caused the degradation of polyphenols. Rutin, kaempferol-3-O-rutinoside and narcissoside rapidly degraded and converted to quercetin, kaempferol and isorhamnetin when the temperature exceeded 160 °C. The maximum yields of quercetin, kaempferol and isorhamnetin were at 220 °C for 30 min, 90 min and 90 min, respectively. Meanwhile, the conversion kinetics conformed to the first-order model. Interestingly, these newly formed polyphenols possessed better XO inhibitory effects than their derivatives with 3-O-rutinoside. CONCLUSION: Polyphenol conversion during hydrothermal treatment was the main reason for enhancing XO inhibitory activity. Therefore, hydrothermal treatment is an appropriate method for improving the XO inhibitory effect of FSI. © 2022 Society of Chemical Industry.

Sodium butyrate exerts antioxidant stress effects and attenuates Aß25-35-induced cytotoxicity in PC12 cells.

Alzheimer's disease (AD), a common neurodegenerative disease, is characterised by the deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles. An increasing number of studies have demonstrated that Aß causes neuronal damage and mitochondrial dysfunction. Herein, we evaluated the neuroprotective effect of sodium butyrate (NaB) against Aß induced neurotoxicity in PC12 cells. The results revealed that 3 mM of NaB promoted the expression of angiotensin-converting enzyme and brain-derived neurotrophic factor, which exert a neuroprotective effect by activating G protein-coupled receptors. Moreover, NaB could significantly improve mitochondrial dysfunction caused by Aß. In conclusion, NaB protected PC12 cells from Aß-induced cell damage, highlighting the potential of NaB in AD treatment.

In vitro inhibitory effects of polyphenols from Tartary buckwheat on xanthine oxidase: Identification, inhibitory activity, and action mechanism.

The xanthine oxidase (XO) inhibitory activity is an important way to evaluate the anti-hyperuricemia effect of natural products. In the present work, the XO inhibitory effect of Tartary buckwheat was elucidated by polyphenols determination, omission experiment, interaction assay, inhibition types, fluorescence spectroscopy, and molecular docking. The results revealed that eight primary polyphenols were identified, including rutin (544 mg/100 g) and quercetin (261 mg/100 g). Quercetin (IC50 = 0.03 mg/mL) was a mixed-type inhibitor and exhibited the strongest inhibitory effect, followed by kaempferol (IC50 = 0.11 mg/mL). Moreover, a sub-additive effect was exhibited in the complex of quercetin-kaempferol, but the combination of quercetin and other polyphenols caused interference or antagonism effects. Furthermore, quercetin and kaempferol showed an obvious fluorescence quenching effect on XO, and the bindings were mainly driven by hydrophobic forces and hydrogen bonds. This study shows that Tartary buckwheat may be a potential functional food to inhibit XO activity.

Photodynamic Therapy for Recurrent Early Central Lung Cancer of Great Longitudinal Extent Following Two Surgical Lung Resections: A Case Report.

Photodynamic therapy (PDT) is an endobronchial treatment requiring a photosensitizer activated by a specific wavelength light to kill tumor cells. PDT is effective in treating early central lung cancer (ECLC) ,especially for lesions <1.0 cm in length. We present a patient with history of two lung resections for squamous cell carcinoma, who had unresectable ECLC lesions (4.0 - 5.0 cm in length) treated by PDTs successfully without other modalities, such as radiotherapy or chemotherapy. After sequential PDTs, the patient achieved complete response for 2 months and partial response for 16 months, with greatly improved quality of life, despite mild skin photosensitization and acute exacerbation of chronic obstructive pulmonary disease. There was no evidence of metastasis during standard evaluation. As it was less-invasive and highly targeted, PDT might be a relatively safe and effective alternative therapy for ECLC lesions unsuitable for surgery, even lesions longer than 1.0 cm.

[Clinical and genetic analysis of four patients with congenital neutropenia].

OBJECTIVE: To delineate the clinical feature and genetic basis of four patients with congenital neutropenia. METHODS: All patients were subjected to whole exome sequencing (WES). Suspected variants were verified by Sanger sequencing. RESULTS: The patients (two boys and two girls), aged 7 to 15 months, suffered from neutropenia and recurrent infections. Bone marrow smears showed a significant decrease in the proportion of rod-shaped and lobulated granulocytes, which suggested impaired development and maturation of bone marrow neutrophils. WES has discovered heterozygous variants (c.496G>A, c.58C>G, c.391G>A and IVS1+5T>A) of the ELANE gene in the patients. Among these, c.58C>G and IVS1+5T>A were unreported previously. Follow up revealed patients 1 and 3 had periodic neutropenia, while patients 2 and 4 had severe congenital neutropenia. After attaining the definite diagnosis, the patients were treated symptomatically. CONCLUSION: The main clinical feature of congenital neutropenia is refractory recurrent bacterial infections, for which mutations of the ELANE gene are a common cause. Two novel pathogenic ELANE variants have been discovered in this study.

Sodium Butyrate Protects N2a Cells against Aß Toxicity In Vitro.

Alzheimer's disease (AD) is a common neurodegenerative disease. Aß plays an important role in the pathogenesis of AD. Sodium butyrate (NaB) is a short-chain fatty acid salt that exerts neuroprotective effects such as anti-inflammatory, antioxidant, antiapoptotic, and cognitive improvement in central nervous system diseases. The aim of this study is to research the protective effects of NaB on neurons against Aß toxicity and to uncover the underlying mechanisms. The results showed that 2 mM NaB had a significant improvement effect on Aß-induced N2a cell injury, by increasing cell viability and reducing ROS to reduce injury. In addition, by acting on the GPR109A receptor, NaB regulates the expression of AD-related genes such as APP, NEP, and BDNF. Therefore, NaB protects N2a cells from Aß-induced cell damage through activating GPR109A, which provides an innovative idea for the treatment of AD.

[Clinical applications of rigid bronchoscopy in central airway obstructions].

OBJECTIVE: Rigid bronchoscopy has expanded for therapeutic purposes lately. It has a large diameter working channel, the ability to maintain proper ventilation during operation, and the capacity to deal with massive bleeding and other complications. Our purpose was to describe the effectiveness and safety of rigid bronchoscopy in central airway stenosis. METHODS: We retrospectively analyzed all patients who had received rigid bronchoscopy for central airway obstruction in our respiratory department of this teaching hospital between December of 2008 and December of 2014. The advantages and limitations of the operations were analyzed through observing the changes of the degree of stenosis, pulmonary function, and Karnofsky performance status scale. Complications were also recorded. RESULTS: Totally 209 rigid bronchoscopic procedures were performed in 132 patients with central airway stenosis (86 men; median age, 59 years; range, 9 to 85 years), of them 68% was malignancy. The rigid bronchoscopy provided immediate relief of central airway obstruction. Tracheal obstruction was (63.3 ± 22.4)% before and (17.8 ± 16.0)% after the procedures; obstruction in the left main bronchus was (71.1 ± 23.9)% before and (27.0 ± 24.0)% after the procedures; and the right main bronchus was (73.0 ± 26.2)% before and (34.9 ± 29.8)% after the procedures, (t=21.85, 12.27, 11.17 separately, P<0.01). Spirometry revealed that FEV1 improved significantly from (1.6 ± 0.8) L before to (2.0 ± 0.8) L after the procedures. Besides, many sophisticated procedures, such as stent implantation, corrupted metal stent removing and lithotripsy were performed under rigid bronchoscopy. There were no fatal complications. CONCLUSIONS: Rigid bronchoscopy provides immediate relief of central airway obstruction and maintains proper ventilation during sophisticated intraluminal operations. It provides better visualization for advanced procedures and is an optimal selection for securing the airway in severe central airway obstruction even with respiratory failure.

[Diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration in pulmonary sarcoidosis].

OBJECTIVE: The aim of this study was to observe the diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in sarcoidosis. METHODS: We retrospectively analyzed the diagnostic efficiency of standard bronchoscopy and EBUS-TBNA in all patients diagnosed as sarcoidosis in Peking University First Hospitals between August 2010 and October 2011. The relationship between biopsy puncture numbers and sensitivity was calculated. RESULTS: There were 17 sarcoidosis patients among a total of 107 patients who had received EBUS-TBNA. Forteen patients had a positive TBNA result and the sensitive of EBUS-TBNA was 82%. The sensitivity of standard brochoscopy was 53% and when combined with EBUS-TBNA, the sensitivity increased to 88%. The sensitivity of EBUS-TBNA was associated with the size of lymph nodes. Lymph nodes with a diameter ≥ 2 cm showed a higher positive rate. Four punctures for 1 lymph node showed a concordance rate of 100% with the final results. CONCLUSIONS: EBUS-TBNA was a safe and effective method in diagnosing pulmonary sarcoidosis. For patients with suspected sarcoidosis EBUS-TBNA should be performed in the largest lymph nodes with at least 4 punctures.