The causal relationship between gut microbiota and immune skin diseases: A bidirectional Mendelian randomization.

BACKGROUND: Increasing evidence suggests that alterations in gut microbiota are associated with a variety of skin diseases. However, whether this association reflects a causal relationship remains unknown. We aimed to reveal the causal relationship between gut microbiota and skin diseases, including psoriasis, atopic dermatitis, acne, and lichen planus. METHODS: We obtained full genetic association summary data for gut microbiota, psoriasis, atopic dermatitis, acne, and lichen planus from public databases and used three methods, mainly inverse variance weighting, to analyze the causal relationships between gut microbiota and these skin diseases using bidirectional Mendelian randomization, as well as sensitivity and stability analysis of the results using multiple methods. RESULTS: The results showed that there were five associated genera in the psoriasis group, seven associated genera were obtained in the atopic dermatitis group, a total of ten associated genera in the acne group, and four associated genera in the lichen planus group. The results corrected for false discovery rate showed that Eubacteriumfissicatenagroup (P = 2.20E-04, OR = 1.24, 95%CI:1.11-1.40) and psoriasis still showed a causal relationship. In contrast, in the reverse Mendelian randomization results, there was no evidence of an association between these skin diseases and gut microbiota. CONCLUSION: We demonstrated a causal relationship between gut microbiota and immune skin diseases and provide a new therapeutic perspective for the study of immune diseases: targeted modulation of dysregulation of specific bacterial taxa to prevent and treat psoriasis, atopic dermatitis, acne, and lichen planus.

Phyllostachys nigra (Lodd. ex Lindl.) derived polysaccharide with enhanced glycolipid metabolism regulation and mice gut microbiome.

This study focuses on the characterization and regulation of glycolipid metabolism of polysaccharides derived from biomass of Phyllostachys nigra (Lodd. ex Lindl.) root (PNr). The extracts from dilute hydrochloric acid, hot water, and 2 % sodium hydroxide solution were characterized through molecular weight, gel permeation chromatography, monosaccharides, Fourier transform infrared, and nuclear magnetic resonance spectroscopy analyses. Polysaccharide from alkali extraction and molecular sieve purification (named as: PNS2A) exhibited optimal inhibitory of 3T3-L1 cellular differentiation and lowered insulin resistance. The PNS2A is made of a hemicellulose-like main chain of →4)-ß-D-Xylp-(1→ that was connected by branches of 4-O-Me-α-GlcAp-(1→, T-α-D-Galp-(1→, T-α-L-Araf-(1→, →2)-α-L-Araf-(1→, as well as ß-D-Glcp-(1→4-ß-D-Glcp-(1→ fragments. Oral delivery of PNS2A in diabetes mice brought down blood glucose and cholesterol levels and regulated glucose and lipid metabolism. PNS2A alleviated diabetes symptoms and body weight and protected liver and kidney function in model animals by altering the gut microbiome. Polysaccharides can be a new approach to develop bamboo resources.

The combination of high-throughput sequencing and LC-MS/MS reveals the mechanism of Staphylococcus inoculation on bacterial community succession and taste development during the processing of dry-cured bacon.

BACKGROUND: To understand the mechanism of co-inoculation of Staphylococcus vitulinus and Staphylococcus xylosus (SX&SV) on taste quality of dry-cured bacon, physicochemical parameters, microbial community, metabolite compositions and taste attributes were investigated during the processing of dry-cured bacon with Staphylococcus inoculation. The potential correlation between core bacteria and metabolites was evaluated, and the metabolic pathway of key metabolites was further explored. RESULTS: The values of pH, water activity and adhesiveness were significantly lower in SX&SV, and more than 2.56- and 2.15-fold higher values in richness and overall acceptance were found in SX&SV bacon than in CK bacon. The overwhelming advantage of Staphylococcus was confirmed in SX&SV by high-throughput sequencing. Sixty-six metabolites were identified by liquid chromatography-tandem mass spectrometry, and oligopeptides, amino acid derivatives and organic acids were the key components. Pearson correlation demonstrated that the accumulation of oligopeptides, amino acid derivatives and organic acids were positively correlated with high abundance of Staphylococcus. The pathways of purine metabolism, glutathione metabolism and glutamate metabolism were mainly involved in developing the taste quality of SX&SV. CONCLUSION: The co-inoculation of Staphylococcus vitulinus and Staphylococcus xylosus enhanced the taste attributes of dry-cured bacon. The present study provides the theoretical reference with respect to regulating the taste quality of fermented meat products by starter cultures of Staphylococcus during manufacture. © 2023 Society of Chemical Industry.

Different clinical characteristics and outcomes of hypertrophic cardiomyopathy with and without hypertension: seeking the truth.

OBJECTIVE: To determine the different clinical characteristics and outcomes of hypertrophic cardiomyopathy (HCM) patients with and without hypertension (HT). METHODS: A total of 696 HCM patients were included in this study and all HCM diagnoses were confirmed by the genetic test. Patients were analyzed separately in the septal reduction therapy (SRT) cohort and the non-SRT cohort. The primary endpoint was cardiovascular death and the secondary endpoint was all-cause death. Outcome analyses were conducted to evaluate the associations between HT and outcomes in HCM. Medications before enrollment and at discharge were collected in the post-hoc analyses. RESULTS: HCM patients without HT were younger, had a lower body mass index, were more likely to have a family history of HCM, and had a smaller left ventricular (LV) end-diastolic diameter than those with HT in both cohorts. A thicker LV wall, a higher level of N-terminal pro-B-type natriuretic peptide, and a higher extent of LV late gadolinium enhancement were additionally observed in patients without HT in the non-SRT cohort. The presence of HT did not alter the distribution pattern of late gadolinium enhancement, as well as the constituent ratio of eight disease-causing sarcomeric gene variants in both cohorts. Outcome analyses showed that in the non-SRT cohort, patients without HT had higher risks of cardiovascular death (HR = 2.537, P = 0.032) and all-cause death (HR = 3.309, P = 0.032). While such prognostic divergence was not observed in the SRT cohort. Further post-hoc analyses in the non-SRT cohort found that patients without HT received fewer non-dihydropyridine calcium channel blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers before enrollment and at discharge. CONCLUSIONS: HCM patients without HT had worse clinical conditions and higher mortality than patients with HT overall, which may result from active medical therapy in HT patients. Active SRT may have a substantial de-risking effect on patients meeting the indications.

The alleviative effect of flavonol-type Nrf2 activator rhamnazin from Physalis alkekengi L. var. franchetii (Mast.) Makino on pulmonary disorders.

Rhamnazin (RN) is a flavonol isolated from the calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino, which has been used for treating pulmonary diseases in traditional Chinese medicine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a therapeutic target for pulmonary diseases. In the present study, the underlying mechanism and pharmacological effect of RN against pulmonary disorders are investigated. Human lung epithelial Beas-2B cell and RAW 264.7 murine macrophage-based cell models, and a cigarette smoke (CS)-induced pulmonary impairment mice model are adopted for investigation in vitro and in vivo. RN is identified to be an Nrf2 activator, which promotes Nrf2 dissociation from Keap1 via reacting with the Cys151 cysteine residue of Keap1, and suppresses Nrf2 ubiquitination. In addition, RN is able to attenuate toxicant-stimulated oxidative stress and inflammatory response in vitro. Importantly, RN significantly relieves CS-induced oxidative insult and inflammation, and RN-induced inhibition of inflammation is related to inhibition of nuclear transcription factor-κB (NF-κB) and induction of cell autophagy. In conclusion, our data indicate that RN is an activator of the Nrf2 pathway and evidently alleviates pulmonary disorders via restricting NF-κB activation and promoting autophagy. RN is a promising candidate for the therapy of pulmonary disorders.

Value of a Machine Learning Approach for Predicting Clinical Outcomes in Young Patients With Hypertension.

Risk stratification of young patients with hypertension remains challenging. Generally, machine learning (ML) is considered a promising alternative to traditional methods for clinical predictions because it is capable of processing large amounts of complex data. We, therefore, explored the feasibility of an ML approach for predicting outcomes in young patients with hypertension and compared its performance with that of approaches now commonly used in clinical practice. Baseline clinical data and a composite end point-comprising all-cause death, acute myocardial infarction, coronary artery revascularization, new-onset heart failure, new-onset atrial fibrillation/atrial flutter, sustained ventricular tachycardia/ventricular fibrillation, peripheral artery revascularization, new-onset stroke, end-stage renal disease-were evaluated in 508 young patients with hypertension (30.83±6.17 years) who had been treated at a tertiary hospital. Construction of the ML model, which consisted of recursive feature elimination, extreme gradient boosting, and 10-fold cross-validation, was performed at the 33-month follow-up evaluation, and the model's performance was compared with that of the Cox regression and recalibrated Framingham Risk Score models. An 11-variable combination was considered most valuable for predicting outcomes using the ML approach. The C statistic for identifying patients with composite end points was 0.757 (95% CI, 0.660-0.854) for the ML model, whereas for Cox regression model and the recalibrated Framingham Risk Score model it was 0.723 (95% CI, 0.636-0.810) and 0.529 (95% CI, 0.403-0.655). The ML approach was comparable with Cox regression for determining the clinical prognosis of young patients with hypertension and was better than that of the recalibrated Framingham Risk Score model.

Steroid metabolism gene variants and their genotype-phenotype correlations in Chinese early-onset hypertension patients.

The genetic factors related to early-onset hypertension are largely unknown. This study aimed to determine the spectrum of steroid metabolism gene variants and the clinical relationships of these variants to phenotypes in Chinese patients with early-onset hypertension. A total of 306 consecutive early-onset hypertensive patients were recruited. All coding exons and flanking intronic regions of KCNJ5, CYP11B1, and CYP17A1 were sequenced. Long-distance polymerase chain reaction was used to search for a CYP11B1/CYP11B2 chimeric gene. Pedigree investigations and genotype-phenotype analyses were performed for patients with rare variants. Nine rare variants were detected in eight patients (2.6%), but no CYP11B1/CYP11B2 chimeric gene was identified. One patient and two of her siblings were found to carry compound heterozygous mutations (C183Y and T390R) in CYP17A1 and were eventually diagnosed with atypical congenital adrenal hyperplasia. Patients with rare variants had younger ages of onset [17 (16, 20) vs. 30 (23, 35) years old, p = 0.010] and higher systolic blood pressure (148.5 ± 9.6 vs. 137.9 ± 17.8 mmHg, p = 0.021) than those without rare variants. Additionally, the patients and their relatives carrying rare variants exhibited increased serum free corticosterone [230.4 (7.4, 533.0) vs. 1.9 (0.9, 6.7)ng/ml, p = 0.001] and 11-deoxycorticosterone [16.16 (0.59, 33.23) vs. 0.77 (0.41, 0.96)ng/ml, p = 0.038] levels. Genetic testing is useful for the etiologic diagnosis of early-onset hypertension. Rare variants in steroid metabolism genes were associated with more severe clinical expression and abnormal circulating steroid metabolites in patients with early-onset hypertension.

Cardiovascular risk in primary aldosteronism: A systematic review and meta-analysis.

AIM: This study aimed to evaluate whether the increased cardiovascular risk and the incidence of cerebrovascular (CCV) events in hypertensive patients were related to primary aldosteronism (PA). METHODS: The PubMed, EmBase, and the Cochrane Central Register of Controlled Trials were searched to evaluate the risk of CCV in PA patients and compared to essential hypertension (EH) patients. The mean differences (MD) and the risk ratios (RR) were calculated to assess the risk of main outcomes, such as stroke, coronary artery disease, left ventricular hypertrophy (LVH), levels of systolic blood pressure (SBP), diastolic blood pressure (DBP), blood glucose, and urinary potassium. RESULTS: We identified 31 individual studies including 4546 patients in PA group and 52,284 patients in EH group. Our results revealed that PA was significantly associated with increased risk of stroke (RR=2.03, 95% CI = 1.71-2.39, Pheterogeneity = .331, I = 12.7%), coronary artery disease (RR = 1.67, 95% CI = 1.23-2.25, Pheterogeneity = .043, I = 48.3%), and LVH (RR = 1.54, 95% CI = 1.29-1.83, Pheterogeneity = .004, I = 62.6%) when compared with those in the EH group. Moreover, PA group had significantly increased levels of SBP (WMD = 4.14, 95% CI = 2.60-5.68, Pheterogeneity < .001, I = 84.3%), DBP (WMD = 2.65, 95% CI = 1.83-3.47, Pheterogeneity < .001, I = 77.7%), and urinary potassium (SMD = 0.04, 95% CI = -0.03-0.11, Pheterogeneity = .827, I = 0%) when compared to EH group. However, no significant difference was observed in the levels of blood glucose between the groups. CONCLUSIONS: These findings suggested that PA significantly increased the risk of cardiac and cerebrovascular complications. In addition, patients with PA might benefit from a periodic assessment of CCV risk.

Artocarmitin B enhances intracellular antioxidant capacity via activation of Nrf2 signaling pathway in human lung epithelial cells.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in redox homeostasis. Activation of Nrf2 pathway by natural molecules effectively inhibits oxidants and toxicants-induced redox imbalance, and thus is able to intervene the onset and progression of many human diseases. In our previous study, a chalcone named as artocarmitin B (ACB), formed by artocarmitin A (ACA) and a trans-feruloyl substituent, was found to be a potential Nrf2 activator. In the present research, we found that ACB up-regulated the expressions of Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase, modifier subunit (GCLM), inhibited Nrf2 degradation and promoted Nrf2 translocation to the nucleus under non-toxic doses. Moreover, ACB enhanced intracellular antioxidant capability in human lung epithelial cells through up-regulating reduced glutathione (GSH) level. Furthermore, ACB-induced activation of Nrf2 was related to the kinase pathways, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and protein kinase R-like endoplasmic reticulum kinase (PERK). In terms of activation of Nrf2 pathway, ACB was more potent than ACA and ferulic acid (FA) individually or in combination. Collectively, our results indicate that ACB is an novel Nrf2 activator and enhances intracellular antioxidant capacity in human lung epithelial cells.

SIRT6 abrogation promotes adrenocortical carcinoma through activation of NF-κB signaling.

As an uncommon malignancy in the adrenal gland, adrenocortical carcinoma (ACC) is characterized by thorny diagnosis and poor clinical outcome, necessitating innovative treatment strategies. Sirtuin 6 (SIRT6), a tumor suppressor, modulates aerobic glycolysis of malignant cells and has an impact on tumorigenesis. This study focused on investigating SIRT6 expression in ACC and how it generates cancer phenotypes. SIRT6 expression was inhibited in ACC tissues according to western blotting, real-time polymerase chain reaction, and immunohistochemistry. MTT assay, TUNEL assay, and flow cytometry were performed to evaluate the contribution of SIRT6 to cell invasion, proliferation, death, and migration. It was shown that SIRT6 knockdown promoted cell invasion, proliferation, and migration, and inhibited cell death. Moreover, it was found that SIRT6 knockdown upregulated TLR4 and reinforced phosphorylation of the nuclear transcription factor-kappa B (NF-κB) subunit p65 as well as inhibitor of nuclear factor kappa-B kinase. Additionally, SIRT6 knockdown significantly enhanced expression of calcitonin gene-related peptide as well as transient receptor potential vanilloid subtype 1. It also reinforced reactive oxygen species generation. Overall, our research findings demonstrate that SIRT6 serves as a tumor suppressor via regulation of the NF-κB pathway, which could offer an innovative strategy to treat ACC.

Lignan and flavonoid support the prevention of cinnamon against oxidative stress related diseases.

BACKGROUND: Oxidative stress contributes to the pathogenesis of many human diseases. Cinnamon is a worldwide used spice, dietary supplement and traditional medicine, and is used for the therapy of oxidative stress related diseases. A well-established concept is that the functions of cinnamon preventing oxidative stress-induced diseases are attributed to the occurrence of cinnamaldehyde and its analogues. HYPOTHESIS: In our continuous searching of natural molecules with antioxidant capacity, we have found that cinnamaldehyde and its analogues in cinnamon are weak inhibitors of oxidative stress, and thus we speculate that there are novel and/or potent molecules inhibiting oxidative stress in cinnamon. STUDY DESIGN AND METHODS: A systemic phytochemical investigation of cinnamon using column chromatography was performed to identify the chemical constituents of cinnamon, and then their capacity of inhibiting oxidative stress and action of mechanism targeting Nrf2 pathway were investigated using diverse bioassay, including NAD(P)H: quinone reductase (QR) assay, immunoblot analysis, luciferase reporter gene assay, immunofluorescence and flow cytometry. RESULTS: Cinnamon improved the intracellular antioxidant capacity. A systemic phytochemical investigation of cinnamon gave the isolation of twenty-two chemical ingredients. The purified constituents were tested for their potential inhibitory effects against oxidative stress. Besides cinnamaldehyde analogues, a lignan pinoresinol (PRO) and a flavonol (-)-(2R,3R)-5,7-dimethoxy-3', 4'-methylenedioxy-flavan-3-ol (MFO) were firstly identified to be inhibitors of oxidative stress. Further study indicated that PRO and MFO activated Nrf2-mediated antioxidant response, and protected human lung epithelial cells against sodium arsenite [As(III)]-induced oxidative insults. CONCLUSION: The lignan PRO and the flavonoid MFO are two novel Nrf2 activators protecting tissues against oxidative insults, and these two constituents support the application of cinnamon as an agent against oxidative stress related diseases.

Protective effect of the ethanol extract from Ligusticum chuanxiong rhizome against streptozotocin-induced diabetic nephropathy in mice.

ETHNOPHARMACOLOGY RELEVANCE: Rhizome of Ligusticum chuanxiong Hort. (Abbreviated as LC) is a frequently prescribed component in plenty of traditional Chinese medicine (TCM) formulas which are used to treat diabetic nephropathy (DN). The aims of the present study are to investigate the protective effect of the ethanol extract of LC rhizome (EEL) against DN in vivo, evaluate its potential mechanism, and find the evidence supporting its enthopharmacological use as an anti-DN agent. MATERIALS AND METHODS: Hepa 1c1c7 murine hepatoma cells, human breast carcinoma MDA-MB-231 cells, human renal glomerular endothelial cells (HRGEC), and RAW 264.7 murine macrophages were adopted to test the effects of EEL and its active constituents on inhibitions of oxidative stress and inflammation in vitro. A streptozotocin (STZ) -induced DN C57BL/6 mice model was established and used to investigate the preventive effect of EEL against DN in vivo. RESULTS: EEL demonstrated potential inhibitory effects against oxidative stress and inflammation in vitro. Using a STZ-induced DN mice model, it has been found that EEL treatment significantly prevented STZ-induced increases of urine production, urinary albumin excretion (UAE) and urine albumin-to-creatinine ratio (UACR), and markedly attenuated STZ-induced renal damages (e.g. glomerulosclerosis and fibrosis). The predominant bioactive constituents, Z-ligustilide (LGT), ferulic acid (FA), and tetramethylpyrazine (TMP), were inhibitors of oxidative stress and inflammation through acting with Nrf2 and NF-κB pathways. CONCLUSIONS: EEL attenuates structural and functional damages of kidney in STZ-induced DN model in vivo, which might be related to the functions of EEL on inhibitions of oxidative stress and inflammation. These finding definitely supports the ethnopharmacological use of LC as an anti-DN agent.

Clerodane diterpenoids from the Chinese liverwort Jamesoniella autumnalis and their anti-inflammatory activity.

Nine previously undescribed clerodane-type diterpenoids, jamesoniellides M-T and one ent-labdane-type diterpenoid, as well as one known analogue, were isolated from the Chinese liverwort Jamesoniella autumnalis (DC.) Stephani. Their structures were determined using MS, NMR spectroscopy, and electronic circular dichroism (ECD) calculations. Inhibition on LPS-induced NO production in RAW 264.7 murine macrophages was investigated, and the results showed that jamesoniellides Q-S exhibited moderate anti-inflammatory activity, with 50-80% maximum inhibition rate of NO production under the nontoxic tested concentration.

Analysis of the genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients.

BACKGROUND: The study aimed to analyze genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. METHODS: A panel of nine genes, namely SCNN1B, SCNN1G, WNK1, WNK4, KLHL3, CUL3, nuclear receptor subfamily 3, group C (NR3C)1, NR3C2, and HSD11B2 were screened by targeted resequencing in 260 Chinese early-onset hypertensive patients. Additionally, exon 13 of both SCNN1B and SCNN1G was sequenced in an independent cohort of 506 Chinese early-onset hypertensive patients. RESULTS: About 81 nonrare and 41 rare variants were, respectively, detected in 221 (85.0%) and 39 (15.0%) patients from the cohort of 260. Of the total 766 patients, those with rare variants in exon 13 of either SCNN1B or SCNN1G had a significantly earlier onset of hypertension (24.7 ±â€Š7.5 vs. 29.0 ±â€Š7.7 years, P = 0.015) and lower serum potassium (3.57 ±â€Š0.59 vs. 3.96 ±â€Š0.41 mmol/l, P = 0.007) than those without rare variants. However, other identified rare variants had no effects on clinical expression. Seven patients (0.91%) were diagnosed with Liddle's syndrome, and the Liddle's syndrome prevalence was 1.72% among the 407 patients with hypertension diagnosed before the age of 30. Genetic screening of the probands' relatives identified 10 additional Liddle's syndrome patients. Treatment of Liddle's syndrome patients with amiloride resulted in normalization of both blood pressure and serum potassium. CONCLUSION: Liddle's syndrome appears to be the most common low-renin Mendelian hypertension in young Chinese hypertensive patients. Sequencing exon 13 of both SCNN1B and SCNN1G is highly advisable in patients with early-onset and low-renin hypertension.

Cytomegalovirus infection in patients with lupus nephritis: clinical and laboratory features and therapeutic considerations.

To better clarify the clinical features and therapeutic strategy of CMV infection in lupus nephritis patients, we retrospectively surveyed a total of 40 lupus nephritis patients, who had been hospitalized and underwent renal biopsy and diagnosed as having CMV infection during their hospitalization at our institution within the last 10 years. The percentage of CMV infections in the entire hospitalized lupus nephritis population was 5.3% (40/755). The principal clinical features of the 40 CMV-infected patients were hematological disorders (n = 25), fever (n = 21), liver dysfunction (n = 19), and respiratory symptoms (n = 12). Active SLE (SLEDAI 16 ± 5), hypertriglyceridemia (3.16 ± 2.57 mmol/L), and a history of potent immunosuppressive therapy were commonly observed in this patient group. There were no significant differences of SLEDAI (P = 0.290), proteinuria (P = 0.065), hematuria (P = 0.497), CLCR (P = 0.463), and the distribution of histopathologic classes between patients with symptomatic and asymptomatic infection. Ganciclovir was administered in 33 cases; in patients with symptomatic infection, the improvement in CMV symptoms was not observed until ganciclovir was administered, while in asymptomatic patients, no treatment benefit was observed as for survival, the duration of hospital stays, and the number of patients who progressed from asymptomatic to symptomatic infection. In conclusion, CMV infection is not rare in lupus nephritis patients. SLE activity and renal clinical and pathological features between patients with symptomatic and asymptomatic infection are of no significant difference. Although therapy consensus guideline is still lacking, we observed no treatment benefit for the asymptomatic patients.

[Impacts of numerology on acupuncture].

Numerology has a long history in China and has the profound impacts on every academic field in TCM, with acupuncture involved. In this paper, the impacts on acupuncture were discussed in different aspects such as the numbers of meridians, the length of meridian, the time taboo of acupuncture, acupuncture manipulation and time acupuncture. It was found that numerology had laid the critical impact on acupuncture and had the profound imprint nowadays. It is of great significance to study the numerology theory in its impacts on acupuncture, in the exploration on the theories behind acupuncture as well as the comprehensive understanding of acupuncture.