Trace elements and Alzheimer dementia in population-based studies: A bibliometric and meta-analysis.

Alterations in the concentrations of trace elements may play a vital role in Alzheimer dementia progression. However, previous research results are inconsistent, and there is still a lack of review on the relationship between all the studied-trace elements and AD from various perspectives of population-based studies. In this study, we systematically reviewed previous population-based studies and identified the altered trace elements in AD patients. We searched the Web of Science Core Collection, PubMed, and Scopus database, and ultimately included 73 articles. A bibliometric analysis was conducted to explore the evolution of the field from an epidemiological perspective. Bibliometric data such as trace elements, biological materials, detection methods, cognitive tests, co-occurrence and co-citation statistics are all analyzed and presented in a quantitative manner. The 73 included studies analyzed 39 trace elements in total. In a further meta-analysis, standardized mean differences (SMDs) of 13 elements were calculated to evaluate their altered in AD patients, including copper, iron, zinc, selenium, manganese, lead, aluminum, cadmium, chromium, arsenic, mercury, cobalt, and manganese. We identified four trace elements-copper (serum), iron (plasma), zinc (hair), and selenium (plasma)-altered in AD patients, with SMDs of 0.37 (95% confidence interval [CI]: 0.10, 0.65), -0.68 (95% CI: -1.34, -0.02), -0.35 (95% CI: -0.62, -0.08), and -0.61 (95% CI: -0.97, -0.25), respectively. Finally, we formed a database of various trace element levels in AD patients and healthy controls. Our study can help future researchers gain a comprehensive understanding of the advancements in the field, and our results provide comprehensive population-based data for future research.

Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. Objective: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. Design, Setting, and Participants: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. Interventions: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. Main Outcomes and Measures: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. Results: In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. Conclusions and Relevance: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). Trial Registration: ClinicalTrials.gov Identifier: NCT01898923.

Biodegradable hollow mesoporous organosilica nanotheranostics (HMON) for multi-mode imaging and mild photo-therapeutic-induced mitochondrial damage on gastric cancer.

BACKGROUND: CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells' apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells' mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd). RESULTS: HMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, L-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43-45 °C) and PDT under mild NIR power density (0.8 W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo. CONCLUSION: HMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.

Synergistic Effect of Rhamnolipids and Inoculation on the Bioremediation of Petroleum-Contaminated Soils by Bacterial Consortia.

Crude oil is a serious soil pollutant, requiring large-scale remediation efforts. Bacterial consortia in combination with rhamnolipids can be an effective bioremediation method. However, the underlying mechanisms and associated changes in soil bacterial composition remain uncharacterized. Therefore, this study sought to evaluate the effectiveness of rhamnolipids in petroleum hydrocarbon removal, and the associated bacterial community dynamics during bioremediation of petroleum-contaminated soils. Contaminated soils were subjected to natural attenuation, bioremediation with rhamnolipids, bioremediation with bacterial consortia, or bioremediation with bacterial consortia supplemented with rhamnolipids (BMR). High-throughput sequencing of bacterial sample partial 16S rRNA sequences was performed. Additionally, the n-alkanes and aromatic fractions were analyzed by gas chromatography-mass spectroscopy. The results showed that rhamnolipid supplementation increased the rate and extent of total petroleum hydrocarbon biodegradation to a maximum of 81% within 35 days. Further, phylogenetic analysis revealed that the bacterial community was composed of 14 phylotypes (similarity level = 97%). Actinobacteria and Proteobacteria were the two core phyla in all samples, accounting for 63-89%, but Proteobacteria was the most dominant phylum in the BMR sample (~ 53%). Among the top 20 genera, Pseudomonas, Pseudoxanthomonas, Cavicella, Mycobacterium, Rhizobium, and Acinetobacter were more abundant in BMR samples compared to other samples. Predicted functional profiles revealed that rhamnolipid addition also induced changes in gene abundance related to hydrocarbon metabolic pathways. This study provided comprehensive insights into the synergistic effect of rhamnolipids and bacterial consortia for altering bacterial populations and specific functional traits, which may serve to improve bacteria-mediated petroleum hydrocarbon biodegradation in contaminated soils.

Rational Design of Short Peptide Variants by Using Kunitzin-RE, an Amphibian-Derived Bioactivity Peptide, for Acquired Potent Broad-Spectrum Antimicrobial and Improved Therapeutic Potential of Commensalism Coinfection of Pathogens.

Commensalism coinfection of pathogens has seriously jeopardized human health. Currently, Kunitzin-RE, as an amphibian-derived bioactivity peptide, is regarded as a potential antimicrobial candidate. However, its antimicrobial properties were unsatisfactory. In this study, a set of shortened variants of Kunitzin-RE was developed by the interception of a peptide fragment and single-site mutation to investigate the effect of chain length, positive charge, hydrophobicity, amphipathicity, and secondary structure on antimicrobial properties. Among them, W8 (AARIILRWRFR) significantly broadened the antimicrobial spectrum and showed the highest antimicrobial activity (GMall = 2.48 µM) against all the fungi and bacteria tested. Additionally, W8 showed high cell selectivity and salt tolerance in vitro, whereas it showed high effectiveness against mice keratitis cause by infection by C. albicans 2.2086. Additionally, it also had obviously lipopolysaccharide-binding ability and a potent membrane-disruptive mechanism. Overall, these findings contributed to the design of short antimicrobial peptides and to combat the serious threat of commensalism coinfection of pathogens.

Glycosylation and an amino acid insertion in the head of hemagglutinin independently affect the antigenic properties of H5N1 avian influenza viruses.

Antigenic drift forces us to frequently update influenza vaccines; however, the genetic basis for antigenic variation remains largely unknown. In this study, we used clade 7.2 H5 viruses as models to explore the molecular determinants of influenza virus antigenic variation. We generated eight monoclonal antibodies (MAbs) targeted to the hemagglutinin (HA) protein of the index virus A/chicken/Shanxi/2/2006 and found that two representative antigenically drifted clade 7.2 viruses did not react with six of the eight MAbs. The E131N mutation and insertion of leucine at position 134 in the HA protein of the antigenically drifted strains eliminated the reactivity of the virus with the MAbs. We also found that the amino acid N131 in the H5 HA protein is glycosylated. Our results provide experimental evidence that glycosylation and an amino acid insertion or deletion in HA influence antigenic variation.

Favorable surgical outcomes of aldosterone-producing adenoma based on lateralization by CT imaging and hypokalemia: a non-AVS-based strategy.

PURPOSE: To test the efficacy of a strategy based on CT imaging and clinical characteristics on lateralizing origin of excess aldosterone secretion in primary aldosteronism. PATIENTS AND METHODS: Consecutive patients with diagnosed primary hyperaldosteronism from June 2006 to July 2012 in our center underwent adrenal surgeries without pre-operational adrenal venous sampling (AVS) if all the three criteria were met: (1) round- or oval-shaped occupational lesion of low density after contrast enhancement with diameter >1 cm on CT scan was located in one adrenal gland; (2) unequivocally normal contralateral adrenal gland; (3) serum potassium level lower than 3.5 mmol/L. Subjects who had received operation were taken into analysis and follow-ups. RESULTS: One hundred and twenty-five patients fulfilled the criteria and were recruited into our research. One hundred and twenty-two operated patients (97.6%) experienced complete resolution of hypokalemia as well as resolution or improvement in hypertension with reduction in antihypertensive medication, while 3 patients (2.4%) failed to obtain normal kalemia and continued on spironolactone therapy. At a median of 65-month (range 21-93) follow-up of these 122 subjects, 27 patients dropped out (22.1%). The 95 responding patients reported no episodes of paralysis or confirmed hypokalemia or any supplementation of potassium. Multivariate linear correlation analysis showed that plasma potassium level was correlated inversely with tumor diameter (r = -0.258, 95% CI -0.076, -0.514, p = 0.037) and basal plasma aldosterone level (r = -0.251, 95% CI -0.040, -0.464, p = 0.042). CONCLUSIONS: Most patients with typical unilateral adrenal macroadenomas, normal contralateral glands and hypokalemia could attain favorable surgical therapeutic outcomes without pre-operational AVS lateralization.

New insights into the effects and mechanism of a classic traditional Chinese medicinal formula on influenza prevention.

BACKGROUND: KangBingDu (KBD) is a classic traditional Chinese medicinal formula widely used to treat influenza. However, little information is available from controlled studies regarding the anti-influenza pharmacological activities of KBD and its underlying mechanisms, at least partly due to the lack of appropriate study models. PURPOSE: We hypothesized that KBD might provide a protection against influenza infection by reducing the host's susceptibility to viruses. To prove it, mouse restraint stress model was employed. METHODS: Mice were restricted and infected with influenza virus. KBD (13 and 26mg/kg/d) was orally administrated to mice from the first day of restraint stress and lasted for 7 days (twice a day). Mice were monitored daily for morbidity, symptom severity, and mortality for 21 days. The histopathologic changes were examined. For the study of mechanisms of action, we investigated whether KBD could promote mitochondria antiviral signaling protein (MAVS)-mediated antiviral signal and inhibit nuclear factor-kappa B (NF-κB)-mediated inflammation response. RESULTS: KBD significantly decreased the susceptibility of restraint mice to influenza virus, as evidenced by lowered mortality, attenuated inflammation and reduced viral replications in lungs. Further results revealed that KBD elevated the protein expression of MAVS, which subsequently increased the IFN-ß and IFITM3 protein levels, thereby helping to fight viral infections. Finally, we identified that (R,S)-goitrin, mangiferin, forsythin and forsythoside A were effective components in KBD against influenza viral infections. CONCLUSION: KBD can reduce the susceptibility to influenza virus via mitochondrial antiviral signaling.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aß Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing ß-amyloid (Aß) peptide, a cleaved fragment of amyloid precursor protein (APP) via ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aß level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Daidzein and genistein fail to improve glycemic control and insulin sensitivity in Chinese women with impaired glucose regulation: A double-blind, randomized, placebo-controlled trial.

SCOPE: This randomized, double-blind, and placebo-controlled trial evaluated the effect of isolated daidzein and genistein on glycemic control and insulin sensitivity in 165 Chinese women aged 30-70 with impaired glucose regulation (IGR). METHODS AND RESULTS: Participants were randomly assigned to one of three groups with a daily dose of 10 g of soy protein plus (i) no addition, (ii) 50 mg of daidzein, or (iii) 50 mg of genistein for 24 wk. Fasting glucose (FG), insulin, and glycosylated hemoglobin (HbA1c ), and glucose concentrations at 30, 60, 120, and 180 min and insulin concentrations at 30, 60, and 120 min after an oral 75-g glucose tolerance test were assessed at baseline and at 12 and 24 wk postintervention. a total of 158 and 151 subjects completed the measures at wk 12 and 24, respectively. There were no significant differences in the changes (%) of FG and the 2-h glucose, HbA1c , fasting, and 2-h insulin or the area under the curve of glucose and insulin between the three treatment groups at wk 12 or 24 (all p > 0.05). CONCLUSION: Neither isolated daidzein nor genistein has a significant effect on glycemic control and insulin sensitivity in Chinese women with IGR over a 6-month supplementation period.

Adverse effect of metformin therapy on serum vitamin B12 and folate: short-term treatment causes disadvantages?

Diabetes is a global public health challenge that imposes heavy burdens on communities and individuals. Metformin, the first-line medication for diabetes, has the superiority of reducing risk of macrovascular diseases, all-cause mortality and even possibly cancers. Recent observational studies, however, have demonstrated that long-term metformin therapy increases the probability of vitamin B12 and folate deficiency, and might contribute to the progression of diabetic peripheral neuropathy. Despite metformin is widely used and extensively studied, randomized controlled trials performed to explore the effects of metformin on vitamin B12 and folate are limited. Besides, whether short-term treatment causes vitamin deficiency is a pending issue. We postulate that even a few-month treatment with metformin results in the decrease of vitamin B12 and folate. However, supplementation of vitamin B12 rather than the combination of vitamin B12 and folate might be profitable based on the mechanism of metformin on vitamins in patients with type 2 diabetes. This viewpoint differs from those of majority that a combined supplementation of vitamin B12 and folate is inclined to be advised.

Impact of vitamin D on chronic kidney diseases in non-dialysis patients: a meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES: Recent studies have supported a role for both newer and more established vitamin D compounds in improving proteinuria, although systematic evaluation is lacking. Furthermore, concerns remain regarding the influence of vitamin D on the progression of renal function. We analyzed the efficacy and safety of vitamin D in non-dialysis patients and compared the use of newer versus established vitamin D compounds by performing a meta-analysis of randomized controlled trials. DESIGN: A literature search of PubMed (1975 to September, 2012), EMBASE.com (1966 to September, 2012) and Ovid EBM Reviews (through September, 2012) was conducted. RESULTS: Eighteen studies were eligible for final inclusion; of these, six explored the effects of vitamin D on proteinuria, twelve studied the effects of supplementation on renal function, and fifteen discussed the incidence of hypercalcemia. Compared to the placebo or no interference, both the newer and established vitamin D sterols reduced proteinuria to a similar extent (RR, 2.00; 95% CI, 1.42 to 2.81). No decrease in the glomerular filter rate was observed (SMD, -0.10; 95%CI, -0.24 to 0.03), and the risk for dialysis initiation was 1.48 (95% CI, 0.54 to 4.03) with vitamin D treatment. Additionally, there was an increased risk of hypercalcemia for patients treated with either newer or established vitamin D compounds as compared with the controls (RR, 4.78; 95% CI, 2.20 to 10.37). The head-to-head studies showed no differences in the effects of either newer or established compounds on proteinuria or the risk of hypercalcemia. No serious adverse events were associated with the administration of vitamin D. CONCLUSIONS: Vitamin D therapy appears to decrease proteinuria and have no negative influence on renal function in non-dialysis patients. But the occurrence of hypercalcemia should be evaluated when vitamin D is provided. No superiority for newer versus established vitamin D analogue is found.

Fufang Xue Shuan Tong capsules inhibit renal oxidative stress markers and indices of nephropathy in diabetic rats.

Fufang Xue Shuan Tong (FXST) capsules, a traditional Chinese medicine, have been used to treat diabetic nephropathy for many years. FXST has been shown to attenuate elevated levels of oxidative stress in the retina of diabetic rats. However, whether FXST protects kidneys through the same mechanism(s) remains unclear. In this study, diabetes was induced in rats by administration of a high-fat diet and low-dose streptozotocin. Rats were administered low (450 mg/kg/day), middle (900 mg/kg/day) or high (1800 mg/kg/day) doses of FXST orally for 3 months. Another group was administered 50 mg/kg/day orally for the same period. The results indicated that all doses of FXST reduced urinary protein excretion and creatinine clearance and ameliorated the diabetic nephropathy-related mesangial matrix expansion. However, only middle and high doses of FXST prevented glomerular hypertrophy in diabetic rats, and the high dose showed the greatest inhibitory effect with regard to mesangial matrix expansion. Furthermore, superoxide dismutase activities were significantly elevated, whereas malondialdehyde levels were significantly reduced in the renal cortex following FXST treatment. The kidney-protective role of FXST is not inferior to that of captopril, one of the most commonly used drugs for the treatment of diabetic nephropathy. In conclusion, FXST retards the progression of diabetic nephropathy, while high-dose FXST shows the most prominent effect in counteracting the pathological changes of diabetic nephropathy. The renoprotective action of FXST is induced by the reduction of oxidative stress in diabetic nephropathy.

[Study on the optimal extaction of total flavonoids from Tagetes erecta by central composite design-response surface methodology].

OBJECTIVE: To optimize the process of extracting total flavonoids from Tagetes erecta. METHODS: The influential factors were extraction temperature, ethanol concentration, reflux time and solvent volume fold. The evaluating indicator was the extraction rate of total flavonoids from Tagetes erecta. The central composite design-response surface methodology was used to optimize the process and the prediction was carried out. RESULTS: The optimum conditions of extraction were 80% ethanol, 2.5 hours for reflux, 35 volume folds of solvent and 70 degrees C. CONCLUSION: It shows that the optimum model is simple and highly predictive.