The efficacy and safety of Bazi Bushen Capsule in treating premature aging: A randomized, double blind, multicenter, placebo-controlled clinical trial.

PURPOSE: It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. STUDY DESIGN AND METHODS: It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30-78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test-grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. RESULTS: After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. CONCLUSIONS: BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. TRIAL REGISTRY: https://www.chictr.org.cn/showproj.html?proj=166181.

Integrated network pharmacology and molecular docking analyses of the mechanisms underlying the antihypertensive effects of lotusine.

Hypertension is a modifiable cardiovascular risk factor and cause of death worldwide. Lotusine, an alkaloid extracted from a plant used in traditional Chinese Medicine, has shown anti-hypertensive effects. However, its therapeutic efficacy requires further investigation. We adopted integrated network pharmacology and molecular docking approaches with the aim of investigating lotusine's antihypertensive effects and mechanisms of action in rat models. After identifying the optimal intravenous dosage, we observed the effects of lotusine administration on two-kidney, one-clip (2K1C) rats and spontaneously hypertensive rats (SHRs). Based on network pharmacology and molecular docking analyses, we measured renal sympathetic nerve activity (RSNA) to evaluate lotusine's effect. Finally, an abdominal aortic coarctation (AAC) model was established to evaluate lotusine's long-term effects. The network pharmacology analysis identified 21 intersection targets; of these, 17 were also implicated by the neuroactive live receiver interaction. Further integrated analysis showed high lotusine affinity for the cholinergic receptor nicotinic alpha 2 subunit, adrenoceptor beta 2, and adrenoceptor alpha 1B. Blood pressure of the 2K1C rats and SHRs decreased after treatment with 2.0 and 4.0 mg/kg of lotusine (P < 0.001 versus saline control). We also observed RSNA decreases consistent with the network pharmacology and molecular docking analysis results. Results from the AAC rat model indicated that myocardial hypertrophy was decreased with lotusine administration, demonstrated by echocardiography and hematoxylin and eosin and Masson staining. This study provides insights into the antihypertensive effects and underlying mechanisms of lotusine; lotusine may exert long-term protective effects against myocardial hypertrophy caused by elevated blood pressure.

Citalopram in the treatment of elderly chronic heart failure combined with depression: A systematic review and meta-analysis.

Background: Depression is an independent factor to predict the hospitalization and mortality in the chronic HF patients. Citalopram is known as an effective drug for depression treatment. Currently, there is no specific recommendation in the HF guidelines for the treatment of psychological comorbidity. In recent years, many studies have shown that the citalopram may be safe in treating of chronic HF with depression. Objective: To evaluate the efficacy and safety of the citalopram in the treatment of elderly chronic HF combined with depression. Methods: PubMed, EMBASE, Cochrane, Web of Science, CNKI, VIP, CBM, and Wanfang were searched from their inception to May 2022. In the treatment of elderly chronic HF combined with depression, randomized controlled studies of the citalopram were included. Independent screening and extraction of data information were conducted by two researchers, and the quality was assessed by the Cochrane bias risk assessment tool. Review manager 5.4.1 was employed for statistical analysis. Results: The results of meta-analysis prove that the citalopram treatment for depressed patients with chronic HF has a benefit for HAMD-24 (MD: -8.51, 95% CI: -10.15 to -6.88) and LVEF (MD: 2.42, 95% CI: 0.51 to 4.33). Moreover, the score of GDS decreases, and NT-proBNP (MD: -537.78, 95% CI: -718.03 to -357.54) is improved. However, the comparison with the control group indicates that there is no good effect on HAMD-17 (MD: -5.14, 95% CI: -11.60 to 1.32), MADRS (MD: -1.57, 95% CI: -3.47 to 0.32) and LVEDD (MD: -1.45, 95% CI: -3.65 to -0.76). No obvious adverse drug reactions were observed. Conclusion: Citalopram treatment for depressed patients with chronic HF has a positive effect on LVEF and NT-proBNP. It can alleviate HAMD-24 and GDS, but the relative benefits for LVEDD, HAMD-17 and MADRS still need to be verified.Systematic Review Registration: PROSPERO [CRD42021289917].

Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis.

Subendothelial macrophage internalization of modified lipids and foam cell formation are hallmarks of atherosclerosis. Deubiquitinating enzymes (DUBs) are involved in various cellular activities; however, their role in foam cell formation is not fully understood. Here, using a loss-of-function lipid accumulation screening, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a factor that suppressed lipid uptake in macrophages. We found that USP9X expression in lesional macrophages was reduced during atherosclerosis development in both humans and rodents. Atherosclerotic lesions from macrophage USP9X-deficient mice showed increased macrophage infiltration, lipid deposition, and necrotic core content than control apolipoprotein E-KO (Apoe-/-) mice. Additionally, loss-of-function USP9X exacerbated lipid uptake, foam cell formation, and inflammatory responses in macrophages. Mechanistically, the class A1 scavenger receptor (SR-A1) was identified as a USP9X substrate that removed the K63 polyubiquitin chain at the K27 site. Genetic or pharmacological inhibition of USP9X increased SR-A1 cell surface internalization after binding of oxidized LDL (ox-LDL). The K27R mutation of SR-A1 dramatically attenuated basal and USP9X knockdown-induced ox-LDL uptake. Moreover, blocking binding of USP9X to SR-A1 with a cell-penetrating peptide exacerbated foam cell formation and atherosclerosis. In this study, we identified macrophage USP9X as a beneficial regulator of atherosclerosis and revealed the specific mechanisms for the development of potential therapeutic strategies for atherosclerosis.

Acarbose for Postprandial Hypotension With Glucose Metabolism Disorders: A Systematic Review and Meta-Analysis.

Background: Postprandial hypotension (PPH) is an independent predictive factor of all-cause mortality in older people. Drug management has not achieved a satisfactory effect yet. In recent years, many studies have found that acarbose may be effective in the treatment of PPH with glucose metabolism disorders. Objective: To assess the efficacy and safety of acarbose on PPH with glucose metabolism disorders. Methods: PubMed (MEDLINE), Cochrane, EMBASE, Web of Science, Clinical Trials, and relevant Chinese databases were searched from inception to October 1, 2020. Randomized controlled studies of acarbose in the treatment of PPH with glucose metabolism disorders were included. Review Manager 5.3 software was used for quality evaluation and meta-analysis. GRADEpro GDT software was used to GRADE the evidence for the research objectives. Results: A total of 4 randomized controlled studies including 202 participants were identified after screening. The meta-analysis showed that acarbose significantly attenuated the decrease in postprandial systolic blood pressure [weighted mean difference (MD): -9.84, 95% CI: -13.34 to -6.33], diastolic blood pressure (MD: -6.86, 95% CI: -12.89 to -0.83), and mean arterial pressure (MD: -8.10, 95% CI: -12.40 to -3.49) compared with the control group. One study reported a case of adverse reactions that included mild abdominal distension in the acarbose group (4.8%, 1/21). No adverse reactions were reported in the other three studies. Conclusion: Acarbose may attenuate the decrease in postprandial blood pressure and avoid the occurrence of PPH in patients with PPH and abnormal glucose metabolism disorders. More clinical trials are needed to make a clear conclusion. Registration: PROSPERO CRD42020171335.

Cold-induced Yes-associated-protein expression through miR-429 mediates the browning of white adipose tissue.

Targeting the white-to-brown fat conversion is important for developing potential strategies to counteract metabolic diseases; yet the mechanisms are not fully understood. Yes-associated-protein (YAP), a transcription co-activator, was demonstrated to regulate adipose tissue functions; however, its effects on browning of subcutaneous white adipose tissue (sWAT) are unclear. We demonstrated that YAP was highly expressed in cold-induced beige fat. Mechanistically, YAP was found as a target gene of miR-429, which downregulated YAP expression in vivo and in vitro. In addition, miR-429 level was decreased in cold-induced beige fat. Additionally, pharmacological inhibition of the interaction between YAP and transcriptional enhanced associate domains by verteporfin dampened the browning of sWAT. Although adipose tissue-specific YAP overexpression increased energy expenditure with increased basal uncoupling protein 1 expression, it had no additional effects on the browning of sWAT in young mice. However, we found age-related impairment of sWAT browning along with decreased YAP expression. Under these circumstances, YAP overexpression significantly improved the impaired WAT browning in middle-aged mice. In conclusion, YAP as a regulator of sWAT browning, was upregulated by lowering miR-429 level in cold-induced beige fat. Targeting the miR-429-YAP pathway could be exploited for therapeutic strategies for age-related impairment of sWAT browning.

Traditional Chinese Medicine for Essential Hypertension: A Clinical Evidence Map.

We systematically retrieved and summarised clinical studies on traditional Chinese medicine (TCM) for the prevention and treatment of essential hypertension (EH) using the evidence map. We aimed to explore the evidence distribution, identify gaps in evidence, and inform on future research priorities. Clinical studies, systematic reviews, guidelines, and pathway studies related to TCM for the prevention and treatment of EH, published between January 2000 and December 2019, were included from databases CNKI, WanFang Data, VIP, PubMed, Embase, and Web of Science. The distribution of evidence was analysed using text descriptions, tables, and graphs. A total of 9,403 articles were included, including 5,920 randomised controlled studies (RCTs), 16 guidelines, expert consensus and path studies, and 139 systematic reviews (SRs). The articles publishing trend increased over time. This study showed that the intervention time of TCM was concentrated at 4-8 weeks, mainly through Chinese herbal medicine (CHM) for the prevention and treatment of elderly hypertension and the complications. A Measurement Tool to Assess Systematic Reviews (AMSTAR) scores of the included reviews ranged from 2 to 10. Most of the SRs had a potentially positive effect (n = 120), mainly in 5-8 score. Primary studies and SRs show potential benefits of TCM in lowering blood pressure, lowering the TCM syndrome and symptom differentiation scores (TCM-SSD scores), improving the total effective rate, and reducing the adverse events. The adjunctive effect of TCM on improving the total effective rate, lowering the blood pressure, lowering the TCM-SSD scores, and lowering the adverse effects was only supported by low-quality evidence in this research. The evidence map was used to show the overall research on TCM for the treatment of EH; however, due to the existing problems of the primary studies, the current research conclusion needs further research with higher quality and standardisation.

Macrophage K63-Linked Ubiquitination of YAP Promotes Its Nuclear Localization and Exacerbates Atherosclerosis.

The Hippo/Yes-associated protein (YAP) pathway has pivotal roles in innate immune responses against pathogens in macrophages. However, the role of YAP in macrophages during atherosclerosis and its mechanism of YAP activation remain unknown. Here, we find that YAP overexpression in myeloid cells aggravates atherosclerotic lesion size and infiltration of macrophages, whereas YAP deficiency reduces atherosclerotic plaque. Tumor necrosis factor receptor-associated factor 6 (TRAF6), a downstream effector of interleukin-1ß (IL-1ß), triggers YAP ubiquitination at K252, which interrupts the interaction between YAP and angiomotin and results in enhanced YAP nuclear translocation. The recombinant IL-1 receptor antagonist anakinra reduces atherosclerotic lesion formation, which is abrogated by YAP overexpression. YAP level is increased in human and mouse atherosclerotic vessels, and plasma IL-1ß level in patients with STEMI is correlated with YAP protein level in peripheral blood mononuclear cells. These findings elucidate a mechanism of YAP activation, which might be a therapeutic target for atherosclerosis.

Exploratory study on the safety and effectiveness of Yizhi Qingxin Decoction (capsules) in the treatment of hypertension in the elderly with mild cognitive impairment (deficiency of kidney essence syndrome).

BACKGROUND: Hypertension in the elderly with cognitive impairment has been one of the global health issues. Mild cognitive impairment (MCI) is the state of transition between the normal aging process and cognitive changes of unformed dementia. Diagnosis and treatment of MCI are the keys to prevent dementia, and hypertension is one of the important influencing factors of MCI. Our preclinical experiment found that Yizhi Qingxin Decoction (YQD) could effectively reduce the blood pressure of spontaneously hypertensive rats (SHR), improve their spatial learning and memory abilities in Morris water maze, and play a neuroprotective role. The objective is to estimate the safety and efficacy of YQD (capsules) in the treatment of hypertension in the elderly with MCI (deficiency of kidney essence syndrome) through this study. METHODS: According to the random number generated by the block random method, 100 participants will be randomly and equally divided into the treatment group (YQD) or the control group (Ginkgo biloba extract tablets). The conversion rate of dementia will be used as the main evaluating indicator by the CDR scale. The MoCA scale, MMSE scale, ADCS-MCI-ADL-24 scale, CGIC-KDS scale, and 24-h ambulatory blood pressure will be used as the secondary evaluating indicator. Safety will be evaluated based on specific manifestations of adverse reactions and the incidence of adverse events. OBJECTIVE: The objective is to estimate the curative effect of YQD (capsules) on hypertension in the elderly with MCI (deficiency of kidney essence syndrome), and to evaluate the safety of its clinical application. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ICTRP member): ChiCTR2000030292.

The Role of Deubiquitinases in Vascular Diseases.

Deubiquitinases (DUBs) are a major component of the ubiquitin-proteasome system in eukaryotic cells; the system plays a crucial role in many biological processes, such as inflammation, oxidative stress, and cell apoptosis, which are important in vascular biology and pathology. DUBs have drawn significant attention in recent years, and their function is increasingly linked with vascular diseases. In this review, we summarize the indirect and direct evidence for the effects of DUBs on atherosclerosis, abdominal aortic aneurysm, angiogenesis, and hypertension, and point out pathways that could be pursued for investigating DUBs. Intervention in the function of DUBs in vascular diseases has potential therapeutic value.

Multi-shelled ceria hollow spheres with a tunable shell number and thickness and their superior catalytic activity.

In this work, ceria multi-shelled nanospheres with a tunable shell number and thickness were prepared by a facile coordination polymer (CP) precursor method without the use of any template and surfactant. Interestingly, the number, thickness and structure of the shell can be tuned by varying the reaction time, reaction temperature, ratio of reagent and calcination temperature. The formation process of the multi-shelled hollow spheres was also investigated, which experienced a core contraction and shell separation process. Moreover, the multi-shelled CeO2 hollow nanospheres displayed excellent photocatalytic activity in the degradation of RhB. Au and AuPd nanoparticle loaded multi-shelled CeO2 nanocomposites were also prepared. Results show that Au/CeO2 multi-shelled hollow nanospheres showed eximious catalytic activity for the reduction of p-nitrophenol with a reaction rate constant k of 0.416 min. In addition, AuPd/CeO2 exhibited a remarkable catalytic activity for the conversion of CO. Employing this method, heavy rare earth oxide multi-shelled structures and light rare earth oxide solid spheres were obtained. This method may be employed for the preparation of other materials with complex structures.

Intracellular ROS mediates gas plasma-facilitated cellular transfection in 2D and 3D cultures.

This study reports the potential of cold atmospheric plasma (CAP) as a versatile tool for delivering oligonucleotides into mammalian cells. Compared to lipofection and electroporation methods, plasma transfection showed a better uptake efficiency and less cell death in the transfection of oligonucleotides. We demonstrated that the level of extracellular aqueous reactive oxygen species (ROS) produced by gas plasma is correlated with the uptake efficiency and that this is achieved through an increase of intracellular ROS levels and the resulting increase in cell membrane permeability. This finding was supported by the use of ROS scavengers, which reduced CAP-based uptake efficiency. In addition, we found that cold atmospheric plasma could transfer oligonucleotides such as siRNA and miRNA into cells even in 3D cultures, thus suggesting the potential for unique applications of CAP beyond those provided by standard transfection techniques. Together, our results suggest that cold plasma might provide an efficient technique for the delivery of siRNA and miRNA in 2D and 3D culture models.

In Situ OH Generation from O2- and H2O2 Plays a Critical Role in Plasma-Induced Cell Death.

Reactive oxygen and nitrogen species produced by cold atmospheric plasma (CAP) are considered to be the most important species for biomedical applications, including cancer treatment. However, it is not known which species exert the greatest biological effects, and the nature of their interactions with tumor cells remains ill-defined. These questions were addressed in the present study by exposing human mesenchymal stromal and LP-1 cells to reactive oxygen and nitrogen species produced by CAP and evaluating cell viability. Superoxide anion (O2-) and hydrogen peroxide (H2O2) were the two major species present in plasma, but their respective concentrations were not sufficient to cause cell death when used in isolation; however, in the presence of iron, both species enhanced the cell death-inducing effects of plasma. We propose that iron containing proteins in cells catalyze O2- and H2O2 into the highly reactive OH radical that can induce cell death. The results demonstrate how reactive species are transferred to liquid and converted into the OH radical to mediate cytotoxicity and provide mechanistic insight into the molecular mechanisms underlying tumor cell death by plasma treatment.

Preparation and antimicrobial properties of gemini surfactant-supported triiodide complex system.

Iodine is an effective, simple, and inexpensive bactericide in disinfection. However, the poor solubility and stability of iodine in water limit its applications. In addition, the active iodine content in the commercial iodophors is quite low, and the reported triiodide complex is unstable. In this work, a long-term stable triiodide complex antimicrobial system was prepared by mixing iodine and a cationic gemini surfactant into lauryldimethylamine oxide (LDAO) aqueous solution, and its stability was examined by means of UV-vis spectrophotometry. It was found that the content of LDAO, cationic gemini surfactant and H(2)SO(4) played crucial roles in stabilizing antimicrobial system, and the active iodine (i.e., triiodide complex) content of the optimum formulation can remain stable for 150 days, as iodine is encapsulated by the mixed vesicles assembled by the protonated LDAO and the added gemini surfactant. However, the active iodine reduced rapidly when NaCl was added or the pH was increased in the environment. Furthermore, the antimicrobial efficacy of the optimized formulation was studied against Candida albicans, and more than 4 log reduction in viable cell after 5 min of contact was obtained.