Integrating network pharmacology and experimental models to identify notoginsenoside R1 ameliorates atherosclerosis by inhibiting macrophage NLRP3 inflammasome activation.

Atherosclerosis is a cardiovascular disease, accounting for the most common mortality cause worldwide. Notoginsenoside R1 (NGR1) is a characteristic saponin of Radix notoginseng that exhibits anti-inflammatory and antioxidant effects while modulating lipid metabolism. Evidence suggests that NGR1 exerts cardioprotective, neuroprotective, and anti-atherosclerosis effects. However, underlying NGR1 mechanisms alleviating atherosclerosis (AS) have not been examined. This study used a network pharmacology approach to construct the drug-target-disease correlation and protein-protein interaction (PPI) network of NGR1 and AS. Moreover, functional annotation and pathway enrichment analyses deciphered the critical biological processes and signaling pathways potentially regulated by NGR1. The protective effect of NGR1 against AS and the underlying mechanism(s) was assessed in an atherogenic apolipoprotein E-deficient (ApoE-/-) mice in vivo and an oxidized low-density lipoprotein (ox-LDL)-induced macrophage model in vitro. The network pharmacology and molecular docking analyses revealed that NGR1 protects against AS by targeting the NLRP3/caspase-1/IL-1ß pathway. NGR1 reduced foam cell formation in ox-LDL-induced macrophages and decreased atherosclerotic lesion formation, serum lipid metabolism, and inflammatory cytokines in AS mice in vivo. Therefore, NGR1 downregulates the NLRP3 inflammasome complex gene expression of NLRP3, caspase-1, ASC, IL-1ß, and IL-18, in vivo and in vitro.

Medicinal Value, Biological Characteristics, and Domestication of the Wild Mushroom Pholiota adiposa (Agaricomycetes).

Pholiota adiposa is an important edible and medicinal mushroom with high nutritional and medicinal effects. The fruiting body of wild fungi collected from Mudanjiang City, Heilongjiang Province, was identified by morphological description and molecular identification, the biological characteristics and domestication of the fungus was determined by single factor and orthogonal tests. The wild strain isolated was determined to be Ph. adiposa based on morphological characteristics, sequence alignment between ITS and nLSU, and phylogenetic relationship analysis. The single factor results revealed that the optimal carbon source, nitrogen source, culture temperature, and pH for the mycelia growth of Ph. adiposa were glucose, yeast paste, 25°C, and pH 6.5-7.0, respectively. Orthogonal test showed that the optimal formula for mycelia culture was fructose 20 g/L, yeast extract 6 g/L, KH2PO4 1 g/L and MgSO4 2.5 g/L. The highest single bag yield of the fruiting body of Ph. adiposa was 24.96 g in the culture medium formula of sawdust (20%), wheat bran (10%), soybean powder (1%), and quicklime powder (1%). The results will provide basic information for the protection, utilization and domestication of the resources of Ph. adiposa.

Berberine plays a cardioprotective role by inhibiting macrophage Wnt5a/ß-catenin pathway in the myocardium of mice after myocardial infarction.

Myocardial infarction (MI) is one of the diseases with high fatality rate. Berberine (BBR) is a monomer compound with various biological functions. And some studies have confirmed that BBR plays an important role in alleviating cardiomyocyte injury after MI. However, the specific mechanism is unclear. In this study, we induced a model of MI by ligation of the left anterior descending coronary artery and we surprisingly found that BBR significantly improved ventricular remodeling, with a minor inflammatory and oxidative stress injury, and stronger angiogenesis. Moreover, BBR inhibited the secretion of Wnt5a/ß-catenin pathway in macrophages after MI, thus promoting the differentiation of macrophages into M2 type. In summary, BBR effectively improved cardiac function of mice after MI, and the potential protective mechanism was associated with the regulation of inflammatory responses and the inhibition of macrophage Wnt5a/ß-catenin pathway in the infarcted heart tissues. Importantly, these findings supported BBR as an effective cardioprotective drug after MI.

New possible silver lining for pancreatic cancer therapy: Hydrogen sulfide and its donors.

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H2S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation. Similarly, inhibition of endogenous H2S production also suppresses tumor proliferation. Accordingly, H2S biosynthesis inhibitors and H2S supplementation (H2S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H2S on pancreatic cancer has not been studied so far. However, H2S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H2S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H2S donors and NO-H2S dual donors on pancreatic cancer were summarized in this paper. Exogenous H2S donors may be promising compounds for pancreatic cancer treatment.

Modulation of hand motor skill performance induced by motor practice combined with matched or mismatched hand posture motor imagery.

Motor imagery (MI), the mental rehearsal of a movement without muscle activation, combined with motor practice (MP) improves the performance of athletes and promotes rehabilitation of motor function among patients with brain injury. The actual hand posture influences the mental simulation of hand movements such that the ability of MI to affect corticospinal excitability is enhanced when the actual hand posture is consistent with the imagined movement of the hand. However, how MP combined with matched or mismatched hand posture MI modulates hand motor skill performance and the underlying neural mechanisms remain unclear. Thus, we first investigated whether MI hand posture that was compatible or incompatible with the actual MP influenced motor performance and corticospinal excitability induced by MI combined with MP. Twenty-eight healthy young adults repeatedly imagined either (1) closing their right hand into a fist with the thumb on top of the fingers and then opening the hand before actually performing that exact motor action or (2) performing the same motor skill but first imagining the right thumb touching the little finger before opening the hand . Changes in the peak acceleration of the hand grasp were measured to assess motor performance. The amplitudes of motor-evoked potentials (MEPs) in a target muscle were obtained using transcranial magnetic stimulation to assess corticospinal activation, a measure of primary cortex stimulation, before, immediately after, and 20 min after the performance. When the results of two-way repeated-measures analyses of variance assessing the effects of the protocols and time on the various measurements were found to be significant, post hoc paired t tests with Bonferroni corrections for multiple comparisons were applied. The results showed that both peak grasp acceleration and corticospinal excitability significantly increased immediately and 20 min after task completion (p < 0.05 for all) only when the MI hand posture matched with that of the actual MP. We then determined whether this increased corticospinal activity was associated with decreased short-interval intracortical inhibition, as measured using paired-pulse transcranial magnetic stimulation. Similar to our previous results, we found that short-interval intracortical inhibition was significantly decreased immediately and 20 min after task completion (p < 0.05 for both) only when MI matched MP. We concluded that the increased motor performance and corticospinal excitability induced by MI and MP depended on the match between the hand posture in the MI and MP, and that this increased corticospinal excitability was associated with disinhibition of the primary motor cortex activity.

[The effect of Banxia Baizhu Tianma decoction on renal protein expression in spontaneously hypertensive rats].

OBJECTIVE: To study the effect of Banxia Baizhu decoction on the spontaneously hypertensive rats and its possible mechanism. METHODS: Male SHRs of 6 weeks old were randomly and equally divided into two groups, the control SHR group and the group treated with BXBZTMD, the treated group were treated with BXBZTMD orally for 18 weeks, the control SHR group and normotensive WKY group were fed with the same amount of distilled water. Rats' blood pressure was measured through carotid artery catheterization, and protein of kidney tissues was analyzed by two-dimensional electrophoresis after extraction and purification. Different protein spots expressed significantly which were anlyzed by PDQuest software were then identified by MALDI-TOF/TOF MS. The protein expressions of peroxidase 2 and Cu-Zn superoxide in kidney were determined by Western blot. RESULTS: Compared SHR with WKY, 12 protein spots were changed. BXBZTMD could adjust kidney protein expression such as Cu-Zn superoxide dismutase, peroxidase 2 and may change kidney protein expression such as the alpha-beta-crystallin, which were closely related to oxidative stress. These discoveries of the target proteins suggested that BXBZTMD had curative effect by anti-oxidative stress. CONCLUSION: Oxidative stress plays an important role in the process of hypertensive renal injury. BXBZTMD can play a therapeutic role to oxidative stress. The discovery of the target protein provides a theoretical basis for the mechanism of the therapeutic effect of BXBZTMD.

[Effect of banxia baizhu tianma decoction on the vascular endothelial function of spontaneous hypertensive rats].

OBJECTIVE: To study the vascular endothelial function recovery and its mechanism of Banxia Baizhu Tianma Decoction (BBTD). METHODS: 54 SH rats were randomly divided into three groups: the blank control group, BBTD group and Captopril treatment group. BBTD (at the daily dose of 4. 320 g crude drug/kg) and Captopril (at the daily dose of 3.375 g/kg) was administered from the 7th week to the 24th week. Another eighteen Wistar-Kyoto rats of the same ages were taken as the control. Medication was discontinued and effects were observed until the 32nd week. The blood pressure was determined by arterial carotis cannula. The concentration of serum NO2(-) and total anti-oxidation were determined by Griess and fluorescence recovery after photobleaching (FRAP). The acetylcholine (Ach)-dependent relaxation of superior mesenteric artery was detected using in vitro vascular ring. The mRNA expressions of IL-1, IL-6 and iNOS were detected by Real-time PCR at the 18th, 24th, and 32nd week. RESULTS: BBTD could significantly lower blood pressure of SHR and the concentration of serum NO2(-) at the 18th and 24th week (P<0.05). The total anti-oxidation of SH rats increased at the 18th week (P<0.01), and ACh-dependent relaxation of superior mesenteric artery increased at the 24th week. The mRNA expressions of IL-1 was markedly suppressed by BBTD at the 18th, 24th, and 32nd week (P<0.05), while IL-6 and iNOS mRNA expression were significantly lowered only at the 32nd week (P< 0.01). Captopril could significantly lower blood pressure of SHR at the 18th and 24th week (P<0.05). It significantly increased the total anti-oxidation of SH rats at the 18th week (P<0.01). However, it could not increase ACh-dependent relaxation of superior mesenteric artery and regulate the concentration of NO2(-) at the 18th, 24th, and 32nd week. The mRNA expression of iNOS was markedly suppressed by Captopril at the 24th and 32nd week, while mRNA expressions of IL-1 and IL-6 were significantly lower only at the 32nd week (P<0.01). CONCLUSIONS: BBTD showed similar effect in decreasing the blood pressure to captopril, but it showed better effect in improving the mesenteric endothelial dysfunction of SHR, which may be associated with its inhibition on NO and IL-1 expression, and improvement of the oxidative stress state.

[Effect of banxia baizhu tianma decoction on the left ventricular hypertrophy of hypertrophied myocardium in spontaneously hypertensive rat].

OBJECTIVE: To investigate the changes in renin angiotensin system (RAS) in hypertrophied myocardium of spontaneous hypertensive rat (SHR), and the effect of Banxia Baizhu Tianma Decoction (BBTD) on the changes in haemodynamic parameters and mRNA of signaling molecules of RAS at different periods. METHODS: Fifty-four male SHRs of 6 weeks old were randomly and equally divided into three groups: the untreated control group, the test group, and the positive control group, and they were treated respectively with distilled water, BBTD and captopril by dissolving in equal volume of water administrated via gavage for 18 weeks. Besides, 18 age matched Wistar-Kyoto (WKY) rats treated with distilled water were allocated in a normal control group. Rats were managed in batches at their age of 18, 24, and 32 weeks old. Rat's hemodynamic parameters were measured through carotid artery catheterization, myocardial pathology was observed, and their mRNA expressions of angiotensin (AGT), angiotensin-converting (ACE) and angiotension-converting 2 (ACE2) were determined by Real-time PCR. RESULTS: Compared with WKY rats, the arterial pressure and left ventricular mass index (LVMI)in SHR were significantly higher at 18, 24 and 32 weeks respectively (P < 0.01); average cycle rate showed in electrocardiogram was higher (P < 0.05), though the blood stream was similar; mRNA expressions of AGT and ACE in heart tissue were markedly higher (P < 0.01), but that of ACE2 at 18 and 24 weeks were lower (P < 0.01). Compared with untreated SHR, arterial pressure at 18 and 24 weeks was lower (P < 0.05); cardiac muscle structure was improved; LVMI at 24 weeks was improved (P < 0.05); the mRNA expressions of AGT and ACE were suppressed but that of ACE2 increased at 18, 24,and 32 weeks significantly in the test group after BBTD treatment (P < 0.05). CONCLUSIONS: Changes in RAS in the hypertrophied myocardium of SHR may be one of the molecular mechanisms for hypertension leading to left ventricular hypertrophy. BBTD can improve the hemodynamic parameters, regulate RAS, so as to lower the arterial pressure.