Therapeutic improvements of nifedipine controlled-release tablets combined with sacubitril valsartan on patients with diabetic nephropathy complicated with hypertension.

This study aimed to evaluate the efficacy of nifedipine controlled-release tablets combined with sacubitril valsartan in diabetic nephropathy (DN) patients with hypertension. One hundred and twelve DN patients with hypertension were enrolled. They were randomly divided into the control group (treated with nifedipine controlled-release tablets combined with valsartan) and the observation group (treated with nifedipine controlled-release tablets combined with sacubitril valsartan). Renal function, endothelial function and inflammatory response were examined. After three-months treatment, the levels of clinical indexes (glycosylated hemoglobin, fasting blood glucose, systolic and diastolic blood pressure), renal function indicators (urinary albumin excretion rate, blood urea nitrogen, serum creatinine and cystatin C), endothelial function indicators (microalbumin, angiotensin II, thrombomodulin and cartilage oligomeric matrix protein) and inflammatory response factors (interleukin-6 and tumor necrosis factor-α) in the observation group were significantly lower than those in the control group. Nifedipine controlled-release tablets combined with sacubitril valsartan could effectively alleviate the progression of DN combined with hypertension.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Effects of bicyclol on hepatic sinusoidal obstruction syndrome induced by Gynura segetum.

BACKGROUND: The intake of Gynura segetum, a traditional Chinese medicine, may be induce hepatic sinusoidal obstruction syndrome (HSOS). It has a high mortality rate based on the severity of the disease and the absence of therapeutic effectiveness. Therefore, the current study was designed to investigate the effects of bicyclol on HSOS induced by Gynura segetum and the potential molecular mechanisms. METHODS: Gynura segetum (30 g/kg) was administered for 4 weeks in the model group, while the bicyclol pretreatment group received bicyclol (200 mg/kg) administration. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol (CHO), triglyceride (TG), and liver histological assays were detected to assess HSOS. The gene expressions of cytochrome P450 (CYP450) isozymes were quantified by real-time PCR. Moreover, hepatocellular apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, then apoptosis and autophagy-related markers were determined using Western blot. RESULTS: As a result, bicyclol pretreatment is notably protected against Gynura segetum-induced HSOS, as observed by reducing serum ALT levels, inhibiting the reduction in CHO and TG levels, and alleviating the histopathological changes. Bicyclol pretreatment inhibited the changes in mRNA levels of CYP450 isozymes (including the increase in CYP2a5 and decrease in CYP2b10, 2c29, 2c37, 3a11, and 7b1). In addition, the upregulation of Bcl-2 and the downregulation of LC3-II/LC3-I proteins expression in HSOS were inhibited with bicyclol pretreatment. CONCLUSION: Bicyclol exerted a protective effect against HSOS induced by Gynura segetum, which could be attributed to the regulated expressions of CYP450 isozymes and alleviated the downregulation of autophagy.

Novel antihypertensive agents for resistant hypertension: what does the future hold?

Finding complementary compelling novel therapeutic agents for better control of blood pressure in people with resistant hypertension is moving into unchartered territory. The latest therapeutic developments explore approaches in the clinical arena that were either not examined or could only be examined in animal models two decades ago. Four main mechanisms have now been explored and operationalized in drug development: (a) mineralocorticoid receptor blockade using a nonsteroidal structure with many fewer side effects, (b) an aminopeptidase A inhibitor that has central effects on vasopressin, (c) a combined endothelin A and B receptor blocker and (d) an aldosterone synthase inhibitor devoid of glucocorticoid activity. All these agents are either completing Phase II development and starting Phase III or are involved in the ongoing recruitment of Phase III trials. Additionally, novel agents use antisense inhibition to block angiotensinogen development in the liver. These agents are discussed only for completeness, as they are still in Phase II trial development. Last, another agent that was initially being developed as an antihypertensive and once the data were reviewed by the company clearly showed efficacy as a heart failure agent was sacubitril/valsartan, which was ultimately approved. However, there are some discussions about reinvigorating the quest for an indication for hypertension, although no such steps have been formally initiated.

Maternal magnolol supplementation alters placental morphology, promotes placental angiogenesis during mid-gestation and improves offspring growth in a pregnant mouse model.

The placenta is the organ that determines the growth of the fetus and the outcome of pregnancy. Magnolol is a multifunctional polyphenol with antioxidant, anti-inflammatory, anticancer and neuroprotective functions. However, there is less knowledge of the effects or complications in the placenta and the mechanism underlying the effect of magnolol when used during pregnancy. The aim of this study was to explore the effects of maternal magnolol supplementation on pregnancy outcomes and placental alterations in a pregnant mouse model. A total of 128 pregnant mice were randomly divided into 4 groups supplemented with 0, 40, 80 and 160 µM magnolol from gestational day 0 (GD0) to delivery. Our results revealed that the number of large-for-gestation-age fetuses on GD13 and the weaning weight of offspring were increased in the magnolol treatment groups. Moreover, maternal magnolol supplementation increased superoxide dismutase (SOD), decreased malondialdehyde (MDA) in maternal serum, and promoted the expression of heme oxygenase-1 (HO-1) in the placenta. Furthermore, magnolol significantly increased the area of the junctional zone and decidua in the placentas and increased the expression of interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), chemokine (CC Motif) Ligand 3 (CCL3), chemokine (CXC motif) ligand 10 (CXCL10), insulin-like growth factor-1 (IGF-1) and T-box transcription factor 21 (T-bet) in the placenta during GD13 in pregnant mice, while suppressor of cytokine signaling 1 (SOCS1) was reduced. Moreover, the ratio of blood space in the labyrinth area, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were all increased in the magnolol treatment groups on GD13. Taken together, these results indicate that magnolol can improve the growth of offspring, which might be due to the alteration of placental morphology and the promotion of placental angiogenesis during mid-gestation.

A honokiol-enriched Magnolia officinalis Rehder & E.H. Wilson. bark extract possesses anxiolytic-like activity with neuroprotective effect through the modulation of CB1 receptor.

OBJECTIVES: The exposure of neurons to an excessive excitatory stimulation induces the alteration of the normal neuronal function. Mood disorders are among the first signs of alterations in the central nervous system function. Magnolia officinalis bark extract has been extensively used in the traditional medicine systems of several countries, showing several pharmacological activities. Honokiol, the main constituent of M. officinalis, is a GABA modulator and a CB1 agonist, which is deeply investigated for its role in modulating mood disorders. METHODS: Thus, we evaluated the possible neuroprotective effect of a standardized M. officinalis bark extract (MOE), enriched in honokiol, and its effect on animal mood behavioural tests and in an in vitro model of excitotoxicity. KEY FINDINGS: MOE showed neuroprotective effect using SH-SY5Y cells, by normalizing brain-derived neurotrophic factor release. Then, we tested the effect of MOE in different behavioural tests evaluating anxiety and depression and we observed a selective anxiolytic-like effect. Finally, we confirmed the involvement of CB1 in the final effect of MOE by the co-administration of the CB1 antagonist, AM251. CONCLUSION: These results suggest that MOE could be considered an effective and safe anxiolytic candidate with neuroprotective activity.

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

BACKGROUND: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction. METHODS: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality. RESULTS: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P<0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (P<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (P<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P<0.05 for both outcomes). CONCLUSIONS: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.

EZH2 inhibition by tazemetostat: mechanisms of action, safety and efficacy in relapsed/refractory follicular lymphoma.

Epigenetic alterations are major drivers of follicular lymphomagenesis, and these alterations are frequently caused by mutations in or upregulation of EZH2, a histone methyltransferase responsible for PRC2-mediated gene repression. EZH2 hyperactivation increases proliferation of B cells and prevents them from exiting the germinal center, favoring lymphomagenesis. The first FDA-approved EZH2 inhibitor is tazemetostat, which is orally available and targets both mutant and wild-type forms of the protein to induce cell cycle arrest and apoptosis of lymphoma cells in preclinical models. Phase II trials have shown objective response rates of 69% for patients with lymphoma-carrying EZH2 mutations and 35% for those with wild-type EZH2 without major toxicity, leading to tazemetostat approval for this cancer by the US FDA in June 2020.

Lay abstract Follicular lymphoma (FL) is a subtype of B-cell cancer. Initial prognosis of this disease is favorable as first-line treatments provide responses lasting 10 years on average. However, most patients will experience relapse and subsequent treatments are not as efficient nor as well tolerated as the first ones. An important driver of FL is a gene called EZH2 that makes B cells proliferate, either because of mutations that increase its activity or because of a net increase in its concentration in lymphoma cells. Tazemetostat is a drug that was designed to inhibit EZH2 protein and thus lymphoma cell growth. Phase I and II studies have been completed for this drug showing a good safety profile. In Phase II, reponses were seen in 69% of patients who have the EZH2 mutations and 35% of the other patients. The US FDA has approved tazemetostat for patients with FL who have had at least two previous treatments and harbor the EZH2 mutations, or for patients with FL who have no other therapeutic options. However, the drug has not yet been approved in Europe. Randomized trials and long-term follow-up will be of interest to make sure this drug is efficient and safe enough to be given to patients in earlier lines of treatment or in combination with other active agents used to treat patients with FL.

Chaiqin chengqi decoction ameliorates acute pancreatitis in mice via inhibition of neuron activation-mediated acinar cell SP/NK1R signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Chaiqin chengqi decoction (CQCQD) and its derivatives have been widely used in China for the early management of patients with acute pancreatitis (AP). Numerous studies demonstrate the anti-inflammatory and anti-oxidative effects of CQCQD and derivatives, but whether these effects can be attributed to suppressing neurogenic inflammation, has never been studied. AIM OF THE STUDY: To investigate the effects of CQCQD on substance P (SP)-neurokinin 1 receptor (NK1R) based neurogenic inflammation in an experimental AP model. MATERIAL AND METHODS: For AP patients on admission, pain score was accessed by visual analog scale (VAS); the levels of serum SP and expressions of pancreatic SP and NK1R were also determined. For in vivo study, mice received 7 intraperitoneal injections of cerulein (50 µg/kg) at hourly intervals to induce AP, whilst controls received normal saline injections. In the treatment groups, CQCQD (10 g/kg, 200 µl) was intragastrically given at the third, fifth, and seventh of the cerulein injection or the NK1R antagonist CP96345 (5 mg/kg) was intraperitoneally injected 30 min before the first cerulein administration. The von Frey test was performed to evaluate pain behavior. Animals were sacrificed at 12 h from the first cerulein/saline injection for severity assessment. Pharmacology network analysis was used to identify active ingredients of CQCQD for AP and pain. In vitro, freshly isolated pancreatic acinar cells were pre-treated with CQCQD (5 mg/ml), CP96345 (1 µM), or selected active compounds of CQCQD (12.5, 25, and 50 µM) for 30 min, followed by SP incubation for another 30 min. RESULTS: The VAS score as well as the levels of serum SP and expressions of pancreatic SP-NK1R were up-regulated in moderately severe and severe patients compared with those with mild disease. CQCQD, but not CP96345, consistently and significantly ameliorated pain, pancreatic necrosis, and systemic inflammation in cerulein-induced AP as well as inhibited NK1R internalization of pancreatic acinar cells. These effects of CQCQD were associated with reduction of pancreatic SP-NK1R and neuron activity in pancreas, dorsal root ganglia, and spinal cord. Baicalin, emodin, and magnolol, the top 3 active components of CQCQD identified via pharmacology network analysis, suppressed NK1R internalization and NF-κB signal pathway activation in isolated pancreatic acinar cells. CONCLUSIONS: CQCQD ameliorated cerulein-induced AP and its associated pain via inhibiting neuron activation-mediated pancreatic acinar cell SP-NK1R signaling pathways and its active compounds baicalin, emodin, and magnolol contributed to this effect.

Study of Neuroprotection by a Combination of the Biological Antioxidant (Eucalyptus Extract) and the Antihypertensive Drug Candesartan against Chronic Cerebral Ischemia in Rats.

Chronic cerebral ischemia with a notable long-term cessation of blood supply to the brain tissues leads to sensorimotor defects and short- and long-term memory problems. Neuroprotective agents are used in an attempt to save ischemic neurons from necrosis and apoptosis, such as the antioxidant agent Eucalyptus. Numerous studies have demonstrated the involvement of the renin-angiotensin system in the initiation and progression of cardiovascular and neurodegenerative diseases. Candesartan is a drug that acts as an angiotensin II receptor 1 blocker. We established a rat model exhibiting sensorimotor and cognitive impairments due to chronic cerebral ischemia induced by the ligation of the right common carotid artery. Wistar male rats were randomly divided into five groups: Sham group, Untreated Ligated group, Ischemic group treated with Eucalyptus (500 mg/kg), Ischemic group treated with Candesartan (0.5 mg/kg), and Ischemic group treated with a combination of Eucalyptus and Candesartan. To evaluate the sensorimotor disorders, we performed the beam balance test, the beam walking test, and the modified sticky test. Moreover, the object recognition test and the Morris water maze test were performed to assess the memory disorders of the rats. The infarct rat brain regions were subsequently stained using the triphenyltetrazolium chloride staining technique. The rats in the Sham group had normal sensorimotor and cognitive functions without the appearance of microscopic ischemic brain lesions. In parallel, the untreated Ischemic group showed severe impaired neurological functions with the presence of considerable brain infarctions. The treatment of the Ischemic group with a combination of both Eucalyptus and Candesartan was more efficient in improving the sensorimotor and cognitive deficits (p < 0.001) than the treatment with Eucalyptus or Candesartan alone (p < 0.05), by the comparison to the non-treated Ischemic group. Our study shows that the combination of Eucalyptus and Candesartan could decrease ischemic brain injury and improve neurological outcomes.

Therapeutic potential of bicyclol in liver diseases: Lessons from a synthetic drug based on herbal derivative in traditional Chinese medicine.

Bicyclol, an innovative chemical drug with proprietary intellectual property rights in China, is based on derivative of traditional Chinese medicine (TCM) Schisandra chinensis (Wuweizi) of North. Mounting data has proved that bicyclol has therapeutic potential in various pathological conditions in liver. In this narrative review, we provide the first summary of pharmacological activities, pharmacokinetic characteristics and toxicity of bicyclol, and discuss future research perspectives. Our results imply that bicyclol has a wide spectrum of pharmacological properties, including anti-viral, anti-inflammatory, immuno-regulatory, anti-oxidative, antisteatotic, anti-fibrotic, antitumor, cell death regulatory effects and modulation of heat shock proteins. Pharmacokinetic studies have indicated that bicyclol is the main substrate of CYP3A/2E1. Additionally, no obvious drug interactions have been found when bicyclol is administered simultaneously with other prescriptions. Furthermore, the results of chronic toxicity have strongly addressed that bicyclol has no noticeable toxic effects on all biochemical indices and pathological examinations of the main organs. In view of good pharmacological actions and safety, bicyclol is anticipated to be a potential candidate for various liver diseases, including acute liver injury, fulminant hepatitis, non-alcoholic fatty liver disease, fibrosis and hepatocellular carcinoma. Further studies are therefore required to delineate its molecular mechanisms and targets to confer this well-designed drug a far greater potency. We hope that bicyclol-based therapeutics for liver diseases might be broadly used in clinical practice worldwide.

Novel doses of sacubitril/valsartan in patients unable to tolerate traditional therapy: Effects on N-terminal pro B-type natriuretic peptide levels.

BACKGROUND: Widespread use of angiotensin receptor blocker and neprilysin inhibitor (ARNI) remains low, and many patients are unable to tolerate the medication due to hypotension at the currently recommended starting dose. HYPOTHESIS: The aim of this study is to assess if lower than standard doses of ARNI, sacubitril/valsartan (S/V), significantly reduces NT-proBNP and leads to any change in diuretic dose, serum potassium, or creatinine. METHODS: In a retrospective study of 278 patients who were started on a low dose S/V at a single medical center, 45 patients were selected for the study cohort. Patients were subcategorized to Group 1 (n = 10): very low dose S/V (half a tab of 24/26 mg BID), Group 2 (n = 10): very low dose titrated to low dose S/V, and Group 3 (n = 25): low dose S/V (24/26 mg BID). NT-proBNP, diuretic dose, serum potassium, and creatinine were compared before and after initiation of S/V. RESULTS: Among all groups, there was a significant reduction in NT-proBNP level (Group 1: p < .01, Group 2: p < .01, and Group 3: p < .001). In addition, there was a significant reduction in diuretic dose across all groups combined (furosemide 53 mg/day vs. 73 mg/day; p = .03), with 17.8% (8/45) patients being able to discontinue their diuretic completely. There was no significant change in potassium or creatinine. CONCLUSIONS: Lower than standard dose of S/V significantly reduces NT-proBNP and diuretic requirement without change in potassium or creatinine, which provides hope that patients who cannot tolerate standard doses of S/V due to hypotension may be able to receive the benefits of S/V therapy.

Magnolia extract is effective for the chemoprevention of oral cancer through its ability to inhibit mitochondrial respiration at complex I.

BACKGROUND: Magnolia extract (ME) is known to inhibit cancer growth and metastasis in several cell types in vitro and in animal models. However, there is no detailed study on the preventive efficacy of ME for oral cancer, and the key components in ME and their exact mechanisms of action are not clear. The overall goal of this study is to characterize ME preclinically as a potent oral cancer chemopreventive agent and to determine the key components and their molecular mechanism(s) that underlie its chemopreventive efficacy. METHODS: The antitumor efficacy of ME in oral cancer was investigated in a 4-nitroquinoline-1-oxide (4NQO)-induced mouse model and in two oral cancer orthotopic models. The effects of ME on mitochondrial electron transport chain activity and ROS production in mouse oral tumors was also investigated. RESULTS: ME did not cause detectable side effects indicating that it is a promising and safe chemopreventive agent for oral cancer. Three major key active compounds in ME (honokiol, magnolol and 4-O-methylhonokiol) contribute to its chemopreventive effects. ME inhibits mitochondrial respiration at complex I of the electron transport chain, oxidizes peroxiredoxins, activates AMPK, and inhibits STAT3 phosphorylation, resulting in inhibition of the growth and proliferation of oral cancer cells. CONCLUSION: Our data using highly relevant preclinical oral cancer models, which share histopathological features seen in human oral carcinogenesis, suggest a novel signaling and regulatory role for mitochondria-generated superoxide and hydrogen peroxide in suppressing oral cancer cell proliferation, progression, and metastasis. Video abstract.

Cardiovascular Modulating Effects of Magnolol and Honokiol, Two Polyphenolic Compounds from Traditional Chinese Medicine-Magnolia Officinalis.

Honokiol and its isomer magnolol are poly-phenolic compounds isolated from the Magnolia officinalis that exert cardiovascular modulating effects via a variety of mechanisms. They are used as blood-quickening and stasis-dispelling agents in Traditional Chinese Medicine and confirmed to have therapeutic potential in atherosclerosis, thrombosis, hypertension, and cardiac hypertrophy. This comprehensive review summarizes the current data regarding the cardioprotective mechanisms of those compounds and identifies areas for further research.

Inhibition of the H3K4 methyltransferase MLL1/WDR5 complex attenuates renal senescence in ischemia reperfusion mice by reduction of p16INK4a.

Renal function declines with aging and is pathologically characterized by chronic inflammation and fibrosis. Renal senescence is induced not only by aging but also by various stimuli, including ischemia reperfusion injury. Recently, the accumulation of p16INK4a-positive cells in the kidney has been considered a molecular feature of renal senescence, with the p16INK4a gene reportedly regulated by mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5)-mediated histone 3 lysine 4 trimethylation (H3K4me3). Here, we determined whether inhibition of MLL1/WDR5 activity attenuates renal senescence, inflammation, and fibrosis in mice with ischemia reperfusion injury and in cultured rat renal fibroblasts. MM-102 or OICR-9429, both MLL1/WDR5 protein-protein interaction inhibitors, and small interfering RNA (siRNA) for MLL1 or WDR5 suppressed the expression of p16INK4a in mice with ischemia reperfusion injury, accompanied by downregulation of H3K4me3 expression. MM-102 attenuated renal fibrosis and inflammation in the kidney of mice with ischemia reperfusion injury. Moreover, in vitro study showed that transforming growth factor-ß1 induced the expression of MLL1, WDR5, H3K4me3, and p16INK4a. Finally, chromatin immunoprecipitation identified the p16INK4a promoter at an H3K4me3 site in renal fibroblasts. Thus, our findings show that H3K4me3 inhibition ameliorates ischemia reperfusion-induced renal senescence along with fibrosis and inflammation.

Effect of Fatty Acid-Binding Protein 4 Inhibition on Rotator Cuff Muscle Quality: Histological, Biomechanical, and Biomolecular Analysis.

BACKGROUND: A rotator cuff tear (RCT) induces fatty acid-binding protein 4 (FABP4) expression, resulting in ectopic fat accumulation in the rotator cuff muscle. PURPOSE: To evaluate whether FABP4 inhibition reduces fatty infiltration and improves muscle physiology after RCT in a rat model. STUDY DESIGN: Controlled laboratory study. METHODS: Human supraspinatus muscle and deltoid muscle tissues were acquired from patients with RCTs during arthroscopic surgery, and FABP4 expression in the supraspinatus muscle was evaluated as compared with the intact deltoid muscle. A rat RCT model was established by detaching the supraspinatus tendon, after which a specific FABP4 inhibitor was locally injected into the supraspinatus muscle 4 times at 3-day intervals starting 2 weeks after the surgery. Body weight and blood glucose levels were measured at 2 and 4 weeks after the RCT, and the mRNA and protein expressions of various target molecules (including FABP4), histological changes, and biomechanical tensile strength were assessed in the supraspinatus muscles at 4 weeks after the RCT. RESULTS: The expression of human FABP4 was significantly increased in the torn rotator cuff muscle as compared with the intact deltoid muscle. In the rat model, the mRNA and protein expressions of FABP4 and HIF1α were significantly increased by the RCT as compared with the control. The FABP4 inhibitor treatment significantly decreased FABP4 expression when compared with the vehicle treatment; however, HIF1α expression was not significantly decreased versus the vehicle treatment. Histologically, RCT induced noticeable muscle fatty infiltration, which was remarkably reduced by the local injection of the FABP4 inhibitor. Biomechanically, the tensile strength of the rotator cuff muscle after the RCT was significantly improved by the FABP4 inhibitor in terms of load to failure and total energy to failure. CONCLUSION: RCT induces FABP4 expression in human and rat rotator cuff muscles. The FABP4 inhibitor drastically decreased the histological fatty infiltration caused by RCT and improved the tensile strength of the rotator cuff muscle. CLINICAL RELEVANCE: FABP4 inhibitor may have a beneficial effect on the muscle quality after RCT.

Insights on the Multifunctional Activities of Magnolol.

Over years, various biological constituents are isolated from Traditional Chinese Medicine and confirmed to show multifunctional activities. Magnolol, a hydroxylated biphenyl natural compound isolated from Magnolia officinalis, has been extensively documented and shows a range of biological activities. Many signaling pathways include, but are not limited to, NF-κB/MAPK, Nrf2/HO-1, and PI3K/Akt pathways, which are implicated in the biological functions mediated by magnolol. Thus, magnolol is considered as a promising therapeutic agent for clinic research. However, the low water solubility, the low bioavailability, and the rapid metabolism of magnolol dramatically limit its clinical application. In this review, we will comprehensively discuss the last five-year progress of the biological activities of magnolol, including anti-inflammatory, antimicroorganism, antioxidative, anticancer, neuroprotective, cardiovascular protection, metabolism regulation, and ion-mediating activity.

Honokiol inhibits breast cancer cell metastasis by blocking EMT through modulation of Snail/Slug protein translation.

Honokiol (HNK), an active compound isolated from traditional Chinese medicine Magnolia officinalis, has shown potent anticancer activities. In the present study, we investigated the effects of HNK on breast cancer metastasis in vitro and in vivo, as well as the underlying molecular mechanisms. We showed that HNK (10-70 µmol/L) dose-dependently inhibited the viability of human mammary epithelial tumor cell lines MCF7, MDA-MB-231, and mouse mammary tumor cell line 4T1. In the transwell and scratch migration assays, HNK (10, 20, 30 µmol/L) dose-dependently suppressed the invasion and migration of the breast cancer cells. We demonstrated that HNK (10-50 µmol/L) dose-dependently upregulated the epithelial marker E-cadherin and downregulated the mesenchymal markers such as Snail, Slug, and vimentin at the protein level in breast cancer cells. Using a puromycin incorporation assay, we showed that HNK decreased the Snail translation efficiency in the breast cancer cells. In a mouse model of tumor metastasis, administration of HNK (50 mg/kg every day, intraperitoneal (i.p.), 6 times per week for 30 days) significantly decreased the number of metastatic 4T1 cell-derived nodules and ameliorated the histological alterations in the lungs. In addition, HNK-treated mice showed decreased Snail expression and increased E-cadherin expression in metastatic nodules. In conclusion, HNK inhibits EMT in the breast cancer cells by downregulating Snail and Slug protein expression at the mRNA translation level. HNK has potential as an integrative medicine for combating breast cancer by targeting EMT.

Antidepressant-Like Effect and Mechanism of Action of Honokiol on the Mouse Lipopolysaccharide (LPS) Depression Model.

There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from Magnolia officinalis, which is widely used in traditional Chinese medicine, has been shown to exert significant anti-inflammatory effects and improve depression-like behavior caused by inflammation. However, the specific mechanism of action of this activity is still unclear. In this study, the lipopolysaccharide (LPS) mouse model was used to study the effect of honokiol on depression-like behavior induced by LPS in mice and its potential mechanism. A single administration of LPS (1 mg/kg, intraperitoneal injection) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), without affecting autonomous activity. Pretreatment with honokiol (10 mg/kg, oral administration) for 11 consecutive days significantly improved the immobility time of depressed mice in the FST and TST experiments. Moreover, honokiol ameliorated LPS-induced NF-κB activation in the hippocampus and significantly reduced the levels of the pro-inflammatory cytokines; tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interferon γ (IFN-γ). In addition, honokiol inhibited LPS-induced indoleamine 2,3-dioxygenase (IDO) activation and quinolinic acid (a toxic product) increase and reduced the level of free calcium in brain tissue, thereby inhibiting calcium overload. In summary, our results indicate that the anti-depressant-like effects of honokiol are mediated by its anti-inflammatory effects. Honokiol may inhibit the LPS-induced neuroinflammatory response through the NF-κB signaling pathway, reducing the levels of related pro-inflammatory cytokines, and furthermore, this may affect tryptophan metabolism and increase neuroprotective metabolites.

Honokiol for cancer therapeutics: A traditional medicine that can modulate multiple oncogenic targets.

In spite of billions of dollars expended on cancer research every year, the incidence rate and the mortality rate due to this widespread disease has increased drastically over the last few decades. Recent reports from the World Health Organization advocate that overall global cancer burden and deaths due to cancer are expected to double by the next decade. Synthetic drugs developed as chemotherapeutics have repeatedly shown adverse side effects and development of chemoresistance. Cancer is basically a multifactorial disease that necessitates the modulation of multiple targets and oncogenic signaling pathways. Honokiol (C18H18O2) is a biphenolic natural compound isolated from the leaves and barks of Magnolia plant species and has been extensively studied for its beneficial effects against several chronic diseases. Honokiol is capable of efficiently preventing the growth of wide variety of tumors such as those of brain, breast, cervical, colon, liver, lung, prostate, skin, and hematological malignancies. Recent work has shown that this phytochemical can modulate various molecular targets such as activation of pro-apoptotic factors, suppression of anti-apoptotic proteins and different transcription factors, downregulation of various enzymes, chemokines, cell surface adhesion molecules, and cell cycle proteins, and inhibition of activity of protein tyrosine kinases and serine/threonine kinases. Because of its pharmacological safety, honokiol can either be used alone or in combination with other chemotherapeutic drugs for the prevention and treatment of cancer. The current review describes in detail the various reports supporting these anti-cancer studies documented with this promising agent.