Activation of ERß hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.

Novel 4-Aryl-4H-chromene derivative displayed excellent in vivo anti-glioblastoma efficacy as the microtubule-targeting agent.

In this study, a series of novel 4-Aryl-4H-chromene derivatives (D1-D31) were designed and synthesized by integrating quinoline heterocycle to crolibulin template molecule based on the strategy of molecular hybridization. One of these compounds D19 displayed positive antiproliferative activity against U87 cancer cell line (IC50 = 0.90 ± 0.03 µM). Compound D19 was verified as the microtubule-targeting agent through downregulating tubulin related genes of U87 cells, destroying the cytoskeleton of tubulins and interacting with the colchicine-binding site to inhibit the polymerization of tubulins by transcriptome analysis, immune-fluorescence staining, microtubule dynamics and EBI competition assays as well as molecular docking simulations. Moreover, compound D19 induced G2/M phase arrest, resulted in cell apoptosis and inhibited the migration of U87 cells by flow cytometry analysis and wound healing assays. Significantly, compound D19 dose-dependently inhibited the tumor growth of orthotopic glioma xenografts model (GL261-Luc) and effectively prolonged the survival time of mice, which were extremely better than those of positive drug temozolomide (TMZ). Compound D19 exhibited potent in vivo antivascular activity as well as no observable toxicity. Furthermore, the results of in silico simulation studies and P-gp transwell assays verified the positive correlation between compound D19's Blood-Brain Barrier (BBB) permeability and its in vivo anti-GBM activity. Overall, compound D19 can be used as a promising anti-GBM lead compound for the treatment of glioblastoma.

Investigating the disease-modifying properties of sclerotiorin in Alzheimer's therapy using acetylcholinesterase inhibition.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused due to the damage and loss of neurons in specific brain regions. It is the most common form of dementia observed in older people. The symptoms start with memory loss and gradually cause the inability to speak and do day-to-day activities. The cost of caring for those affected individuals is huge and is probably beyond most developing countries capability. Current pharmacotherapy for AD includes compounds that aim to increase neurotransmitters at nerve endings. This can be achieved by cholinergic neurotransmission through inhibition of the cholinesterase enzyme. The current research aims to find natural substances that can be used as drugs to treat AD. The present work identifies and explains compounds with considerable Acetylcholinesterase (AChE) inhibitory activities. The pigment was extracted from the Penicillium mallochii ARA1 (MT373688.1) strain using ethyl acetate, and the active compound was identified using chromatographic techniques followed by structural confirmation with NMR. AChE inhibition experiments, enzyme kinetics, and molecular dynamics simulation studies were done to explain the pharmacological and pharmacodynamic properties. We identified that the compound sclerotiorin in the pigment has AChE inhibitory activity. The compound is stable and can bind to the enzyme non-competitively. Sclerotiorin obeys all the drug-likeliness parameters and can be developed as a promising drug in treating AD.

Comparative appraisal of in vitro biological profile and in vivo wound healing attributes of bergenin and Bergenia ciliata (Haw.) Sternb.

ETHNOPHARMACOLOGICAL RELEVANCE: People of all ages experience injuries, whether mild or severe. The most available option to treat wounds as an alternative to allopathic care in both urban and rural populations is traditional medicine, which is mostly target inflammation. Bergenia ciliata (Haw.) Sternb rhizome and leaf powder are used in Ayurveda and local communities for various ailments including healing of wounds and burns. Owing to this property it is traditionally known as "Zakham-e-hayat" (wound healer). AIM OF THE STUDY: In the present study, we compared biological activity and wound healing potential of B. ciliata rhizome (R) extract and bergenin, a glycoside isolated from B. ciliata. MATERIALS AND METHODS: Reverse-phase high performance liquid chromatography (RP-HPLC) was performed to analyze polyphenols and bergenin in B. ciliata R extract. Samples were subjected to in vitro antioxidant assays including free radical scavenging, ferric chloride reducing power and total antioxidant capacity. Micro-broth dilution method, brine shrimp lethality assay and isolated RBC hemolysis assay were conducted to assess in vitro antibacterial and cytotoxic activities. Moreover, in vivo wound healing potential was determined by an excision wound model in mice. RESULTS: RP-HPLC showed significant content of polyphenols and bergenin (6.05 ± 0.12 µg/mg) in B. ciliata R extract. Crude extract possesses higher overall antioxidant and antibacterial capacities than bergenin due to presence of multiple phytoconstituents in extract. Both samples showed low hemolytic activity indicating their safe profile. Furthermore, mice treated with B. ciliata R extract depicted substantial decrease in wound area (99.3%; p < 0.05) as compared to bergenin, which showed 88.8% of wound closure after 12 days of treatment. Additionally, both treatments reduced epithelization duration by 1.6- and 1.4-fold in B. ciliata R extract (12.0 ± 0.6 days) and bergenin (14.2 ± 0.8 days) treated mice, respectively. This was supported by histopathological examination that showed greater epithelization, fibroblast proliferation, collagen synthesis, and revascularization in mice treated with B. ciliata R. CONCLUSION: Concisely, it is evident that B. ciliata R contains phytoconstituents in addition to bergenin, which potentiated wound healing activity of the extract. Hence, B. ciliata R is good source of compounds for treating wounds.

Synthesis and In Vitro Cytotoxicity of Novel Halogenated Dihydropyrano[3,2-b]Chromene Derivatives.

Lung and breast cancers are among the most common cancers. In the present work, initially, 6-bromo-; and 6-chloro-3-hydroxychromone compounds were prepared. In the next step, a series of 8-bromo-; and 8-chloro-dihyropyrano[3,2-b]chromene derivatives were synthesized by one-pot three component reaction of these two compounds, aromatic aldehydes, and ethyl cyanoacetate in the presence of triethylamine in EtOH at reflux conditions. The synthesized compounds were tested for their in vitro cytotoxic activity against A549 (lung cancer) and MCF-7 (breast cancer) cell lines. It was found that some compounds have high to moderate cytotoxicity, which makes them potential candidates for further studies. This study can be the basis for further studies to design and synthesis potent anticancer compounds and investigating their mechanism of action.

Attenuation of the Severity of Acute Respiratory Distress Syndrome by Pomiferin through Blocking Inflammation and Oxidative Stress in an AKT/Foxo1 Pathway-Dependent Manner.

Acute respiratory distress syndrome (ARDS) gives rise to uncontrolled inflammatory response and oxidative stress, causing very high mortality globally. Pomiferin is a kind of prenylated isoflavonoid extracted from Maclura pomifera, owning anti-inflammatory and antioxidant properties. However, the functions and possible mechanisms of pomiferin in lipopolysaccharide- (LPS-) induced ARDS remain unknown. C57BL/6 mice were injected with LPS (5 mg/kg) intratracheally to induce an in vivo ARDS model while RAW264.7 macrophages were stimulated with LPS (100 ng/ml) to induce an in vitro model. Our data demonstrated that pomiferin (20 mg/kg) significantly improved pulmonary function and lung pathological injury in mice with ARDS, apart from increasing survival rate. Meanwhile, pomiferin treatment also inhibited LPS-induced inflammation as well as oxidative stress in lung tissues. LPS stimulation significantly activated AKT/Foxo1 signal pathway in lung tissues, which could be reversed after pomiferin treatment. In vitro experiments further showed that 10, 20, and 50 µM of pomiferin could enhance cell viability of RAW264.7 macrophages stimulated with LPS. What is more, 3-deoxysappanchalcone (3-DE), one AKT agonist, was used to active AKT in RAW264.7 macrophages. The results further showed that 3-DE could abolish pomiferin-elicited protection in LPS-treated RAW264.7 macrophages, evidenced by activated inflammation and oxidative stress. Taken together, our study showed that pomiferin could exert an ARDS-protective effect by blocking the AKT/Foxo1 signal pathway to inhibit LPS-induced inflammatory response and oxidative injury, which may serve as a potential candidate for the treatment of ARDS in the future.

A Newly Synthesized Derivative and a Natural Parent Molecule: Which Would Be More Beneficial as a Future Antitumor Candidate? Docking and In Vivo Study.

Seeking for new effectual anticancer drugs is of great importance. In this study, a newly synthesized and well-characterized chromene derivative (ethyl 2-amino-4-phenyl-4H-benzo(h)chromene-3-carboxylate) "C" was prepared. Molecular docking studies were done. The new compound "C" in compare to the natural parent Quercetin "Q," as a well-known natural chromene derivative with antioxidant and antitumor activities, were tested for their antitumor activity against Ehrlich ascites carcinoma (EAC)-bearing mice. Both reduced ascites volume, decreased viable EAC cells, and prolonged EAC-bearing mice life span. They normalized troponin, creatine kinase-MB, lactate dehydrogenase, and urea levels, reversed liver enzyme activities towards normal, and increased antioxidant levels while reduced tumor necrosis factor-alpha (TNF-α) levels. Compared to each other, the new synthetic derivative "C" showed stronger antineoplastic effects than the natural parent "Q" may via the anti-inflammatory activities. Therefore, the newly synthesized chromene derivative is more promising as a future antitumor candidate than the natural parent molecule "Quercetin." Finally, our results encourage researchers to pay more attention to developing more novel natural-based derivatives that would be more beneficial as future therapeutics than their natural parents.

Synthesis of Dihydrobenzofuro[3,2-b]chromenes as Potential 3CLpro Inhibitors of SARS-CoV-2: A Molecular Docking and Molecular Dynamics Study.

The recent emergence of pandemic of coronavirus (COVID-19) caused by SARS-CoV-2 has raised significant global health concerns. More importantly, there is no specific therapeutics currently available to combat against this deadly infection. The enzyme 3-chymotrypsin-like cysteine protease (3CLpro) is known to be essential for viral life cycle as it controls the coronavirus replication. 3CLpro could be a potential drug target as established before in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). In the current study, we wanted to explore the potential of fused flavonoids as 3CLpro inhibitors. Fused flavonoids (5a,10a-dihydro-11H-benzofuro[3,2-b]chromene) are unexplored for their potential bioactivities due to their low natural occurrences. Their synthetic congeners are also rare due to unavailability of general synthetic methodology. Here we designed a simple strategy to synthesize 5a,10a-dihydro-11H-benzofuro[3,2-b]chromene skeleton and it's four novel derivatives. Our structural bioinformatics study clearly shows excellent potential of the synthesized compounds in comparison to experimentally validated inhibitor N3. Moreover, in-silico ADMET study displays excellent druggability and extremely low level of toxicity of the synthesized molecules. Further, for better understanding, the molecular dynamic approach was implemented to study the change in dynamicity after the compounds bind to the protein. A detailed investigation through clustering analysis and distance calculation gave us sound comprehensive data about their molecular interaction. In summary, we anticipate that the currently synthesized molecules could not only be a potential set of inhibitors against 3CLpro but also the insights acquired from the current study would be instrumental in further developing novel natural flavonoid based anti-COVID therapeutic spectrums.

Deoxyhypusine hydroxylase as a novel pharmacological target for ischemic stroke via inducing a unique post-translational hypusination modification.

Ischemic stroke remains one of the leading causes of death worldwide, thereby highlighting the urgent necessary to identify new therapeutic targets. Deoxyhypusine hydroxylase (DOHH) is a fundamental enzyme catalyzing a unique posttranslational hypusination modification of eukaryotic translation initiation factor 5A (eIF5A) and is highly involved in the progression of several human diseases, including HIV-1 infection, cancer, malaria, and diabetes. However, the potential therapeutic role of pharmacological regulation of DOHH in ischemic stroke is still poorly understood. Our study first discovered a natural small-molecule brazilin (BZ) with an obvious neuroprotective effect against oxygen-glucose deprivation/reperfusion insult. Then, DOHH was identified as a crucial cellular target of BZ using HuProt™ human proteome microarray. By selectively binding to the Cys232 residue, BZ induced a previously undisclosed allosteric effect to significantly increase DOHH catalytic activity. Furthermore, BZ-mediated DOHH activation amplified mitophagy for mitochondrial function and morphology maintenance via DOHH/eIF5A hypusination signaling pathway, thereby protecting against ischemic neuronal injury in vitro and in vivo. Collectively, our study first identified DOHH as a previously unreported therapeutic target for ischemic stroke, and provided a future drug design direction for DOHH allosteric activators using BZ as a novel molecular template.

Multifunctional Probes with High Utilization Rates: Self-Assembled Merocyanine Nanoparticles in Water as Acid-Base Indicators and Mitochondrion-Targeting Chemotherapeutic Agents.

Multifunctional probes with high utilization rates have great value in practical applications in various fields such as cancer diagnosis and therapy. Here we have synthesized two organic molecules based on merocyanine. They can self-assemble in water to form ∼1.5 nm nanoparticles. Both of them have good application potential in fluorescent anticounterfeit printing ink and pH detection. More importantly, they have excellent mitochondrial targeting ability, intracellular red light and near-infrared dual-channel imaging ability, strong antiphotobleaching ability, and in vivo and in vitro near-infrared imaging capabilities, showing superior chemotherapy capabilities and biocompatibility in the 4T1 tumor-bearing mouse model.

KR-31831 improves survival and protects hematopoietic cells and radiosensitive tissues against radiation-induced injuries in mice.

This study explored the radioprotective effects and possible underlying mechanisms of KR-31831 against radiation-induced injury in a mouse model. KR-31831 (30 and 50 mg/kg) was administered to mice 24 h and 30 min before exposure to a single lethal or sublethal dose of whole-body irradiation (WBI) (7 or 4 Gy, respectively). These animals were then evaluated for changes in mortality, various hematological and biochemical parameters, and histological features in response to these treatments. In addition, RNA sequencing was used to profile the radiation-induced transcriptomic response in the bone marrow cells. The results showed that KR-31831 dose-dependently prolonged the 30-day survival period and prevented damage to radiation-sensitive organs, such as the intestine and testis, in response to WBI. Damage to the hematopoietic system was also notably improved in the KR-31831-treated mice, as evidenced by an increase in bone marrow and peripheral blood cells, as well as recovery of the histopathological characteristics of the bone marrow. These protective effects were achieved, at least in part, via the suppression of radiation-induced increases in apoptotic cell death and erythropoietin levels in the plasma. Furthermore, the gene expression profiles of the bone marrow cells of the WBI-treated mice suggested that KR-31831 upregulates the expression of the genes involved in regulating apoptosis and modulating the immune response, both of which are required for protecting the bone marrow. These results suggest the potential therapeutic efficacy of KR-31831 for protection against radiation-induced injury.

Brazilin: Biological activities and therapeutic potential in chronic degenerative diseases and cancer.

Caesalpinia sappan and Haematoxylum brasiletto belong to the Fabaceae family, predominantly distributed in Southeast Asia and America. The isoflavonoid brazilin has been identified from the bark and heartwood of these plants. This review summarizes the studies describing the biological activities of these plants and brazilin. Mainly, brazilin protects cells from oxidative stress, shows anti-inflammatory and antibacterial properties, and hypoglycemic effect. In addition, it has a biological impact on various pathologies such as Alzheimer's disease, Parkinson's disease, fibrillogenesis, and osteoarthritis. Interestingly, most of the antecedents are related to the anticancer effect of brazilin. In several cancers such as osteosarcoma, neuroblastoma, multiple myeloma, glioblastoma, bladder, melanoma, breast, tongue, colon, cervical, head, and neck squamous cell carcinoma, brazilin induces autophagy by increasing the levels of the LC3-II protein. Furthermore, it inhibits cell proliferation and induces apoptosis through increased expression of Bcl-2, Bcl-XL, p21, p27, activation of caspase-3 and -7, and the cleavage of PARP and inhibiting the expression of Bax. In addition, it blocks the expression of JNK and regulates the nuclear translocation of Nrf2. Together, these data positions brazilin as a compound of natural origin with multiple bioactivities and therapeutic potential in various chronic degenerative diseases and cancer.

Imino-2H-Chromene Based Derivatives as Potential Anti-Alzheimer's Agents: Design, Synthesis, Biological Evaluation and in Silico Study.

A new series of imino-2H-chromene derivatives were rationally designed and synthesized as novel multifunctional agents against Alzheimer's disease. A set of phenylimino-2H-chromenes as well as the newly synthesized iminochromene derivatives were evaluated as BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitors. The results indicated that among the iminochromene set, 10c bearing fluorobenzyl moiety was the most potent BACE1 inhibitor with an IC50 value 6.31 µM. In vitro anti-cholinergic activities demonstrated that compound 10a bearing benzyl pendant was the best inhibitor of AChE (% inhibition at 30 µM=24.4) and BuChE (IC50 =3.3 µM). Kinetic analysis of compound 10a against BuChE was also performed and showed a mixed-type inhibition pattern. The neuroprotective assessment revealed that compound 11b, a phenylimino-2H-chromene derivative with hydroxyethyl moiety, provided 32.3 % protection at 25 µM against Aß-induced PC12 neuronal cell damage. In addition, docking and simulation studies of the most potent compounds against BACE1 and BuChE confirmed the experimental results.

New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics.

Schizophrenia is associated with substantial unmet needs, highlighting the necessity for new treatments. This narrative review compares the pharmacology, clinical trial data and tolerability of novel medications to representative antipsychotics. Cariprazine, brexpiprazole and brilaroxazine are partial dopamine agonists effective in acute relapse. Lumateperone (serotonin and dopamine receptor antagonist) additionally benefits asocial and depressive symptoms. F17464 (D3 antagonist and 5-HT1A partial agonist) has one positive phase II study. Lu AF35700 (dopamine and serotonin receptor antagonist) was tested in treatment-resistance with no positive results. Pimavanserin, roluperidone, ulotaront and xanomeline do not act directly on the D2 receptor at clinical doses. Initial studies indicate pimavanserin and roluperidone improve negative symptoms. Ulotaront and xanomeline showed efficacy for positive and negative symptoms of schizophrenia in phase II trials. BI 409306, BI 425809 and MK-8189 target glutamatergic dysfunction in schizophrenia, though of these only BI 425809 showed efficacy. These medications largely have favourable cardiometabolic side-effect profiles. Overall, the novel pharmacology, clinical trial and tolerability data indicate these compounds are promising new additions to the therapeutic arsenal.

Novel Combined Preparation and Investigation of Bergenin-Loaded Albumin Nanoparticles for the Treatment of Acute Lung Injury: In Vitro and In Vivo Evaluations.

A new method for targeting lung infections is of great interest using biodegradable nanoparticles. In this study, bergenin-loaded BSA NPs were developed against lung injury. Briefly, bergenin-loaded bovine serum albumin nanoparticles (BG@BSA NPs) were synthesized and characterized. HPLC recorded the major peak of bergenin. UV-Vis spectra had an absorbance at 376 nm. XRD revealed the presence of crystalline particles. FTIR confirmed the occurrence of functionalized molecules in the synthesized NPs. The particles were highly stable with a net negative charge of - 24.2. The morphology of NPs was determined by SEM and TEM. The mean particle size was 124.26 nm. The production of NO by NR8383 cells was decreased by BG@BSA NPs. Also, in mice, lipopolysaccharide-mediated acute lung inflammation was induced. BG@BSA NPs reduced macrophages and neutrophils in BALF and remarkably enhanced wet weight-to-dry weight (W/D) ratios and myeloperoxidase (MPO) activity. Further, BG@BSA NPs inhibited the production of inflammatory cells as well as tumor necrosis factor. The histopathological studies revealed that the damage and neutrophil infiltration were greatly inhibited by BG@BSA NPs. This indicates that BG@BSA NPs may be used to treat lung infections. Therefore, this study has given new insight into producing an active drug for the treatment of lung-associated diseases in the future.

Bergenin, a PPARγ agonist, inhibits Th17 differentiation and subsequent neutrophilic asthma by preventing GLS1-dependent glutaminolysis.

Bergenin is a natural PPARγ agonist that can prevent neutrophil aggregation, and often be used in clinics for treating respiratory diseases. Recent data show that Th17 cells are important for neutrophil aggregation and asthma through secreting IL-17A. In this study, we investigated the effects of bergenin on Th17 differentiation in vitro and subsequent neutrophilic asthma in mice. Naïve T cells isolated from mouse mesenteric lymph nodes were treated with IL-23, TGF-ß, and IL-6 to induce Th17 differentiation. We showed that in naïve T cells under Th17-polarizing condition, the addition of bergenin (3, 10, 30 µM) concentration-dependently decreased the percentage of CD4+ IL-17A+ T cells and mRNA expression of specific transcription factor RORγt, and function-related factors IL-17A/F, IL-21, and IL-22, but did not affect the cell vitality and apoptosis. Furthermore, bergenin treatment prevented GLS1-dependent glutaminolysis in the progress of Th17 differentiation, slightly affected the levels of SLC1A5, SLC38A1, GLUD1, GOT1, and GPT2. Glutamine deprivation, the addition of glutamate (1 mM), α-ketoglutarate (1 mM), or GLS1 plasmid all significantly attenuated the above-mentioned actions of bergenin. Besides, we demonstrated that bergenin (3, 10, and 30 µM) concentration-dependently activated PPARγ in naïve T cells, whereas PPARγ antagonist GW9662 and siPPARγ abolished bergenin-caused inhibition on glutaminolysis and Th17 differentiation. Furthermore, we revealed that bergenin inhibited glutaminolysis by regulating the level of CDK1, phosphorylation and degradation of Cdh1, and APC/C-Cdh1-mediated ubiquitin-proteasomal degradation of GLS1 after activating PPARγ. We demonstrated a correlation existing among bergenin-affected GLS1-dependent glutaminolysis, PPARγ, "CDK1-APC/C-Cdh1" signaling, and Th17 differentiation. Finally, the therapeutic effect and mechanisms for bergenin-inhibited Th17 responses and neutrophilic asthma were confirmed in a mouse model of neutrophilic asthma by administration of GW9662 or GLS1 overexpression plasmid in vivo. In conclusion, bergenin repressed Th17 differentiation and then alleviated neutrophilic asthma in mice by inhibiting GLS1-dependent glutaminolysis via regulating the "CDK1-APC/C-Cdh1" signaling after activating PPARγ.

Anti-Inflammatory Azaphilones from the Edible Alga-Derived Fungus Penicillium sclerotiorum.

To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae Grateloupia sp. Two new azaphilones, 8a-epi-hypocrellone A (1), 8a-epi-eupenicilazaphilone C (2), together with five known azaphilones, hypocrellone A (3), eupenicilazaphilone C (4), ((1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde (5), sclerotiorin (6), and isochromophilone IV (7) were isolated from the alga-derived fungus Penicillium sclerotiorum. The structures of isolated azaphilones (1-7) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound 1 showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 µM of compounds 1, 3, and 7 inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds 2 and 6 respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-ß.

Potent efficacy of Stachybotrys microspora triprenyl phenol-7, a small molecule having anti-inflammatory and antioxidant activities, in a mouse model of acute kidney injury.

Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD), complicates existing CKD, and can lead to the end-stage renal disease. However, there are no approved effective therapeutics for AKI. Recent studies have suggested that inflammation and oxidative stress are the primary causes of AKI. We previously reported the potential anti-inflammatory and antioxidant activities of Stachybotrys microspora triprenyl phenol-7 (SMTP-7). The aim of the present study was to evaluate the efficacy of SMTP-7 in AKI model mice. AKI was induced in mice by ischemia of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the removal of right kidney. The efficacy of SMTP-7 was determined by measuring the renal function using urine and serum samples and morphological assessment. For deciphering the mechanism of action of SMTP-7, inflammatory cytokines and oxidative stress in kidney were detected. SMTP-7 (0.01, 0.1, 1, 10 mg/kg) dose-dependently improved the renal function. In addition, it improved the damage to renal tubules and exhibited anti-inflammatory and antioxidant activities in the kidney of AKI mice. These results indicate the potential of SMTP-7 as a medicinal compound for the treatment of AKI.

The role of nebivolol in the management of hypertensive patients: from pharmacological profile to treatment guidelines.

According to the most recent international guidelines, ß-blockers maintain a central role in the management of hypertension, being recommended at any treatment step when there is a specific indication, such as heart failure, angina, postacute myocardial infarction, atrial fibrillation or pregnancy. However, ß-blockers are not a homogeneous class: individual molecules differ in terms of pharmacological and clinical profile and are therefore suitable for different patient subtypes. In particular nebivolol, a third generation ß1-selective ß-blocker with vasodilating properties, neutral metabolic effects and good tolerability, proved to have advantages over other ß-blockers, which makes the drug suitable in a wide variety of hypertensive patients with or without comorbidities.

Lay abstract ß-blockers are the main class of antihypertensive agents currently available. Nebivolol is one of the most recent ß-blocking agents and it has vasodilating effects which may be useful in hypertensive patients with heart disease of ischemic (restriction in blood supply) origin or with erectile dysfunction. It has a good tolerability profile which makes it safe to use in patients with metabolic abnormalities (such as diabetes or dyslipidemia) or chronic obstructive pulmonary diseases.

Antiviral activity of Mulberroside C against enterovirus A71 in vitro and in vivo.

Enterovirus A71 (EV-A71) is one of the main causative agents of hand, foot and mouth disease which seriously threatens young children's health and lives. However, there is no effective therapy currently available for treating these infections. Therefore, effective drugs to prevent and treat EV-A71 infections are urgently needed. Here, we identified Mulberroside C potently against the proliferation of EV-A71. The in-vitro anti-EV-A71 activity of Mulberroside C was assessed by cytopathic effect inhibition and viral plaque reduction assays, and the results showed that Mulberroside C significantly inhibited EV-A71 infection. The downstream assays affirmed that Mulberroside C inhibited viral protein and RNA synthesis. Furthermore, Mulberroside C effectively reduced clinical symptoms in EV-A71 infected mice and reduced mortality at higher concentrations. The mechanism study indicated that Mulberroside C bound to the hydrophobic pocket of viral capsid protein VP1, thereby preventing viral uncoating and genome release. Taken together, our study indicated that Mulberroside C could be a promising EV-A71 inhibitor and worth extensive preclinical investigation as a lead compound.