Novel molecular photosensitizer with simultaneously GSH depletion, aggregation inhibition and accelerated elimination for improved and safe photodynamic therapy.

The major challenges in photodynamic therapy (PDT) are the neutralization of cytotoxic reactive oxygen species (ROS) by the excessive antioxidant glutathione (GSH) in tumor cells, high self-aggregation of most photosensitizers (PSs), and long time to protect from light after treatment. Thus, to develop the molecular PSs for the improved and safe PDT in clinic, a novel and versatile PS (Mal-Pc) has been designed by di-substituting maleimides to the axial positions of silicon (Ⅳ) phthalocyanine. Owning to the conjugation of maleimides, Mal-Pc can not only entry tumor cells more easily and faster, but also can react with the intracellular overexpressed GSH after entry. In addition, upon electrophilic reaction with GSH, the inhibition of self-aggregation of Mal-Pc has been demonstrated by the restoration of the fluorescence emission in aqueous media. As a result, the intracellular ROS levels and photocytotoxicity of Mal-Pc are dramatically enhanced. Finally, the high hydrophilicity of the product GS-conjugates facilitates Mal-Pc eliminate from the normal cells more rapidly. Overall, this work revealed the high potential of the versatile molecular Mal-Pc for highly efficient and safe PDT in clinical translation.

Coumarinolignans with Reactive Oxygen Species (ROS) and NF-κB Inhibitory Activities from the Roots of Waltheria indica.

Seven new coumarinolignans, walthindicins A-F (1a, 1b, 2-5, 7), along with five known analogs (6, 8-11), were isolated from the roots of Waltheria indica. The structures of the new compounds are determined by detailed nuclear magnetic resonance (NMR), circular dichroism (CD) with extensive computational support, and mass spectroscopic data interpretation. Compounds were tested for their antioxidant activity in Human Cervical Cancer cells (HeLa cells). Compounds 1a and 6 showed higher reactive oxygen species (ROS) inhibitory activity at 20 µg/mL when compared with other natural compound-based antioxidants such as ascorbic acid. Considering the role of ROS in nuclear-factor kappa B (NF-κB) activation, compounds 1a and 6 were evaluated for NF-κB inhibitory activity and showed a concentration-dependent inhibition in Human Embryonic Kidney 293 cells (Luc-HEK-293).

Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca2+-NF-κB Signaling.

Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased ß-galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca2+) and activity of nuclear factor kappa B (NF-κB). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca2+, activated NF-κB, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF-κB mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca2+-NF-κB signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence.

Protective role of activating PPARγ in advanced glycation end products-induced impairment of coronary artery vasodilation via inhibiting p38 phosphorylation and reactive oxygen species production.

Advanced glycation end products (AGEs) can damage voltage-gated K+ (Kv) channels and attenuate coronary artery vasodilation, but the underlying mechanisms remain unclear. The aim of this study was to investigate the role and potential mechanism of PPARγ in AGEs-induced Kv 1 channels impairment. We used both primary rat coronary smooth muscle cells (CSMCs) in vitro and Zucker Diabetic Fatty (ZDF) rat model in vivo. Overexpression of the Pparg gene by lentivirus vector (LV-Pparg) was used to transfect CSMCs for upregulation PPARγ. Kv 1.2 and Kv 1.5 currents were measured by patch clamp. The vascular tone of coronary artery was evaluated by isometric force measurements. The proteins expression of Kv1.2 and Kv1.5 channel were detected by western blot. PPARγ was detected by immunofluorescence and western blot. Oxidative stress markers including superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA) were detected by enzyme linked immunosorbent assay (ELISA). The phosphorylation of p38 mitogen-activated protein kinase (MAPK) and total p38 expression were detected by western blot. The intracellular ROS levels were measured by the fluorescent dye 2',7'- dichlorofluorescein diacetate (DCFDA) and a cellular ROS assay kit. We found that activating PPARγ via LV-Pparg (100 MOI, 5 × 108 TU/mL) prevented AGEs (100 µg/mL) -mediated impairment of Kv 1.2 and Kv 1.5 channels activity and improved the reduction of Kv 1.2 and Kv 1.5 protein expression in CSMCs. Isometric force measurements showed that activating PPARγ by pioglitazone (10 mg/kg/d, intragastric administration) improved the impairment of coronary artery vasodilation, and western blot analysis showed that activating PPARγ increased the Kv 1.2 and Kv 1.5 protein expression, while inhibiting PPARγ by GW9662 (10 mg/kg/d, intraperitoneal injection) attenuated these effects in ZDF rats. Furthermore, LV-Pparg overexpression PPARγ attenuated NADPH oxidase activity, which was shown as the reduction of the NOX2 and p22phox expression by western blot analysis, decreased the MDA production and increased the SOD and GPx activities by ELISA, finally led to reduce AGEs-mediated ROS production. Moreover, activating PPARγ by LV-Pparg inhibited AGEs-induced phosphorylation of p38 MAPK, by which could reduce AGEs-mediated NOX2, p22phox expression and ROS production, while CSMCs treatment with SB203580 (10 µmol/L), a p38 MAPK inhibitor, attenuated these effects. Activating PPARγ plays a protective role in AGEs-induced impairment of coronary artery vasodilation by inhibiting p38 phosphorylation to attenuate NOX2 and p22phox expression and further decrease oxidative stress induced by ROS overproduction.

Rational Design of a Cu Chelator That Mitigates Cu-Induced ROS Production by Amyloid Beta.

Alzheimer's disease severely perturbs transition metal homeostasis in the brain leading to the accumulation of excess metals in extracellular and intraneuronal locations. The amyloid beta protein binds these transition metals, ultimately causing severe oxidative stress in the brain. Metal chelation therapy is an approach to sequester metals from amyloid beta and relieve the oxidative stress. Here we have designed a mixed N/O donor Cu chelator inspired by the proposed ligand set of Cu in amyloid beta. We demonstrate that the chelator effectively removes Cu from amyloid beta and suppresses reactive oxygen species (ROS) production by redox silencing and radical scavenging both in vitro and in cellulo. The impact of ROS on the extent of oxidation of the different aggregated forms of the peptide is studied by mass spectrometry, which, along with other ROS assays, shows that the oligomers are pro-oxidants in nature. The aliphatic Leu34, which was previously unobserved, has been identified as a new oxidation site.

Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.

D(-)-salicin inhibits RANKL-induced osteoclast differentiation and function in vitro.

Osteoporosis is a disease, which causes huge economic and social burden. Using natural compound to treat such disease is beneficial for the fewer side effects and effectiveness. D-(-)-salicin (DSA) is a component extracted from the bark of Populus and Salix species. In our research, we discovered that DSA suppressed RANKL-induced differentiation of osteoclast in vitro in a dose-dependent manner. It was also found that the mineral resorbing activity by osteoclasts was depressed via DSA. For the mechanism, we confirmed the inhibitory effect, by which DSA suppressed osteoclast formation and function, was through the inhibition of ROS signaling, MAPK and NF-κB cascades. DSA also suppressed the expression and activity of NFATc1. Therefore, by inhibiting the ROS production, MAPK and NF-κB signal cascade, DSA inhibited the osteoclast differentiation and function in vitro.

Berberine Influences the Survival of Fat Grafting by Inhibiting Autophagy and Apoptosis of Human Adipose Derived Mesenchymal Stem Cells.

OBJECTIVE: Human adipose-derived mesenchymal stem cells (ADSCs) have the potential to be applied to solid organ treatments. However, tissue regeneration is limited by the death of transplanted cells. Ischemia is the main cause of the poor outcome. This study aimed to investigate the effect of berberine (BBR) on ADSCs after fat grafting. METHODS: The antioxidant BBR on apoptosis and autophagy of ADSCs in vitro ischemia model was induced by hypoxia and serum deprivation (HY/SD). The autophagy promoter rapamycin and autophagy inhibitor 3-MA were incubated separately to investigate the crosstalk between autophagy and apoptosis. Pathway inhibitors further verified whether the autophagy and apoptosis were regulated by AMPK/mTor signaling pathway. Fat survival, fibrosis, level of inflammatory cell infiltration, and the effect of angiogenesis after BBR treatment were observed in vivo. RESULTS: BBR could reduce ROS production and reverse the decreasing cell survival rate. HY/SD would induce apoptosis and autophagy in ADSCs, and BBR could alleviate these processes. After interfering with the level of autophagy, we also proved that apoptosis was regulated by autophagy and changed accordingly. The results also indicated that BBR could protect against autophagy and apoptosis of ADSCs through AMPK/mTor pathway. The treated human-derived adipose tissue was transplanted into BALB/c nude mice, and with the intervention of BBR, the fat grafting had a higher survival rate, lower inflammatory cell infiltration and fibrosis level. CONCLUSION: Our present study revealed that BBR was a promising anti-autophagy and apoptosis agent for improving the survival rate of ADSCs during cell transplantation.

Curcumin for parkinson´s disease: potential therapeutic effects, molecular mechanisms, and nanoformulations to enhance its efficacy.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders worldwide. It is caused by the degeneration of dopaminergic neurons from the substantia nigra pars compacta. This neuronal loss causes the dopamine deficiency that leads to a series of functional changes within the basal ganglia, producing motor control abnormalities. L-DOPA is considered the gold standard for PD treatment, and it may alleviate its clinical manifestations for some time. However, its prolonged administration produces tolerance and several severe side effects, including dyskinesias and gastrointestinal disorders. Thus, there is an urgent need to find effective medications, and current trends have proposed some natural products as emerging options for this purpose. Concerning this, curcumin represents a promising bioactive compound with high therapeutic potential. Diverse studies in cellular and animal models have suggested that curcumin could be employed for the treatment of PD. Therefore, the objective of this narrative mini-review is to present an overview of the possible therapeutic effects of curcumin and the subjacent molecular mechanisms. Moreover, we describe several possible nanocarrier-based approaches to improve the bioavailability of curcumin and enhance its biological activity.

Understanding the Photochemical Properties of Polythiophene Polyelectrolyte Soft Aggregates with Sodium Dodecyl Sulfate for Antimicrobial Activity.

The threat of antibiotic-resistant bacteria is an ever-increasing problem in public health. In this report, we examine the photochemical properties with a proof-of-principle biocidal assay for a novel series of regio-regular imidazolium derivative poly-(3-hexylthiophene)/sodium dodecyl sulfate (P3HT-Im/SDS) materials from ultrafast sub-ps dynamics to µs generation of reactive oxygen species (ROS) and 30 min biocidal reactivity with Escherichia coli (E. coli). This broad series encompassing pure P3HT-Im to cationic, neutral, and anionic P3HT-Im/SDS materials are all interrogated by a variety of techniques to characterize the physical material structure, electronic structure, and antimicrobial activity. Our results show that SDS complexation with P3HT-Im results in aggregate materials with reduced ROS generation and light-induced anti-microbial activity. However, our characterization reveals that the presence of non-aggregated or lightly SDS-covered polymer segments is still capable of ROS generation. Full encapsulation of the P3HT-Im polymer completely deactivates the light killing pathway. High SDS concentrations, near and above critical micelle concentration, further deactivate all anti-microbial activity (light and dark) even though the P3HT-Im regains its electronic properties to generate ROS.

Farrerol suppresses the progression of laryngeal squamous cell carcinoma via the mitochondria-mediated pathway.

PURPOSE: In the context of well-known inhibitory effects of Farrerol on the invasion of lung squamous cell carcinoma cells, the unexplored effect and regulatory mechanism of Farrerol on laryngeal squamous cell carcinoma (LSCC) emerged as the target in this study. METHODS: After treatment with Farrerol alone, or together with MitoTempo, the viability, apoptosis, cell cycle distribution, migration, and invasion of LSCC cells were measured using MTT, flow cytometry, wound-healing, and transwell assays, respectively. Meanwhile, the levels of cytochrome C (Cyt C), Cleaved caspase-3/9, Cyclin D1, E-cadherin, N-cadherin, and Vimentin in LSCC cells were evaluated by Western blot; the reactive oxygen species (ROS) formation intensity and the disruption of mitochondrial membrane potential (MMP) of LSCC cells were assessed using flow cytometry; and the effect of Farrerol on xenograft tumor formation was evaluated in animal experiment. RESULTS: Farrerol (10, 20, 50 µM) inhibited the viability, proliferation, cell cycle progression, migration and invasion, but promoted apoptosis, ROS formation intensity and disruption of MMP of LSCC cells. Moreover, Farrerol up-regulated Cyt C (in the cytoplasm), Cleaved caspase-3/9 and E-cadherin levels, but down-regulated Cyclin D1, N-cadherin and Vimentin levels in LSCC cells. Additionally, we uncovered that MitoTempo reversed the promoting effects of Farrerol on ROS formation intensity, apoptosis, and Cyt C and Cleaved caspase-3/9 levels in LSCC cells, while improving the disruption of MMP in Farrerol-treated LSCC cells. Also, Farrerol lessened the volume and weight of mice tumors. CONCLUSIONS: Farrerol suppressed the migration, invasion, and induced the apoptosis of LSCC cells via the mitochondria-mediated pathway.

Azoxystrobin Impairs Neuronal Migration and Induces ROS Dependent Apoptosis in Cortical Neurons.

Fungicides often cause genotoxic stress and neurodevelopmental disorders such as autism (ASD). Fungicide-azoxystrobin (AZOX) showed acute and chronic toxicity to various organisms, and remained a concern for ill effects in developing neurons. We evaluated the neurotoxicity of AZOX in developing mouse brains, and observed prenatal exposure to AZOX reduced neuronal viability, neurite outgrowth, and cortical migration process in developing brains. The 50% inhibitory concentration (IC50) of AZOX for acute (24 h) and chronic (7 days) exposures were 30 and 10 µM, respectively. Loss in viability was due to the accumulation of reactive oxygen species (ROS), and inhibited neurite outgrowth was due to the deactivation of mTORC1 kinase activity. Pretreatment with ROS scavenger- N-acetylcysteine (NAC) reserved the viability loss and forced activation of mTORC1 kinase revived the neurite outgrowth in AZOX treated neurons. Intra-amniotic injection of AZOX coupled with in utero electroporation of GFP-labelled plasmid in E15.5 mouse was performed and 20 mg/kg AZOX inhibited radial neuronal migration. Moreover, the accumulation of mitochondria was significantly reduced in AZOX treated primary neurons, indicative of mitochondrial deactivation and induction of apoptosis, which was quantified by Bcl2/Bax ratio and caspase 3 cleavage assay. This study elucidated the neurotoxicity of AZOX and explained the possible cure from it.

Triangulating the pharmacological properties of thymoquinone in regulating reactive oxygen species, inflammation, and cancer: Therapeutic applications and mechanistic pathways.

Cancer is a heterogeneous disease with high morbidity and mortality rate involving changes in redox balance and deregulation of redox signalling. For decades, studies have involved developing an effective cancer treatment to combat treatment resistance. As natural products such as thymoquinone have numerous health benefits, studies are also focusing on using them as a viable method for cancer treatment, as they have minimal toxic effects compared with standard cancer treatments. Thymoquinone studies have shown numerous mechanisms of action, such as regulation of reactive species interfering with DNA structure, modulating various potential targets and their signalling pathways as well as immunomodulatory effects in vitro and in vivo. Thymoquinone's anti-cancer effect is mainly due to the induction of apoptotic mechanisms, such as activation of caspases, downregulation of precancerous genes, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), anti-tumour cell proliferation, ROS regulation, hypoxia and anti-metastasis. Insight into thymoquinone's potential as an alternative treatment for chemoprevention and inflammation can be accomplished via compiling these studies, to provide a better understanding on how and why it works, as well as its interactions with common chemotherapeutic treatments.

A Family of [Zn6] Complexes from the Carboxylate-Bridge-Supported Assembly of [Zn2] Building Units: Synthetic, Structural, Spectroscopic, and Systematic Biological Studies.

The three discrete [Zn6] complexes [Na3Zn6(cpdp)3(µ-Bz)3(CH3OH)6][ZnCl4][ZnCl3(H2O)]·3CH3OH·1.5H2O (1), [Na3Zn6(cpdp)3(µ-p-OBz)3(CH3OH)6]·2H2O (2), and [Na3Zn6(cpdp)3(µ-p-NO2Bz)3(CH3OH)6]Cl3·2H2O (3), supported by the carboxylate-based multidentate ligand N,N'-bis[2-carboxybenzomethyl]-N,N'-bis[2-pyridylmethyl]-1,3-diaminopropan-2-ol (H3cpdp), have been successfully synthesized and fully characterized (Bz = benzoate; p-OBz = dianion of p-hydroxybenzoic acid; p-NO2Bz = p-nitrobenzoate). The complexes have been characterized by elemental analysis, FTIR, UV-vis, NMR spectroscopy, PXRD, and thermal analysis, including single-crystal X-ray crystallography of 1 and 2. The molecular architectures of 1-3 are built from the self-assembly of their corresponding [Zn2] units, which are interconnected to the central [Na3(CH3OH)6]3+ core by six endogenous benzoate groups, with each linking one Zn(II) and one Na(I) ion in a µ2:η1:η1-syn-anti bidentate fashion. The composition of the (cpdp3-)3/(Zn2+)6 complexes in 1-3 has been observed to be 1:2, on the basis of the UV-vis titration and NMR spectroscopic results, which is further supported by X-ray crystallography. Systematic biological studies performed with a mice model suggested possible antidiabetic efficacy as well as anticancer activities of the complexes. When complexes 1-3 were administered intraperitoneally in mice, 1 showed a lowering in the blood glucose level, overall maintenance of the pancreatic tissue mass, restriction of DNA damage in pancreatic cells, and retention of lipid droplet (LD) frequency, whereas 2 and 3 showed hepatic tissue mass consistency by inhibiting the DNA damage in hepatic cells, prior to the exposure to a potent diabetic inducer, alloxan (ALX). Similar trends of results were observed in inhibiting the generation of reactive oxygen species (ROS) in the pancreatic and hepatic cells, as examined by spectrofluorometric methods. Thus, 1 seems to be a better compound for overall diabetic management and control, whereas 2 and 3 seem to be promising compounds for designing chemopreventive drugs against hepatic carcinoma.

GPR120 Inhibits RANKL-Induced Osteoclast Formation and Resorption by Attenuating Reactive Oxygen Species Production in RAW264.7 Murine Macrophages.

Osteoclasts are large, multinucleated cells that are responsible for the resorption of bone. Bone degenerative diseases, such as osteoporosis, are characterized by overactive osteoclasts. Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) binding to its receptor on osteoclast precursors will trigger osteoclast formation and resorption. The production of reactive oxygen species (ROS) is known to play a crucial role in RANKL-induced osteoclast formation and resorption. G-protein coupled receptor 120 (GPR120) signalling has been shown to affect osteoclast formation, but the exact mechanisms of action require further investigation. RAW264.7 murine macrophages were seeded into culture plates and exposed to the GPR120 agonist, TUG-891, at varying concentrations (20-100 µM) and RANKL to induce osteoclast formation. TUG-891 was shown to inhibit osteoclast formation and resorption without affecting cell viability in RAW264.7 macrophages. TUG-891 further decreased ROS production when compared to RANKL only cells. Antioxidant proteins, Nrf2, HO-1 and NQO1 were shown to be upregulated while the ROS inducing protein, Nox1, was downregulated by TUG-891. Gene silencing revealed that TUG-891 exerted its effects specifically through GPR120. This study reveals that GPR120 signalling may inhibit osteoclast formation and resorption through inhibition on ROS production.

Salpyran: A Cu(II) Selective Chelator with Therapeutic Potential.

We report the rational design of a tunable Cu(II) chelating scaffold, 2-(((2-((pyridin-2-ylmethyl)amino)ethyl)amino)methyl)phenol, Salpyran (HL). This tetradentate ligand is predicated to have suitable permeation, has an extremely high affinity for Cu compared to clioquinol (pCu7.4 = 10.65 vs 5.91), and exhibits excellent selectivity for Cu(II) over Zn(II) in aqueous media. Solid and solution studies corroborate the formation of a stable [Cu(II)L]+ monocationic species at physiological pH values (7.4). Its action as an antioxidant was tested in ascorbate, tau, and human prion protein assays, which reveal that Salpyran prevents the formation of reactive oxygen species from the binary Cu(II)/H2O2 system, demonstrating its potential use as a therapeutic small molecule metal chelator.

Mechanistic Insight into the Design of Chemical Tools to Control Multiple Pathogenic Features in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by memory loss and cognitive decline. Approximately 50 million people worldwide are suffering from AD and related dementias. Very recently, the first new drug targeting amyloid-ß (Aß) aggregates has been approved by the United States Food and Drug Administration, but its efficacy against AD is still debatable. Other available treatments temporarily relieve the symptoms of AD. The difficulty in discovering effective therapeutics for AD originates from its complicated nature, which results from the interrelated pathogenic pathways led by multiple factors. Therefore, to develop potent disease-modifying drugs, multiple pathological features found in AD should be fully elucidated.Our laboratory has been designing small molecules as chemical tools to investigate the individual and interrelated pathologies triggered by four pathogenic elements found in the AD-affected brain: metal-free Aß, metal-bound Aß, reactive oxygen species (ROS), and acetylcholinesterase (AChE). Aß peptides are partially folded and aggregate into oligomers, protofibrils, and fibrils. Aß aggregates are considered to be neurotoxic, causing membrane disruption, aberrant cellular signaling, and organelle dysfunction. In addition, highly concentrated metal ions accumulate in senile plaques mainly composed of Aß aggregates, which indicates that metal ions can directly interact with Aß. Metal binding to Aß affects the aggregation and conformation of the peptide. Moreover, the impaired homeostasis of redox-active Fe(II/III) and Cu(I/II) induces the overproduction of ROS through Fenton chemistry and Fenton-like reactions, respectively. Dysregulated ROS prompt oxidative-stress-damaging biological components such as lipids, proteins, and nucleic acids and, consequently, lead to neuronal death. Finally, the loss of cholinergic transmission mediated by the neurotransmitter acetylcholine (ACh) contributes to cognitive deficits observed in AD.In this Account, we illustrate the design principles for small-molecule-based chemical tools with reactivities against metal-free Aß, metal-bound Aß, ROS, and AChE. More importantly, mechanistic details at the molecular level are highlighted with some examples of chemical tools that were developed by our group. The aggregation of metal-free Aß can be modulated by modifying amino acid residues responsible for self-assembling Aß or disassembling preformed fibrils. To alter the aggregation and cytotoxicity profiles of metal-bound Aß, ternary complexation, metal chelation, and modifications onto metal-binding residues can be effective tactics. The presence and production of ROS are able to be controlled by small molecules with antioxidant and metal-binding properties. Finally, inhibiting substrate access or substrate binding at the active site of AChE can diminish its activity, which restores the levels of ACh. Overall, our rational approaches demonstrate the feasibility of developing small molecules as chemical tools that can target and modulate multiple pathological factors associated with AD and can be useful for gaining a greater understanding of the multifaceted pathology of the disease.

Gene-editing, immunological and iPSCs based therapeutics for muscular dystrophy.

Muscular dystrophy is a well-known genetically heterogeneous group of rare muscle disorders. This progressive disease causes the breakdown of skeletal muscles over time and leads to grave weakness. This breakdown is caused by a diverse pattern of mutations in dystrophin and dystrophin associated protein complex. These mutations lead to the production of altered proteins in response to which, the body stimulates production of various cytokines and immune cells, particularly reactive oxygen species and NFκB. Immune cells display/exhibit a dual role by inducing muscle damage and muscle repair. Various anti-oxidants, anti-inflammatory and glucocorticoid drugs serve as potent therapeutics for muscular dystrophy. Along with the above mentioned therapeutics, induced pluripotent stem cells also serve as a novel approach paving a way for personalized treatment. These pluripotent stem cells allow regeneration of large numbers of regenerative myogenic progenitors that can be administered in muscular dystrophy patients which assist in the recovery of lost muscle fibers. In this review, we have summarized gene-editing, immunological and induced pluripotent stem cell based therapeutics for muscular dystrophy treatment.

What are the immunopharmacological effects of furazolidone? A systematic review.

Furazolidone (FZD) is a widely used drug in human and veterinary medicine, and has antibacterial and antiprotozoal action. Although it is widely used as a therapy in various pathological conditions, studies on the efficacy of FZD associated with immune responses are still limited. In this review, we seek to describe which immunopharmacological responses are caused by the administration of FZD. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review of clinical trials and in vitro and in vivo experimental studies was carried out, which resulted in 943 papers, of which 35 were considered eligible and, of these 35, 4 were selected for analysis. The studies listed indicated that administration of FZD can modulate pro- or anti-inflammatory pathways, with a probable increase in the expression of reactive oxygen species and a modulation of apoptotic pathways.

NAD+ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway.

BACKGROUND: Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD+) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear. METHODS: The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD+ for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD+ treatment effects on mitochondrial injury and neuroinflammation. RESULTS: NAD+ administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD+ treatment markedly reversed their decrease. In vitro study confirmed that NAD+ administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD+ treatment in BV2 microglia. CONCLUSIONS: NAD+ ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway.