Acupuncture protects from 6-OHDA-induced neuronal damage by balancing the ratio of DMT1/Fpn1

ObjectiveAcupuncture is a commonly used method to provide motor-symptomatic relief for patients with Parkinson s disease (PD). Our objective was to evaluate protective effects of acupuncture treatment and potential underlying mechanisms according to the “gut-brain axis” theory.MethodsWe employed a 6-OHDA-induced PD rat model. The effects of acupuncture on disease development were assessed by behavioural tests and immunohistochistry (IHC). ELISA, qPCR and western blot (WB) were employed to measure inflammatory parameters and Fe metabolism in the substantia nigra (SN), striatum, duodenum and blood, respectively.ResultsOur data show that acupuncture can significantly increase the expression of tyrosine hydroxylase (TH), compared with untreated and madopa treated rats (P < 0.01 and P < 0.05, respectively). Furthermore we could observe significantly decreased levels of pro-inflammatory markers in the duodenum and serum (P < 0.05), reduced deposition of Fe in the substantia nigra (P < 0.05) and but no change in transferrin expression after acupuncture treatment. The mRNA ratio of DMT1/Fpn1 in the SN of acupuncture treated rats (1.1) was comparable to that of the sham group (1.0) which differed both significantly from the untreated and madopa treated groups (P < 0.05). Furthermore, after acupuncture expression of α-synuclein was decreased in the duodenum.ConclusionsAcupuncture can reduce iron accumulation in the SN and protect the loss of dopamine neurons by promoting balanced expression of the iron importer DMT1 and the iron exporter Fpn1. Furthermore CNS iron homeostasis may be affected by reduced systemic and intestinal inflammation.     

The biotrophy-associated secreted protein 4 (BAS4) participates in the transition of Magnaporthe oryzae from the biotrophic to the necrotrophic phase

The physiological and metabolic processes of host plants are manipulated and remodeled by phytopathogenic fungi during infection, revealed obvious signs of biotrophy of the hemibiotrophic pathogen. As we known that effector proteins play key roles in interaction of hemibiotrophic fungi and their host plants. BAS4 (biotrophy-associated secreted protein 4) is an EIHM (extrainvasive hyphal membrane) matrix protein that was highly expressed in infectious hyphae. In order to study whether BAS4 is involved in the transition of rice blast fungus from biotrophic to necrotrophic phase, The susceptible rice cultivar Lijiangxintuanheigu (LTH) that were pre-treated with prokaryotic expression product of BAS4 and then followed with inoculation of the blast strain, more serious blast disease symptom, more biomass such as sporulation and fungal relative growth, and lower expression level of pathogenicity-related genes appeared in lesion of the rice leaves than those of the PBS-pretreated-leaves followed with inoculation of the same blast strain, which demonstrating that BAS4 invitro changed rice defense system to facilitate infection of rice blast strain. And the susceptible rice cultivar (LTH) were inoculated withBAS4-overexpressed blast strain, we also found more serious blast disease symptom and more biomass also appeared in lesion of leaves inoculated with BAS4-overexpressed strain than those of leaves inoculated with the wild-type strain, and expression level of pathogenicity-related genes appeared lower in biotrophic phase and higher in necrotrophic phase of infection, indicating BAS4 maybe in vivo regulate defense system of rice to facilitate transition of biotrophic to necrotrophic phase. Our data demonstrates that BAS4 in vitro and in vivo participates in transition from the biotrophic to the necrotrophic phase of Magnaporthe oryzae.     

LAMMER kinase contributes to genome stability in Ustilago maydis

Here we report identification of the lkh1 gene encoding a LAMMER kinase homolog (Lkh1) from a screen for DNA repair-deficient mutants in Ustilago maydis. The mutant allele isolated results from a mutation at glutamine codon 488 to a stop codon that would be predicted to lead to truncation of the carboxy-terminal kinase domain of the protein. This mutant (lkh1^Q488*) is highly sensitive to ultraviolet light, methyl methanesulfonate, and hydroxyurea. In contrast, a null mutant (lkh1Δ) deleted of the entire lkh1 gene has a less severe phenotype. No epistasis was observed when an lkh1^Q488* rad51Δ double mutant was tested for genotoxin sensitivity. However, overexpressing the gene for Rad51, its regulator Brh2, or the Brh2 regulator Dss1 partially restored genotoxin resistance of the lkh1Δ and lkh1^Q488* mutants. Deletion of lkh1 in a chk1Δ mutant enabled these double mutant cells to continue to cycle when challenged with hydroxyurea. lkh1Δ and lkh1^Q488* mutants were able to complete the meiotic process but exhibited reduced heteroallelic recombination and aberrant chromosome segregation. The observations suggest that Lkh1 serves in some aspect of cell cycle regulation after DNA damage or replication stress and that it also contributes to proper chromosome segregation in meiosis.     

Role of interleukin-6 to differentiate sepsis from non-infectious systemic inflammatory response syndrome

Differentiating between sepsis and non-infectious systemic inflammatory response syndrome (SIRS) poses a great challenge. Several potential bloodstream biomarkers including Interleukin 6 (IL-6) have been investigated for their ability to diagnose sepsis. We conducted the present meta-analysis to evaluate the diagnostic quality of IL-6 in differentiating sepsis from non-infectious SIRS in adults. We also compared its accuracy with procalcitonin (PCT) and C-reactive protein (CRP). PubMed and EMBASE were systematically searched for studies published up to January 18, 2016. Twenty articles containing 22 studies and 2680 critically ill patients were included, of which, 21 studies also involved PCT and 14 involved CRP. Quantitative synthesis of studies showed that the pooled sensitivity/specificity of IL-6 and PCT were 0.68/0.73 and 0.78/0.67. The area under the curve (AUC) of IL-6, PCT and CPR for diagnosis of sepsis was 0.80, 0.83, and 0.71, respectively. This meta-analysis provides evidence that the IL-6 test has moderate diagnostic performance in differentiating sepsis from non-infectious SIRS in adults. IL-6 and PCT test has similar diagnostic value but higher than CRP. Considering its relatively high specificity, we recommend the use of IL-6 as a diagnostic aid to confirm infection rather than exclude infection in patients with SIRS.     

Potential chemical transformation of phosphinic acid derivatives and their applications in the synthesis of drugs

The chemical transformation of phosphinic acid is a well-considered mature area of research on account of the historical significant reactions such as Kabachnik–Fields, Mannich, Arbuzov, Michaelis–Becker, etc. Considerable advances have been made over last years especially in metal-catalyzed, free-radical processes and asymmetric synthesis using catalytic enantioselective. As a result, the aim of this synopsis is to make the reader familiar with advances in the approaches of phosphinic acids toward the synthesis of highly functionalized and valuable buildings blocks. Another purpose of this survey is to provide the current status of the applications of phosphinic acids in the synthesis of drugs.     

Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties

Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates.     

Role of antigen presentation in the production of pro-inflammatory cytokines in obese adipose tissue

Type II diabetes regroups different physiological anomalies that ultimately lead to low-grade chronic inflammation, insulin resistance and loss of pancreatic β-cells. Obesity is one of the best examples of such a condition that can develop into Metabolic Syndrome, causing serious health problems of great socio-economic consequences. The pathological outcome of obesity has a genetic basis and depends on the delicate balance between pro- and anti-inflammatory effectors of the immune system. The causal link between obesity and inflammation is well established. While innate immunity plays a key role in the development of a pro-inflammatory state in obese adipose tissues, it has now become clear that adaptive immune cells are also involved and participate in the cascade of events that lead to metabolic perturbations. The efficacy of some immunotherapeutic protocols in reducing the symptoms of obesity-driven metabolic syndrome in mice implicated all arms of the immune response. Recently, the production of pathogenic immunoglobulins and pro-inflammatory cytokines by B and T lymphocytes suggested an auto-immune basis for the establishment of a non-healthy obese state. Understanding the cellular landscape of obese adipose tissues and how immune cells sustain chronic inflammation holds the key to the development of targeted therapies. In this review, we emphasize the role of antigen-presenting cells and MHC molecules in obese adipose tissue and the general contribution of the adaptive arm of the immune system in inflammation-induced insulin resistance.     

The steroid hormone 20-hydroxyecdysone promotes switching from autophagy to apoptosis by increasing intracellular calcium levels

Autophagy regulates cell survival (or cell death in several cases), whereas apoptosis regulates cell death. However, the relationship between autophagy and apoptosis and the regulative mechanism is unclear. We report that steroid hormone 20-hydroxyecdysone (20E) promotes switching from autophagy to apoptosis by increasing intracellular calcium levels in the midgut of the lepidopteran insect Helicoverpa armigera. Autophagy and apoptosis sequentially occurred during midgut programmed cell death under 20E regulation, in which lower concentrations of 20E induced microtubule-associated protein 1 light chain 3–phosphatidylethanolamine (LC3–II, also known as autophagy-related gene 8, ATG8) expression and autophagy. High concentrations of 20E induced cleavage of ATG5 to NtATG5 and pro-caspase-3 to active caspase-3, which led to a switch from autophagy to apoptosis. Blocking autophagy by knockdown of ATG5, ATG7, or ATG12, or with the autophagy inhibitor 3-methyladenine, inhibited 20E-induced autophagy and apoptosis. Blocking apoptosis by using the apoptosis inhibitor Ac-DEVD-CHO did not prevent 20E-induced autophagy, suggesting that apoptosis relies on autophagy. ATG5 knockdown resulted in abnormal pupation and delayed pupation time. High concentrations of 20E induced high levels of intracellular Ca²⁺, NtATG5, and active caspase-3, which mediated the switch from autophagy to apoptosis. Blocking 20E-mediated increase of cellular Ca²⁺ caused a decrease of NtATG5 and active caspase-3 and repressed the transformation from autophagy to apoptosis, thereby promoting cell survival. 20E induces an increase in the concentration of intracellular Ca²⁺, thereby switching autophagic cell survival to apoptotic cell death.     

The relationship of corticospinal excitability with pain,motor performance and disability in subjects with chronic wrist/hand pain

There is a growing body of evidence of changes in corticospinal excitability associated with musculoskeletal disorders, however there is a lack of knowledge of how these changes relate to measures of pain, motor performance and disability. An exploratory study was performed utilizing Transcranial Magnetic Stimulation to investigate differences in corticospinal excitability in the Abductor Pollicis Brevis (APB) between 15 pain-free subjects and 15 subjects with chronic wrist/hand pain and to determine how corticospinal excitability was associated with measures of pain (visual analog scale, AUSCAN™), hand motor performance (isometric and key pinch strength, Purdue Pegboard Test), disability (AUSCAN™), and spinal motoneuronal excitability. Input–output curves demonstrated increased corticospinal excitability of the APB in the affected hand of subjects with chronic pain (p < 0.01). Changes in corticospinal excitability were significantly correlated with pain intensity (r = 0.77), disability (r = 0.58), and negatively correlated with motoneuronal excitability (r = −0.57). Corticospinal excitability in subjects with heterogeneous injuries of the wrist/hand was associated with disability and pain.     

Therapeutic utility of the newly discovered properties of interleukin-21

Since its discovery in 2000, interleukin-21 (IL-21) has been shown to display a broad spectrum of pleiotropic actions including the regulation of development, differentiation and function of lymphoid-myeloid cells. More specifically, IL-21 modulates the effector functions of T, B and NK cells, which not only have key roles in antitumoral and antiviral immunity but also in exerting major effects on inflammatory responses promoting the development of autoimmune diseases. Recent studies have unveiled an unexpected role for IL-21 in immune regulation and de novo T-cell development. While highlighting its critical role in immunity, this review will mainly focus on recent advances in IL-21 biology and how such newly discovered properties could potentially be exploited therapeutically in the establishment of future clinical trials.     

EWGWS insert in Plasmodium falciparum ookinete surface enolase is involved in binding of PWWP containing peptides: Implications to mosquito midgut invasion by the parasite

There are multiple stages in the life cycle of Plasmodium that invade host cells. Molecular machinery involved is such host–pathogen interactions constitute excellent drug targets and/or vaccine candidates. A screen using a phage display library has previously demonstrated presence of enolase on the surface of the Plasmodium ookinete. Phage-displayed peptides that bound to the ookinete contained a conserved motif (PWWP) in their sequence. Here, direct binding of these peptides with recombinant Plasmodium falciparum enolase (rPfeno) was investigated. These peptides showed specific binding to rPfeno, but failed to bind to other enolases. Plasmodium spp enolases are distinct in having an insert of five amino acids (¹⁰⁴EWGWS¹⁰⁸) that is not found in host enolases. The possibility of this insert being the recognition motif for the PWWP containing peptides was examined, (i) by comparing the binding of the peptides with rPfeno and a deletion variant Δ-rPfeno lacking ¹⁰⁴EWGWS¹⁰⁸, (ii) by measuring the changes in proton chemical shifts of PWWP peptides on binding to different enolases and (iii) by inter-molecular docking experiment to locate the peptide binding site. Results from these studies showed that the pentapeptide insert of Pfeno indeed constitutes the binding site for the PWWP domain containing peptide ligands. Search for sequences homologous to phage displayed peptides among peritrophic matrix proteins resulted in identification of perlecan, laminin, peritrophin and spacran. The possibility of these PWWP domain-containing proteins in the peritrophic matrix of insect gut to interact with ookinete cell surface enolase and facilitate the invasion of mosquito midgut epithelium is discussed.     

Understanding the local actions of lipids in bone physiology

The adult skeleton is a metabolically active organ system that undergoes continuous remodeling to remove old and/or stressed bone (resorption) and replace it with new bone (formation) in order to maintain a constant bone mass and preserve bone strength from micro-damage accumulation. In that remodeling process, cellular balances – adipocytogenesis/osteoblastogenesis and osteoblastogenesis/osteoclastogenesis – are critical and tightly controlled by many factors, including lipids as discussed in the present review.Interest in the bone lipid area has increased as a result of in vivo evidences indicating a reciprocal relationship between bone mass and marrow adiposity. Lipids in bones are usually assumed to be present only in the bone marrow. However, the mineralized bone tissue itself also contains small amounts of lipids which might play an important role in bone physiology. Fatty acids, cholesterol, phospholipids and several endogenous metabolites (i.e., prostaglandins, oxysterols) have been purported to act on bone cell survival and functions, the bone mineralization process, and critical signaling pathways. Thus, they can be regarded as regulatory molecules important in bone health. Recently, several specific lipids derived from membrane phospholipids (i.e., sphingosine-1-phosphate, lysophosphatidic acid and different fatty acid amides) have emerged as important mediators in bone physiology and the number of such molecules will probably increase in the near future. The present paper reviews the current knowledge about: (1°) bone lipid composition in both bone marrow and mineralized tissue compartments, and (2°) local actions of lipids on bone physiology in relation to their metabolism. Understanding the roles of lipids in bone is essential to knowing how an imbalance in their signaling pathways might contribute to bone pathologies, such as osteoporosis.     

Differential changes in galactolipid and phospholipid species in soybean leaves and roots under nitrogen deficiency and after nodulation

The availability of nitrogen (N) to plants has a profound impact on carbohydrate and protein metabolism, but little is known about its effect on membrane lipid species. This study examines the changes in galactolipid and phospholipid species in soybean as affected by the availability of N, either supplied to soil or obtained through Bradyrhizobium japonicum nodulation. When N was limited in soil, the content of galactolipids, monogalactosyldiacylglycerol (MGDG) and digalactosyldiacyglycerol (DGDG), decreased drastically in leaves, while a smaller decrease of DGDG was observed in roots. In both leaves and roots, the overall content of different phospholipid classes was largely unchanged by N limitation, although some individual phospholipid molecular species did display significant changes. Nodulation with Bradyrhizobium of soybean grown in N-deficient soil resulted in a large increase in levels of plastidic lipid classes, MGDG, DGDG, and phosphatidylglycerol, along with smaller increases in non-plastidic phospholipids in leaves. Nodulation also led to higher levels of phospholipids in roots without changes in root levels of MGDG and DGDG. Overall, N availability alters lipid content more in leaves than roots and more in galactolipids than phospholipids. Increased N availability leads to increased galactolipid accumulation in leaves, regardless of whether N is supplied from the soil or symbiotic fixation.     

Novel quinazolin-4-one derivatives as potentiating agents of doxorubicin cytotoxicity

We report the design, synthesis and biological evaluation of 17 novel 8-aryl-2-morpholino-3,4-dihydroquinazoline derivatives based on the standard model of DNA-PK and PI3K inhibitors. Novel compounds are sub-divided into two series where the second series of five derivatives was designed to have a better solubility profile over the first one. A combination of in vitro and in silico techniques suggested a plausible synergistic effect with doxorubicin of the most potent compound 14d on cell proliferation via DNA-PK and poly(ADP-ribose) polymerase-1 (PARP-1) inhibition, while alone having a negligible effect on cell proliferation.     

The effect of Zn2+ on Euphausia superba arginine kinase: Unfolding and aggregation studies

Arginine kinase plays an important role in the cellular energy metabolism of invertebrates. We investigated the effects of Zn²⁺ on the enzymatic activity and unfolding and aggregation of Euphausia superba arginine kinase (ESAK). Zn²⁺ inhibited the activity of ESAK (IC₅₀ = 0.027 ± 0.002 mM) following first-order kinetics consistent with the transition from a mono-phasic to a bi-phasic reaction. Double-reciprocal Lineweaver–Burk plots indicated that Zn²⁺ induced non-competitive inhibition of arginine and ATP. Circular dichroism spectra and spectrofluorometry results showed that Zn²⁺ induced secondary and tertiary structural changes in ESAK with exposure of hydrophobic surfaces and directly induced ESAK aggregation. The addition of osmolytes such as glycine and proline successfully blocked ESAK aggregation, recovering the conformation and activity of ESAK. Our study demonstrates the effect of Zn²⁺ on ESAK enzymatic function and folding and unfolding mechanisms, and might provide important insights into other metabolic enzymes of invertebrates in extreme climatic marine environments.     

Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC

Chronic exposure to arsenic, most often through contaminated drinking water, has been linked to several types of cancer in humans, including skin and lung cancer. However, the mechanisms underlying its role in causing cancer are not well understood. There is evidence that exposure to arsenic can enhance the carcinogenicity of UV light in inducing skin cancers and may enhance the carcinogenicity of tobacco smoke in inducing lung cancers. The nucleotide excision repair (NER) pathway removes different types of DNA damage including those produced by UV light and components of tobacco smoke. The aim of the present study was to investigate the effect of sodium arsenite on the NER pathway in human lung fibroblasts (IMR-90 cells) and primary mouse keratinocytes. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts (6-4 PP) and cyclobutane pyrimidine dimers (CPDs). We find a concentration-dependent inhibition of the removal of 6-4 PPs and CPDs in both cell types treated with arsenite. Treatment of both cell types with arsenite resulted in a significant reduction in the abundance of XPC, a protein that is critical for DNA damage recognition in NER. The abundance of RNA expressed from several key NER genes was also significantly reduced by treatment of IMR-90 cells with arsenite. Finally, treatment of IMR-90 cells with MG-132 abrogated the reduction in XPC protein, suggesting an involvement of the proteasome in the reduction of XPC protein produced by treatment of cells with arsenic. The inhibition of NER by arsenic may reflect one mechanism underlying the role of arsenic exposure in enhancing cigarette smoke-induced lung carcinogenesis and UV light-induced skin cancer, and it may provide some insights into the emergence of arsenic trioxide as a chemotherapeutic agent.     

Promising antibacterial agents against multidrug resistant Staphylococcus aureus

Rapid emergence of multidrug resistant Staphylococcus aureus infections has created a critical health menace universally. Resistance to all the available chemotherapeutics has been on rise which led to WHO to stratify Staphylococcus aureus as high tier priorty II pathogen. Hence, discovery and development of new antibacterial agents with new mode of action is crucial to address the multidrug resistant Staphylococcus aureus infections. The egressing understanding of new antibacterials on their biological target provides opportunities for new therapeutic agents. This review underlines on various aspects of drug design, structure activity relationships (SARs) and mechanism of action of various new antibacterial agents and also covers the recent reports on new antibacterial agents with potent activity against multidrug resistant Staphylococcus aureus. This review provides attention on in vitro and in vivo pharmacological activities of new antibacterial agents in the point of view of drug discovery and development.     

Negative regulation of the hepatic fibrogenic response by suppressor of cytokine signaling 1

Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFNγ signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFNγ, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFNγ-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in HSC activation. Liver fibrosis was induced in Socs1^−/−Ifng^−/− mice with dimethylnitrosamine or carbon tetrachloride. Ifng^−/− and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1^−/−Ifng^−/− mice showed elevated serum ALT levels and increased liver fibrosis compared to Ifng^−/− mice. The latter group showed higher ALT levels and fibrosis than C57BL/6 controls. The livers of SOCS1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. SOCS1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from SOCS1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of SOCS1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFNγ and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability.     

Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major impediment for clinical cancer therapy. 19 novel aromatic amides with triazole-core as MDR reversal agents were designed and synthesized via click chemistry to reverse MDR. Among them, compound 42 was identified as the most promising candidate with high potency (EC₅₀ = 78.1 ± 5.4 nM), low cytotoxity (SI > 1282) and persistent duration in reversing doxorubicin (DOX) resistance in K562/A02 cells. 42 also enhanced the potency of other P-gp associated cytotoxic agents with different structures. In further study, remarkably increased intracellular accumulation of Rh123 and DOX in K562/A02 cells was achieved by compound 42, while CYP3A4 activity had no change by compound 42. These results indicate that compound 42 as a relatively safe modulator of P-gp-mediated MDR has good potential for further development.