Acid Synthesis Research Articles

Enzymatic Synthesis of l-threo-β-Hydroxy-α-Amino Acids via Asymmetric Hydroxylation Using 2-Oxoglutarate-Dependent Hydroxylase from Sulfobacillus thermotolerans Strain Y0017.

β-Hydroxy-α-amino acids are useful compounds for pharmaceutical development. Enzymatic synthesis of β-hydroxy-α-amino acids has attracted considerable interest as a selective, sustainable, and environmentally benign process. In this study, we identified a novel amino acid hydroxylase, AEP14369, from Sulfobacillus thermotolerans Y0017, which is included in a previously constructed CAS-like superfamily protein library, to widen the variety of amino acid hydroxylases. The detailed structures determined by nuclear magnetic resonance and X-ray crystallography analysis of the enzymatically produced compounds revealed that AEP14369 catalyzed threo-β-selective hydroxylation of l-His and l-Gln in a 2-oxoglutarate-dependent manner. Furthermore, the production of l-threo-β-hydroxy-His and l-threo-β-hydroxy-Gln was achieved using Escherichia coli expressing the gene encoding AEP14369 as a whole-cell biocatalyst. Under optimized reaction conditions, 137 mM (23.4 g liter-1) l-threo-β-hydroxy-His and 150 mM l-threo-β-hydroxy-Gln (24.3 g liter-1) were obtained, indicating that the enzyme is applicable for preparative-scale production. AEP14369, an l-His/l-Gln threo-β-hydroxylase, increases the availability of 2-oxoglutarate-dependent hydroxylase and opens the way for the practical production of β-hydroxy-α-amino acids in the future. The amino acids produced in this study would also contribute to the structural diversification of pharmaceuticals that affect important bioactivities. IMPORTANCE Owing to an increasing concern for sustainability, enzymatic approaches for producing industrially useful compounds have attracted considerable attention as a powerful complement to chemical synthesis for environment-friendly synthesis. In this study, we developed a bioproduction method for β-hydroxy-α-amino acid synthesis using a newly discovered enzyme. AEP14369 from the moderate thermophilic bacterium Sulfobacillus thermotolerans Y0017 catalyzed the hydroxylation of l-His and l-Gln in a regioselective and stereoselective fashion. Furthermore, we biotechnologically synthesized both l-threo-β-hydroxy-His and l-threo-β-hydroxy-Gln with a titer of over 20 g liter-1 through whole-cell bioconversion using recombinant Escherichia coli cells. As β-hydroxy-α-amino acids are important compounds for pharmaceutical development, this achievement would facilitate future sustainable and economical industrial applications.

Spectral quality as an eliciting agent in the production of phenolic compounds in the callus of Hyptis marrubioides Epling

Hyptis marrubioides Epling is a species of the Brazilian cerrado traditionally used to treat gastrointestinal and cutaneous infections, pain, and cramps. The use of visible and ultraviolet C (UVC) radiation is a promising strategy to optimize the production of the bioactive metabolites. Therefore, the effect of the spectral quality of light on the production of metabolites was evaluated in H. marrubioides callus. The callus was inoculated on MS medium with 50% of the salt concentration containing 2 mg L-1 naphthaleneacetic acid (NAA) and 1 mg L-1 benzylaminopurine (BAP). The callus cultures were exposed for 20 days to the spectral qualities of white light, blue, red, and blue + red as well as to darkness. In addition, the callus cultivated under white light were exposed to UVC on the 21st day for 0, 30, 60, 120, and 240 seconds. The exposure of H. marrubioides callus to blue light negatively affects the synthesis of phenolic compounds. Red light stimulates the synthesis of caffeic acid and luteolin. Darkness was the best condition among those studied because it was associated with the increased accumulation of caffeic acid, chlorogenic acid, rosmarinic acid, and luteolin. The exposure of H. marrubioides callus cultivated under white light to UVC radiation promoted an increase in the synthesis of chlorogenic acid, ferulic acid, rosmarinic acid, and luteolin.

Coenzyme Q10. Structure, role, sources and application in cosmetology

Cell division, the synthesis of amino acids, glycosaminoglycans and enzymes as well as the maturation of collagen and elastin fibers are the basic processes that take place in healthy skin. These reactions are possible due to participation of cellular energy of ATP (adenosine triphosphate), which is produced inside the mitochondria. Within one eukaryotic cell there are from several to several thousand mitochondria. The process of producing energy in the mitochondria is called cellular respiration, known also as the citric acid cycle or the Krebs cycle. Coenzyme Q10 is a key carrier of electrons in the respiratory chain. At the same time, it is responsible for the neutralization of free radicals formed in the Krebs cycle, leading to reduction oxidative stress and minimalization the aging processes of tissues. The article presents the collected information on coenzyme Q10, its structure, role, sources and application in cosmetology. Supplementation in case of coenzyme Q10 deficiency in the skin is possible through the use of appropriate cosmetic preparations, cosmetology treatments and dietary supplements.

Identification of Novel Inhibitors of Type-I Mycobacterium Tuberculosis Fatty Acid Synthase Using Docking-Based Virtual Screening and Molecular Dynamics Simulation

Mycobacterial fatty acid synthase type-I (FAS-I) has an important role in the de novo synthesis of fatty acids, which constitute a major component of the cell wall. The essentiality of FAS-I in the survival and growth of mycobacterium makes it an attractive drug target. However, targeted inhibitors against Mycobacterial FAS-I have not been reported yet. Recently, the structure of FAS-I from Mycobacterium tuberculosis was solved. Therefore, in a quest to find potential inhibitors against FAS-I, molecular docking-based virtual screening and molecular dynamics simulation were done. Subsequently, molecular dynamic simulations based on binding free energy calculations were done to gain insight into the predicted binding mode of putative hits. The detailed analysis resulted in the selection of four putative inhibitors. For compounds BTB14738, RH00608, SPB02705, and CD01000, binding free energy was calculated as −72.27 ± 12.63, −68.06 ± 11.80, −63.57 ± 12.22, and −51.28 ± 13.74 KJ/mol, respectively. These compounds are proposed to be promising pioneer hits.

Copper-Catalyzed Synthesis of Cyclic β-Amino Acids from Isoxazolidin-5-one Derivatives

Copper-Catalyzed Synthesis of Cyclic β-Amino Acids from Isoxazolidin-5-one Derivatives

Changes in Reserve Mobilization Caused by Salinity Could Interfere in the Initial Growth of Jatropha curcas

Salinity in soil can affect Jatropha seedling metabolism, interfering with plant establishment. In this study, the effect of salinity on the mobilization of reserves during the development of Jatropha seedlings was tested. Two genotypes of Jatropha were used and three concentrations of NaCl were applied between the 4th and 8th days after germination. The effects of salinity on seedling growth, in terms of fresh and dry phytomass, ionic partition, and sugar quantification, starch, proteins, amino acids, and lipids were evaluated in cotyledon leaves, hypocotyls, and roots. There was an increase in the content of all classes of macromolecules analyzed in at least one of the organs. It is hypothesized that the hypocotyls acted as an accumulating organ of Na+. The accumulations of amino acids and protein in roots suggest that metabolic responses occurred in response to the ionic and osmotic effects of NaCl, although this accumulation did not appear to prevent biomass losses in seedlings. Furthermore, the findings of this study demonstrate that salinity inhibits the mobilization of lipids and carbon stocks from cotyledon leaves to the rest of the plant, and together with the synthesis of proteins and amino acids that occurred primarily in roots, contributed to response of these plants to salinity.

Abstract 1004: Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma

Abstract Cancer cells increase lipid metabolism by up-regulation lipogenic enzymes such as stearoyl-CoA desaturase 1 (SCD1). It is the rate-limiting enzyme in the de novo synthesis of fatty acids (FAs), catalyzing the conversion and biosynthesis of saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). We developed SSI-4, a novel highly specific SCD1 inhibitor. The anti-tumor activity ofSSI-4 was examined against different cholangiocarcinoma (CCA) models that included human and mouseCCA cell lines, CCA patient-derived xenografts (PDX) NOD SCID gamma (NSG) mouse models, and CCA PDX derived organoids. Using cell proliferation assay, we examined twelve CCA cell lines and 4 were very sensitive to SSI-4 (1-40 nM IC50). The remaining CCA cell lines showed moderate to no sensitivity to SSI-4. Studies at the protein level have shown that SCD1 is present in both sensitive and non-sensitive cells. Thus, SCD1 must be present in sensitive cells but is not predictive of response to an SCD1 inhibitor. In an effort to identify biomarkers predicting response to therapy, we performed assays, such as lipid, lactate, or energy phenotype which identified elevated lactate and unsaturated fatty acid levels as well as a glycolytic energy phenotype. In vivo, CCA PDX models have demonstrated that SSI-4strongly inhibited tumor growth. Immunohistochemical analysis of CCA tumors revealed elevated glycolytic genes in sensitive cells and thus, a potential predictive biomarker. We are currently pursuing a better understanding of the relationship between glycolysis and fatty acid synthesis/metabolism. We are also testing novel combination therapy of SSI-4 with the standard of care and other drugs to develop novel treatments for CCA. Using CCA PDX derived organoids showed synergistic antitumor activity of SSI-4in combination with cancer standard of care drugs such as gemcitabine and cisplatin. Collectively, we expect to develop a biomarker-driven selection of CCA patients sensitive to SCD1 inhibitors and novel SSI-4 combination therapy leading to improved patient survival. Citation Format: Justyna J. Gleba, Laura A. Marlow, Erin E. Miller, James L. Miller, Aylin Alasonyalilar-Demirer, Yi Guo, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, John A. Copland. Defining stearoyl-CoA desaturase 1 as a molecular therapeutic target against cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1004.

Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway

Nuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P < 0.001) and selected for functional characterization. NSLC01 selectively inhibited the viabilities of four out of seven conventional pancreatic cancer cell lines and induced dramatic apoptosis in the cells with high NRF2 activation. The selective anticancer activity of NSLC01 was further validated with a panel of nine low-passage pancreatic patient-derived cell lines, and a significant reverse correlation between log(IC50) of NSLC01 and NQO1 expression was confirmed (r = −0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P < 0.01, n = 7–8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers.

Abstract 2466: Stochastic loss of GLUL expression correlates with STK11-loss-dependent glutamine addiction and may impact anti-PD1 therapy resistance in NSCLC

Abstract Our work aims to delineate the molecular interactions linking somatic disruption of Serine-Threonine Kinase 11 (STK11) with anti-PD1 therapy resistance in KRAS-driven lung adenocarcinoma (LUAD). Data presented here suggests glutamine synthetase (GLUL) may modulate this phenotype. Immune checkpoint inhibitors (ICIs), including anti-PD1 monoclonal antibody therapy, represent a promising therapeutic option for non-small cell lung cancer (NSCLC) patients. Unfortunately, efficient use of these drugs is hampered by an inability to accurately predict which patients will respond. Clinical observations have correlated anti-PD1 therapy resistance in KRAS-driven LUAD with somatic STK11 disruption, but the mechanism(s) responsible remains unknown. To investigate this connection we knocked out STK11 in three different human KRAS-driven LUAD cell lines and performed RNA-seq analysis to identify STK11-loss-dependent differentially expressed genes. Intriguingly, GLUL expression was reproducibly lost in a subset of KRAS-driven/STK11 null clones across two different human lung adenocarcinoma cell lines. GLUL is an enzyme that converts glutamate to glutamine. Glutamine is a critical metabolite supplying carbon and nitrogen necessary for amino acid, nucleotide, and lipid synthesis. Additionally, glutamine plays an important role in redox homeostasis, chromatin organization, and intra-tumoral signaling. Glutamine dependency is a common phenotype across many solid tumor types, and has previously been linked with STK11-deficiency in the context of polycystic kidney disease. Our current work suggests loss of GLUL expression correlates with an altered tumor-intrinsic response to nutrient stress in KRAS-driven LUAD culminating in immune evasion and anti-PD1 therapy resistance. Ongoing experiments aimed to define the relationship between STK11 loss and GLUL expression suggest this phenomenon is stochastic in nature and may provide tumor cells with a selective advantage. In conclusion, understanding the biology underlying the molecular connection between STK11 and GLUL may reveal reliable biomarkers for anti-PD1 therapy response and suggest a method for restoring sensitivity to current therapies. Citation Format: Sean M. Lenahan, Hailey M. Sarausky, David Joseph Seward. Stochastic loss of GLUL expression correlates with STK11-loss-dependent glutamine addiction and may impact anti-PD1 therapy resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2466.

Synthesis of water-soluble ester-linked ursolic acid–gallic acid hybrids with various hydrolytic stabilities

To obtain derivatives of ursolic acid with improved water solubility and antioxidant activity, new ester-linked hybrids of ursolic acid and gallic acid were synthesized. In the reaction of methyl gallate with ursoloyl chloride acetate, both mono- and diacylation products were obtained. To prepare mono-alkylated and mono-acylated derivatives of gallic acid, 4,5-O-methoxymethylene-protected methyl gallate was used. It was found that ursolic-gallic acid hybrids containing phenolic ester linkage readily underwent hydrolysis at C-28 of triterpenoid. The dioxolane protection allowed selective hydrolysis of the methyl ester at the aromatic moiety of the hybrid compound leaving intact the labile C-28 ester at the triterpenoid moiety. The hybrids possessing an ester–ether linker (terpenoid-COO–CH2CH2–O-aryl) are stable to the hydrolysis. The majority of the obtained ursolic–gallic acid hybrids containing free phenolic hydroxyl groups possess excellent antioxidant activity. Notable water solubilities (∼0.5 mg/mL) of novel hybrids containing both carboxyl group and hydroxyls at aromatic moiety were found.

Synthesis of Isoquinolone-Containing Amino Acids by Rhodium-Catalyzed C–H Annulation

Synthesis of Isoquinolone-Containing Amino Acids by Rhodium-Catalyzed C–H Annulation

Influence of enzyme treatment of rice bran on gamma‐aminobutyric acid synthesis by Lacto bacillus

AbstractGamma‐aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system. The production GABA from the cheaper glutamic acid is a valuable process. Rice bran is a potential source of glutamic acid decarboxylase which was therefore selected for production of gamma‐aminobutyric acid (GABA) using lactic acid bacteria (Lactobacillus brevis (Lb.brevis) VTCC‐B397). The influences of treatment of defatted rice bran with α‐amylase, Alcalase (Al), Flavourzyme (Fl) and their combinations at different concentration ratios on the GABA synthesis were examined. With α‐amylase impacts, concentration of GABA (6.41 mg mL−1) was about 2.38 times higher than the control sample (2.69 mg mL−1) under hydrolysis conditions of pH 6.5, temperature of 95 °C and α‐amylase concentration of 0.15% (v/w) for 45 min. The α‐amylase hydrolysis as prerequisite for protein hydrolysis using Al: Fl (ratio Al: Fl of 3: 7, concentration of 2% (w/w), pH = 8, temperature of 50 °C) reached the highest GABA synthesis efficiency, at 8.43 mg mL−1. Results showed that the enzyme treatment positively affected the fermentation using Lb. brevis for GABA biosynthesis from defatted rice bran.

169-LB: Type 1 Diabetes Mellitus and Stiff-Person Syndrome

Introduction: Type 1 diabetes mellitus (T1DM) is often associated with other autoimmune diseases. One of them is Stiff-Person Syndrome (SPS), a rare neurological disorder characterized by muscle spasms and progressive muscle stiffness, which most often affects females. Glutamic acid decarboxylase antibodies (anti-GAD) are associated with the pathogenesis of this disease as well as T1DM. These antibodies cause a deficit in the synthesis of γ-aminobutyric acid (GABA) that is essential both in the function as neurotransmitter and in the secretion of insulin in pancreatic β cells. Clinical case: We present the case of a 32-year-old female patient diagnosed with T1DM at 18 years old. Currently under intensive functional insulin therapy and flash glucose monitoring (FGM). Since 2019 with subcutaneous insulin infusion system. At the age of 26, the patient reports dystonia in the left lower limb with subsequent involvement of the contralateral lower limb, upper limbs, trunk and face. Collaboration was made with the Neurology department. Among the laboratory findings, of note: positive serum anti-GAD65 (5437 U/mL; &amp;lt;1) and positive cerebrospinal fluid anti-GAD65 (126.23 U /mL; &amp;lt;1). The diagnosis of SPS was made. The patient started human immunoglobulin therapy with progressive clinical improvement. Estimated HbA1c from FGM was 6,8 % at February, 2021. Discussion: The association between T1DM and SPS is frequent. In this case, a patient with a known history of T1DM was presented, but cases of diagnosis of T1DM in patients with SPS have also been described. About 43% of patients have T1DM at the time of diagnosis of SPS. Anti-GAD are involved in the pathophysiology of these two diseases and anti-GAD titers are much higher in cases of association with SPS (about 50 to 100 times). In the treatment of patients with T1DM, physicians should be alert to the onset of other autoimmune diseases and active surveillance is essential for early diagnosis. Disclosure C. A. Araújo: None. C. Baptista: None. I. Paiva: None. A. Morgadinho: None.

A Novel Telescoped Kilogram-Scale Process for Preparation of Obeticholic Acid

A novel scalable four-step process has been developed to improve the synthesis of obeticholic acid (OCA). The key step of this process was the isolation of the amide intermediate, which underwent hydrogenation, basic epimerization, ketone reduction, and amide hydrolysis in a one-pot procedure. The use of efficient single recrystallization for the final purification in this process made the corresponding work-up procedure more concise and environmentally friendly. A kilogram-scale production of OCA following this process could achieve over 70% yield with all impurities controlled below 0.10%.

Modeling of stringent-response reflects nutrient stress induced growth impairment and essential amino acids in different Staphylococcus aureus mutants

Stapylococcus aureus colonises the nose of healthy individuals but can also cause a wide range of infections. Amino acid (AA) synthesis and their availability is crucial to adapt to conditions encountered in vivo. Most S. aureus genomes comprise all genes required for AA biosynthesis. Nevertheless, different strains require specific sets of AAs for growth. In this study we show that regulation inactivates pathways under certain conditions which result in these observed auxotrophies. We analyzed in vitro and modeled in silico in a Boolean semiquantitative model (195 nodes, 320 edges) the regulatory impact of stringent response (SR) on AA requirement in S. aureus HG001 (wild-type) and in mutant strains lacking the metabolic regulators RSH, CodY and CcpA, respectively. Growth in medium lacking single AAs was analyzed. Results correlated qualitatively to the in silico predictions of the final model in 92% and quantitatively in 81%. Remaining gaps in our knowledge are evaluated and discussed. This in silico model is made fully available and explains how integration of different inputs is achieved in SR and AA metabolism of S. aureus. The in vitro data and in silico modeling stress the role of SR and central regulators such as CodY for AA metabolisms in S. aureus.

In Silico Structural and Functional Analysis of Bacillus Uricases

Background: Excluding humans, the peroxisomal uricase is responsible for the catabolism of uric acid into allantoin in many species like microorganisms, plants, and invertebrates. Particularly in humans, the synthesis and excretion of uric acid are naturally balanced. When the uric acid concentration crosses 7 mg/dl, it results in conditions such as hyperuricemia and gout. Uricase is one of the potential sources for the reduction of uric acid in humans. Uricase is also widely used as a commercial diagnostic reagent in medical and clinical biochemistry to estimate the uric acid concentration in blood and other biological fluids. Computational approaches can be used for screening and investigation of uricase enzyme with desirable characteristics that can be employed in diverse industrial applications. Objectives: The present study deals with computational-based structural, functional, and phylogenetic analyses of uricase enzymes from various Bacillus species. Methods: Seventy uricase protein sequences from Bacillus species were selected for multiple sequence alignment, phylogenetic analysis, motif assessment, domain architecture examination, understanding of basic physicochemical properties and in silico identification of the composition of amino acids in uricase. Further, structural (secondary and tertiary structure prediction), and functional (CYS_REC, MOTIF scan, CD-search, STRING, SOSUI, and PeptideCutter) analyses of uricase were performed. Results: Bacillus simplex (WP_063232385.1) was chosen as the representative species of the Bacillus genera. The three-dimensional (3D) structure of B. simplex uricase was predicted and validated using QMEAN, RAMPAGE, ERRAT, Verify 3D and PROQ servers. The analysis revealed that the tertiary structure of the selected uricase has good quality and acceptability. Conclusion: Computational analysis of uricase from various Bacillus sources revealed that all the selected Bacillus uricases are active within acidic to a neutral environment, and thermally stable with a molecular weight ranging from 35.59-59.85kDa. The secondary structure analysis showed that all uricases are rich in alpha-helices and sheets. The CDD tool identified two conserved domains, one of which belongs to OHCU decarboxylase and another belongs to Uricase superfamily. The quality estimation of 3D modeled protein gave a high overall quality factor score of 94.64. Also, all Bacillus species of uricase enzyme and their corresponding genes showed a strong correlation from the phylogenetic comparison of the selected taxa. The present detailed computational investigation on the uricase protein could help in screening a suitable uricase producing microbe with desirable characteristics for industrial application.

Regioselective Synthesis, Structure, and Chemosensitizing Antitumor Activity of Cyclic Hydroxamic Acid Based on DL-Valine

Regioselective Synthesis, Structure, and Chemosensitizing Antitumor Activity of Cyclic Hydroxamic Acid Based on DL-Valine

High-fat diet accelerate hepatic fatty acids synthesis in offspring male rats induced by perinatal exposure to nonylphenol

BackgroundLow dose of NP exposure can alter adipose tissue formation, and the intake of high-fat diet (HFD) can also lead to the fatty liver disease. We investigated the combined effect of NP and HFD on the first offspring of rats, and whether this effect can be passed to the next generation and the possible mechanisms involved.MethodsPregnant rats had access to be treated with 5 μg/kg/day NP and normal diet. The first generation rats were given normal diet and HFD on postnatal day 21, respectively. Then the second generation rats started to only receive normal diet without NP or HFD. Body weight, organ coefficient of liver tissues, lipid profile, biochemical indexes and the expression of genes involved in lipid metabolism, as well as liver histopathology were investigated in male offspring of rats.ResultsNP and HFD interaction had significant effect on the birth weight, body weight and liver tissue organ coefficient of first generation male rats. And HFD aggravated abnormal lipid metabolism, even abnormal liver function and liver histopathological damage of first generation male rats produced by the NP. And this effect can be passed on to the second generation rats. HFD also accelerated the mRNA level of fatty acid synthesis genes such as Lpl, Fas, Srebp-1 and Ppar-γ of first generation rats induced by perinatal exposure to NP, even passed on to the second generation of male rats. NP and HFD resulted in synergistical decrease of the protein expression level of ERα in liver tissue in F2 male rats.ConclusionHFD and NP synergistically accelerated synthesis of fatty acids in liver of male offspring rats through reducing the expression of ERα, which induced abnormal lipid metabolism, abnormal liver function and hepatic steatosis. Moreover, all of these damage passed on to the next generation rats.

SYNTHESIS AND RESEARCH OF A CHELATE FORMING SORBENT BASED ON CARBAMIDE, FORMALDEHYDE AND 2-AMINOPENTANDIC ACID

SYNTHESIS AND RESEARCH OF A CHELATE FORMING SORBENT BASED ON CARBAMIDE, FORMALDEHYDE AND 2-AMINOPENTANDIC ACID

Current Promising Therapeutic Targets for Aspergillosis Treatment

Aspergillosis is a fungal disease caused by different species of Aspergillus. They live in soil,dust and decomposed material. Number of Aspergillus species found till now is about 300 and more are still to be identified. Only few Aspergillus species can cause human disease and the most common species for human infection is Aspergillus fumigatus, which is a ubiquitous airborne saprophytic fungus. Severity of the disease ranges from an allergic response to life-threatening generalized infection. They grow optimally at 37°C and can grow upto 50°C. The fungal conidia are being constantly inhaled by humans and animals everyday normally gets eliminated by innate immune mechanism. Due to increasing number of immunocompromised patients, severe and fatal Aspergillosis cases have augmented. Currently, available antifungal drug for the treatment of Aspergillosis act on these three molecular target are 14 alpha demethylase for Azoles, ergosterol for Polyene and β-1,3-glucan synthase for Echinocandin. These antifungal drug show high resistance problem and toxicity. So, it is high time to develop new drugs for treatment with reduced toxicity and drug resistant problem. Synthesis of essential amino acid is absent in human as they obtain it from their diet but fungi synthesis these amino acid. Thus, enzymes in this pathway acts as novel drug target. This article summarizes promising drug targets presents in different metabolic pathway of Aspergillus genome and discusses their molecular functions in detail. This review also list down the inhibitors of these novel target. We present a comprehensive review that will pave way for discovery and development of novel antifungals against these drug targets for Aspergillosis treatment.