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PHA synthase (PhaC): interpreting the functions of bioplastic-producing enzyme from a structural perspective

Chek MF, Hiroe A, Hakoshima T, Sudesh K, Taguchi S

Appl Microbiol Biotechnol, 2019 Feb;103(3):1131-1141.
PMID: 30511262 DOI: 10.1007/s00253-018-9538-8

Polyhydroxyalkanoates (PHAs) are biopolymers synthesized by a wide range of bacteria, which serve as a promising candidate in replacing some conventional petrochemical-based plastics. PHA synthase (PhaC) is the key enzyme in the polymerization of PHA, and the crystal structures were successfully determined using the catalytic domain of PhaC from Cupriavidus necator (PhaCCn-CAT) and Chromobacterium sp. USM2 (PhaCCs-CAT). Here, we review the beneficial mutations discovered in PhaCs from a structural perspective. The structural comparison of the residues involved in beneficial mutation reveals that the residues are near to the catalytic triad, but not inside the catalytic pocket. For instance, Ala510 of PhaCCn is near catalytic His508 and may be involved in the open-close regulation, which presumably play an important role in substrate specificity and activity. In the class II PhaC1 from Pseudomonas sp. 61-3 (PhaC1Ps), Ser325 stabilizes the catalytic cysteine through hydrogen bonding. Another residue, Gln508 of PhaC1Ps is located in a conserved hydrophobic pocket which is next to the catalytic Asp and His. A class I, II-conserved Phe420 of PhaCCn is one of the residues involved in dimerization and its mutation to serine greatly reduced the lag phase. The current structural analysis shows that the Phe362 and Phe518 of PhaC from Aeromonas caviae (PhaCAc) are assisting the dimer formation and maintaining the integrity of the core beta-sheet, respectively. The structure-function relationship of PhaCs discussed in this review will serve as valuable reference for future protein engineering works to enhance the performance of PhaCs and to produce novel biopolymers.

Matched MeSH terms: Serine
Comparative proteomes, immunoreactivities and neutralization of procoagulant activities of Calloselasma rhodostoma (Malayan pit viper) venoms from four regions in Southeast Asia

Tang ELH, Tan NH, Fung SY, Tan CH

Toxicon, 2019 Aug 22;169:91-102.
PMID: 31445943 DOI: 10.1016/j.toxicon.2019.08.004

The intraspecific geographical venom variations of Calloselasma rhodostoma from Malaysia (CR-M), Indonesia (CR-I), Thailand (CR-T) and Vietnam (CR-V) were investigated through 1D SDS-PAGE and nano-ESI-LCMS/MS. The venom antigenicity, procoagulant activities and neutralization using Thai C. rhodostoma Monovalent Antivenom (CRMAV) were also investigated. SDS-PAGE patterns of the venoms were relatively similar with minor variations. Proteomic analysis revealed that snake venom metalloproteinases (SVMPs, particularly P-I class), serine proteases (SVSPs) and snaclecs dominated the venom protein composition (68.96-81.80%), followed by L-amino acid oxidase (LAAO) and phospholipase A2 (PLA2) (7.37-11.08% and 5.18-13.81%, respectively), corroborating C. rhodostoma envenoming effects (hemorrhage, consumptive coagulopathy, thrombocytopenia and local tissue necrosis). Other proteins of lower abundances (2.82-9.13%) identified include cysteine-rich secretory proteins (CRISP), phospholipase B, phosphodiesterase, nerve growth factor, 5'-nucleotidase, aminopeptidase and hyaluronidase. All four venoms exhibited strong procoagulant effects which were neutralized by CRMAV to different extents. CRMAV immunoreactivity was high toward venoms of CR-M, CR-I and CR-T but relatively low for CR-V venom. Among the venom samples from different locales, CR-V venom proteome has the smallest SVMP composition while SVSP, PLA2 and phosphodiesterase were more abundant in the venom. These variations in C. rhodostoma venom protein composition could partly explain the differences seen in immunoreactivity. (198 words).

Matched MeSH terms: Serine Proteases
Fulltext From the Molecular Mechanism to Pre-clinical Results: Anti-epileptic Effects of Fingolimod

Paudel YN, Angelopoulou E, Piperi C, Gnatkovsky V, Othman I, Shaikh MF

Curr Neuropharmacol, 2020;18(11):1126-1137.
PMID: 32310049 DOI: 10.2174/1570159X18666200420125017

Epilepsy is a devastating neurological condition characterized by long-term tendency to generate unprovoked seizures, affecting around 1-2 % of the population worldwide. Epilepsy is a serious health concern which often associates with other neurobehavioral comorbidities that further worsen disease conditions. Despite tremendous research, the mainstream anti-epileptic drugs (AEDs) exert only symptomatic relief leading to 30% of untreatable patients. This reflects the complexity of the disease pathogenesis and urges the precise understanding of underlying mechanisms in order to explore novel therapeutic strategies that might alter the disease progression as well as minimize the epilepsy-associated comorbidities. Unfortunately, the development of novel AEDs might be a difficult process engaging huge funds, tremendous scientific efforts and stringent regulatory compliance with a possible chance of end-stage drug failure. Hence, an alternate strategy is drug repurposing, where anti-epileptic effects are elicited from drugs that are already used to treat non-epileptic disorders. Herein, we provide evidence of the anti-epileptic effects of Fingolimod (FTY720), a modulator of sphingosine-1-phosphate (S1P) receptor, USFDA approved already for Relapsing-Remitting Multiple Sclerosis (RRMS). Emerging experimental findings suggest that Fingolimod treatment exerts disease-modifying anti-epileptic effects based on its anti-neuroinflammatory properties, potent neuroprotection, anti-gliotic effects, myelin protection, reduction of mTOR signaling pathway and activation of microglia and astrocytes. We further discuss the underlying molecular crosstalk associated with the anti-epileptic effects of Fingolimod and provide evidence for repurposing Fingolimod to overcome the limitations of current AEDs.

Matched MeSH terms: TOR Serine-Threonine Kinases
Fulltext Description of Sarcocystis scandentiborneensis sp. nov. from treeshrews (Tupaia minor, T. tana) in northern Borneo with annotations on the utility of COI and 18S rDNA sequences for species delineation

Ortega Pérez P, Wibbelt G, Brinkmann A, Galindo Puentes JA, Tuh FYY, Lakim MB, et al.

Int J Parasitol Parasites Wildl, 2020 Aug;12:220-231.
PMID: 32695576 DOI: 10.1016/j.ijppaw.2020.07.003

Sarcocystis scandentiborneensis sp. nov. was discovered in histological sections of striated musculature of treeshrews (Tupaia minor, T. tana) from Northern Borneo. Sarcocysts were cigar-shaped, 102 μm-545 μm long, and on average 53 μm in diameter. The striated cyst wall varied in thickness (2-10 μm), depending on whether the finger-like, villous protrusions (VP) were bent. Ultrastructurally, sarcocysts were similar to wall type 12 but basal microtubules extended into VPs that tapered off with a unique U-shaped, electron-dense apical structure. In phylogenetic trees of the nuclear 18S rRNA gene, S. scandentiborneensis formed a distinct branch within a monophyletic subclade of Sarcocystis spp. with (colubrid) snake-rodent life cycle. We mapped all intraspecific (two haplotypes) and interspecific nucleotide substitutions to the secondary structure of the 18S rRNA gene: in both cases, the highest variability occurred within helices V2 and V4 but intraspecific variability mostly related to transitions, while transition/transversion ratios between S. scandentiborneensis, S. zuoi, and S. clethrionomyelaphis were skewed towards transversions. Lack of relevant sequences restricted phylogenetic analysis of the mitochondrial Cytochrome C oxidase subunit I (COI) gene to include only one species of Sarcocystis recovered from a snake host (S. pantherophisi) with which the new species formed a sister relationship. We confirm the presence of the functionally important elements of the COI barcode amino acid sequence of S. scandentiborneensis, whereby the frequency of functionally important amino acids (Alanine, Serine) was markedly different to other taxa of the Sarcocystidae. We regard S. scandentiborneensis a new species, highlighting that structurally or functionally important aspects of the 18S rRNA and COI could expand their utility for delineation of species. We also address the question why treeshrews, believed to be close to primates, carry a parasite that is genetically close to a Sarcocystis lineage preferably developing in the Rodentia as intermediate hosts.

Matched MeSH terms: Serine
Fulltext Loop-mediated isothermal amplification (LAMP) reaction as viable PCR substitute for diagnostic applications: a comparative analysis study of LAMP, conventional PCR, nested PCR (nPCR) and real-time PCR (qPCR) based on Entamoeba histolytica DNA derived from faecal sample

Foo PC, Nurul Najian AB, Muhamad NA, Ahamad M, Mohamed M, Yean Yean C, et al.

BMC Biotechnol, 2020 Jun 22;20(1):34.
PMID: 32571286 DOI: 10.1186/s12896-020-00629-8

BACKGROUND: This study reports the analytical sensitivity and specificity of a Loop-mediated isothermal amplification (LAMP) and compares its amplification performance with conventional PCR, nested PCR (nPCR) and real-time PCR (qPCR). All the assays demonstrated in this study were developed based on Serine-rich Entamoeba histolytica protein (SREHP) gene as study model.
RESULTS: A set of SREHP gene specific LAMP primers were designed for the specific detection of Entamoeba histolytica. This set of primers recorded 100% specificity when it was evaluated against 3 medically important Entamoeba species and 75 other pathogenic microorganisms. These primers were later modified for conventional PCR, nPCR and qPCR applications. Besides, 3 different post-LAMP analyses including agarose gel electrophoresis, nucleic acid lateral flow immunoassay and calcein-manganese dye techniques were used to compare their limit of detection (LoD). One E. histolytica trophozoite was recorded as the LoD for all the 3 post-LAMP analysis methods when tested with E. histolytica DNA extracted from spiked stool samples. In contrast, none of the PCR method outperformed LAMP as both qPCR and nPCR recorded LoD of 100 trophozoites while the LoD of conventional PCR was 1000 trophozoites.
CONCLUSIONS: The analytical sensitivity comparison among the conventional PCR, nPCR, qPCR and LAMP reveals that the LAMP outperformed the others in terms of LoD and amplification time. Hence, LAMP is a relevant alternative DNA-based amplification platform for sensitive and specific detection of pathogens.

Matched MeSH terms: Serine
Fulltext Proteins from Lignosus tigris with selective apoptotic cytotoxicity towards MCF7 cell line and suppresses MCF7-xenograft tumor growth

Kong BH, Teoh KH, Tan NH, Tan CS, Ng ST, Fung SY

PeerJ, 2020;8:e9650.
PMID: 32832273 DOI: 10.7717/peerj.9650

Background: Lignosus tigris, a recently discovered species of the unique Lignosus family, has been traditionally used by the indigenous communities in Peninsular Malaysia to treat various ailments and as an alternative medicine for cancer treatment. The L. tigris cultivar sclerotia (Ligno TG-K) was found to contain numerous bioactive compounds with beneficial biomedicinal properties and the sclerotial extract exhibited potent antioxidant activity. However, the anticancer property of the Ligno TG-K including in vitro and in vivo antitumor effects as well as its anticancer active compounds and the mechanisms has yet to be investigated.
Methods: The cytotoxicity of the Ligno TG-K against human breast (MCF7), prostate (PC3) and lung (A549) adenocarcinoma cell lines was evaluated using MTT cytotoxicity assay. The cytotoxic mechanisms of the active high molecular weight proteins (HMWp) fraction were investigated through detection of caspases activity and apoptotic-related proteins expression by Western blotting. The in vivo antitumor activity of the isolated HMWp was examined using MCF7 mouse xenograft model. Shotgun LC-MS/MS analysis was performed to identify the proteins in the HMWp.
Results and Discussion: Cold water extract of the sclerotia inhibited proliferation of MCF7, A549 and PC3 cells with IC50 ranged from 28.9 to 95.0 µg/mL. Bioassay guided fractionation of the extract revealed that HMWp exhibited selective cytotoxicity against MCF7 cells via induction of cellular apoptosis by the activation of extrinsic and intrinsic signaling pathways. HMWp activated expression of caspase-8 and -9 enzymes, and pro-apoptotic Bax protein whilst inhibiting expression of tumor survivor protein, Bcl-2. HMWp induced tumor-cell apoptosis and suppressed growth of tumor in MCF-7 xenograft mice. Lectins, serine proteases, RNase Gf29 and a 230NA deoxyribonuclease are the major cytotoxic proteins that accounted for 55.93% of the HMWp.
Conclusion: The findings from this study provided scientific evidences to support the traditional use of the L. tigris sclerotia for treatment of breast cancer. Several cytotoxic proteins with high abundance have been identified in the HMWp of the sclerotial extract and these proteins have potential to be developed into new anticancer agents or as adjunct cancer therapy.

Matched MeSH terms: Serine Proteases
Fulltext Genotypic to Phenotypic Resistance Discrepancies Identified Involving β-Lactamase Genes, blaKPC, blaIMP, blaNDM-1, and blaVIM in Uropathogenic Klebsiella pneumoniae

Urmi UL, Nahar S, Rana M, Sultana F, Jahan N, Hossain B, et al.

Infect Drug Resist, 2020;13:2863-2875.
PMID: 32903880 DOI: 10.2147/IDR.S262493

Introduction: Klebsiella pneumoniae carbapenemase (KPC) belongs to the Group-A β-lactamases that incorporate serine at their active site and hydrolyze various penicillins, cephalosporins, and carbapenems. Metallo-beta-lactamases (MBLs) are group-B enzymes that contain one or two essential zinc ions in the active sites and hydrolyze almost all clinically available β-lactam antibiotics. Klebsiella pneumoniae remains the pathogen with the most antimicrobial resistance to KPC and MBLs.
Methods: This research investigated the blaKPC, and MBL genes, namely, blaIMP, blaVIM, and blaNDM-1 and their phenotypic resistance to K. pneumoniae isolated from urinary tract infections (UTI) in Bangladesh. Isolated UTI K. pneumoniae were identified by API-20E and 16s rDNA gene analysis. Their phenotypic antimicrobial resistance was examined by the Kirby-Bauer disc diffusion method, followed by minimal inhibitory concentration (MIC) determination. blaKPC, blaIMP, blaNDM-1, and blaVIM genes were evaluated by polymerase chain reactions (PCR) and confirmed by sequencing.
Results: Fifty-eight K. pneumoniae were identified from 142 acute UTI cases. Their phenotypic resistance to amoxycillin-clavulanic acid, cephalexin, cefuroxime, ceftriaxone, and imipenem were 98.3%, 100%, 96.5%, 91.4%, 75.1%, respectively. Over half (31/58) of the isolates contained either blaKPC or one of the MBL genes. Individual prevalence of blaKPC, blaIMP, blaNDM-1, and blaVIM were 15.5% (9), 10.3% (6), 22.4% (13), and 19% (11), respectively. Of these, eight isolates (25.8%, 8/31) were found to have two genes in four different combinations. The co-existence of the ESBL genes generated more resistance than each one individually. Some isolates appeared phenotypically susceptible to imipenem in the presence of blaKPC, blaIMP, blaVIM, and blaNDM-1 genes, singly or in combination.
Conclusion: The discrepancy of genotype and phenotype resistance has significant consequences for clinical bacteriology, precision in diagnosis, the prudent selection of antimicrobials, and rational prescribing. Heterogeneous phenotypes of antimicrobial susceptibility testing should be taken seriously to avoid inappropriate diagnostic and therapeutic decisions.

Matched MeSH terms: Serine
Diosgenin, a steroidal saponin, and its analogs: Effective therapies against different chronic diseases

Parama D, Boruah M, Yachna K, Rana V, Banik K, Harsha C, et al.

Life Sci, 2020 Nov 01;260:118182.
PMID: 32781063 DOI: 10.1016/j.lfs.2020.118182

BACKGROUND: Chronic diseases are a major cause of mortality worldwide, and despite the recent development in treatment modalities, synthetic drugs have continued to show toxic side effects and development of chemoresistance, thereby limiting their application. The use of phytochemicals has gained attention as they show minimal side effects. Diosgenin is one such phytochemical which has gained importance for its efficacy against the life-threatening diseases, such as cardiovascular diseases, cancer, nervous system disorders, asthma, arthritis, diabetes, and many more.
AIM: To evaluate the literature available on the potential of diosgenin and its analogs in modulating different molecular targets leading to the prevention and treatment of chronic diseases.
METHOD: A detailed literature search has been carried out on PubMed for gathering information related to the sources, biosynthesis, physicochemical properties, biological activities, pharmacokinetics, bioavailability and toxicity of diosgenin and its analogs.
KEY FINDINGS: The literature search resulted in many in vitro, in vivo and clinical trials that reported the efficacy of diosgenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK, etc., which play a crucial role in the development of most of the diseases. Reports have also revealed the safety of the compound and the adaptation of nanotechnological approaches for enhancing its bioavailability and pharmacokinetic properties.
SIGNIFICANCE: Thus, the review summarizes the efficacy of diosgenin and its analogs for developing as a potent drug against several chronic diseases.

Matched MeSH terms: TOR Serine-Threonine Kinases
Fulltext Urinary amino acids profile of vegetarians and non-vegetarians

Chia, Yoke Yin, Ton, So Ha

Malays J Nutr, 2006;12(1):67-78.
MyJurnal

The objective of the study was to quantify and to profile the amino acids content in urine samples. The amino acids content in urine was determined in 162 individuals (62 young non-vegetarians aged 15-45 years, 24 elderly non-vegetarians aged 46-70 years, 40 young vegetarians and 36 elderly vegetarians) by high performance liquid chromatography (HPLC). The most common amino acids detected in the young and elderly individuals on vegetarian and non-vegetarian diets were phenylalanine, threonine, arginine and asparagine, while leucine, aspartic acid and alanine were not found in any urine samples in both groups. Isoleucine was not detected in the urine of vegetarians. The concentrations of the majority of essential amino acids were between 0.10 - 2.00 mgl24hrs except for histidine which had a range of 4.1 - 5.0 mgl24hrs. The concentrations of non-essential amino acids varied. Proline, glycine and tyrosine concentrations were between 0.10 - 1.00 mg/24hrs, while cysteine, glutamine, glutamic acid and cystine concentrations were between 11.0 - 21.0 mg124hrs. Asparagine and hydroxy-proline had a range of 0.10 - 5.00 mg/24hrs, while serine and arginine ranged between 31.0 - 50.0 mg124hrs. Isoleucine and serine were not detected in elderly vegetarians while histidine, glycine, glutamic acid and hydroxy-proline were not detected in elderly non-vegetarians. Isoleucine, glycine and hydroxy proline were detected in young non-vegetarians but not in young vegetarians. The levels of amino acids showed no significant statistical differences between young vegetarians and non-vegetarians as well as between elderly vegetarians and non-vegetarians. Phenylalanine, threonine and trypthophan were commonly detected in the lacto-ovo and lacto vegetarians, while valine, cysteine, arginine and asparagine were commonly detected in vegans. In conclusion, except for isoleucine, general differences were seen in urinary amino acid excretions between vegetarians and non-vegetarians even though the differences were statistically not significant. Therefore lacto-ovo diets could be nutritionally adequate as the nutrients were substituted by dairy or plant products.

Matched MeSH terms: Serine
Fulltext Physicochemical properties and composition of Snakehead fish (Channa striatus) whole fillet powder prepared with pre-filleting freezing treatments

Tan, B.H., Azhar, M.E.

International Food Research Journal, 2014;21(3):1255-1260.
MyJurnal

Channa striatus (“haruan”) fish destined for fillet preparation was subjected to two freezing treatments, freezing with distilled water (FW) or freezing directly without distilled water (DF). Fish that was freshly processed without freezing served as control (C). Fillet yield (%) was in the range 33.8% to 35.3% and the highest yield was recorded in FW samples. Whole Fillet Powder (WFP) was prepared from the fillets through low temperature vacuum oven drying (50°C) and its composition and physicochemical properties were assessed. There was no significant difference in moisture and protein contents of all samples (p > 0.05). All WFP were generally dark in colour with whiteness indices ranging from 55.23 - 63.98. The redness (a*) values were 4.33, 11.12, 8.83 whilst the yellowness (b*) were 19.31, 23.04, 21.20 for C, WFP-FW and WFP-DF respectively. WFPs were generally high in histidine, arginine, threonine and tyrosine when compared to egg whites and these (except histidine) and other amino acids (serine, glycine, methionine and phenylalanine) were significantly higher (p < 0.05) in WFP-FW compared to other samples. Overall, freezing treatments affected the composition and physicochemical properties of WFPs.

Matched MeSH terms: Serine
Fulltext Anti-malarial Activities of Two Soil Actinomycete Isolates from Sabah via Inhibition of Glycogen Synthase Kinase 3β

Dahari DE, Salleh RM, Mahmud F, Chin LP, Embi N, Sidek HM

Trop Life Sci Res, 2016 Aug;27(2):53-71.
PMID: 27688851 MyJurnal DOI: 10.21315/tlsr2016.27.2.5

Exploiting natural resources for bioactive compounds is an attractive drug discovery strategy in search for new anti-malarial drugs with novel modes of action. Initial screening efforts in our laboratory revealed two preparations of soil-derived actinomycetes (H11809 and FH025) with potent anti-malarial activities. Both crude extracts showed glycogen synthase kinase 3β (GSK3β)-inhibitory activities in a yeast-based kinase assay. We have previously shown that the GSK3 inhibitor, lithium chloride (LiCl), was able to suppress parasitaemia development in a rodent model of malarial infection. The present study aims to evaluate whether anti-malarial activities of H11809 and FH025 involve the inhibition of GSK3β. The acetone crude extracts of H11809 and FH025 each exerted strong inhibition on the growth of Plasmodium falciparum 3D7 in vitro with 50% inhibitory concentration (IC50) values of 0.57 ± 0.09 and 1.28 ± 0.11 µg/mL, respectively. The tested extracts exhibited Selectivity Index (SI) values exceeding 10 for the 3D7 strain. Both H11809 and FH025 showed dosage-dependent chemo-suppressive activities in vivo and improved animal survivability compared to non-treated infected mice. Western analysis revealed increased phosphorylation of serine (Ser 9) GSK3β (by 6.79 to 6.83-fold) in liver samples from infected mice treated with H11809 or FH025 compared to samples from non-infected or non-treated infected mice. A compound already identified in H11809 (data not shown), dibutyl phthalate (DBP) showed active anti-plasmodial activity against 3D7 (IC50 4.87 ± 1.26 µg/mL which is equivalent to 17.50 µM) and good chemo-suppressive activity in vivo (60.80% chemo-suppression at 300 mg/kg body weight [bw] dosage). DBP administration also resulted in increased phosphorylation of Ser 9 GSK3β compared to controls. Findings from the present study demonstrate that the potent anti-malarial activities of H11809 and FH025 were mediated via inhibition of host GSK3β. In addition, our study suggests that DBP is in part the bioactive component contributing to the anti-malarial activity displayed by H11809 acting through the inhibition of GSK3β.

Matched MeSH terms: Serine
Fulltext Changes in the urinary metabolites in losartan-treated spontaneously hypertensive rats

Norasikin Ab Azis, Mohd Saleh Ahmad Kamal, Zurain Radjeni, Ahmed Mediani, Renu Agarwal

Journal of Clinical and Health Sciences, 2021;6(1):32-45.
MyJurnal

Introduction: This study examined the association of losartan induced changes in urinary
metabolomic profile with the changes in blood pressure (BP) and renin-angiotensinaldosterone system (RAAS) in spontaneously hypertensive rats (SHR). Methods: Male SHR
were administered with either 0.5 mL of distilled water (control group, n=6) or 10 mg.kg-1 of
losartan (group 2, n=6) daily by oral gavage for 4 weeks. Body weight, BP, food and water
intake were measured weekly. At week 4, urine was collected for urinary electrolyte analysis
and metabolite profiling, after which the animals were euthanised by decapitation and blood
was collected for analysis of components of RAAS and electrolyte concentrations. Urine
metabolite profile of SHR was determined using proton nuclear magnetic resonance (
1H-NMR)
spectrometry combined with multivariate data analysis. Results: At week 4, losartan-treated
SHR had significantly lower BP than non-treated SHR. There were no differences in water
and food intake, body weight, serum and urinary electrolyte concentrations or in their urinary
excretions between the two groups. No differences were evident in the components of RAAS
except that the angiotensinogen level was significantly higher in losartan-treated SHR
compared to non-treated SHR. Orthogonal partial least squares discriminant analysis (OPLSDA) showed clear separation of urinary metabolites between control and losartan-treated
SHR. Losartan-treated SHR group was separated from the control group by changes in the
intermediates involved in glycine, serine and threonine metabolism. Conclusion:
Antihypertensive effect of losartan in SHR seems to be associated with changes in urinary
metabolite profile, particularly involving the metabolism of glycine, serine and threonine.

Matched MeSH terms: Serine
Fulltext Leptin: a pleitropic factor in physiology

Fayez A Almabhouh, Faizatul Isyraqiah Ahmad Muhammad, Hisham Ibrahim, Harbindarjeet Singh

Journal of Clinical and Health Sciences, 2019;4(2):31-57.
MyJurnal

Leptin, a 16 kDa protein and a product of the ob/ob gene, has a tertiary structure similar to that
of a cytokine. It is primarily secreted by white adipose tissue and its levels in the blood correlate
positively with percentage body fat. Leptin was first identified in 1994 as a major factor that
regulated food intake and energy balance. Leptin in the circulation exists either as a free
monomeric hormone or bound to its soluble receptor. Its serum levels usually range from 0.5 to
37.7 ng/ml in males and 2.0 to 45.2 ng/ml in females. The half-life of leptin is between 20 - 30
minutes and it is eliminated mainly by the kidneys. However, research over the last 25 years
has revealed numerous other physiological roles for leptin, including roles in inflammation,
immune function, neuro-endocrine function, bone metabolism, blood pressure regulation and
sexual maturation. Most of these roles have been identified from studies on leptin deficient
rodents. Apart from energy balance and sexual maturation, where its role is direct and obvious,
its actions on the rest of the other systems are permissive. Actions of leptin are both centrally
and peripherally mediated involving receptors that are widely distributed in the body. Six leptin
receptor isoforms, belonging to the class 1 cytokine receptor family, have been identified.
These receptors are products of the OBR gene. The cellular actions of leptin are mediated
through any one of five different signalling pathways that include the JAK-STAT, PI3K, MAPK,
AMPK, and the mTOR signalling pathways.

Matched MeSH terms: TOR Serine-Threonine Kinases
Fulltext Potential Roles of Stevia rebaudiana Bertoni in Abrogating Insulin Resistance and Diabetes: A Review

Mohd-Radzman NH, Ismail WI, Adam Z, Jaapar SS, Adam A

Evid Based Complement Alternat Med, 2013;2013:718049.
PMID: 24324517 DOI: 10.1155/2013/718049

Insulin resistance is a key factor in metabolic disorders like hyperglycemia and hyperinsulinemia, which are promoted by obesity and may later lead to Type II diabetes mellitus. In recent years, researchers have identified links between insulin resistance and many noncommunicable illnesses other than diabetes. Hence, studying insulin resistance is of particular importance in unravelling the pathways employed by such diseases. In this review, mechanisms involving free fatty acids, adipocytokines such as TNF α and PPAR γ and serine kinases like JNK and IKK β , asserted to be responsible in the development of insulin resistance, will be discussed. Suggested mechanisms for actions in normal and disrupted states were also visualised in several manually constructed diagrams to capture an overall view of the insulin-signalling pathway and its related components. The underlying constituents of medicinal significance found in the Stevia rebaudiana Bertoni plant (among other plants that potentiate antihyperglycemic activities) were explored in further depth. Understanding these factors and their mechanisms may be essential for comprehending the progression of insulin resistance towards the development of diabetes mellitus.

Matched MeSH terms: Serine
Extracellular vesicle-transmitted miR-671-5p alleviates lung inflammation and injury by regulating the AAK1/NF-κB axis

Lian J, Zhu X, Du J, Huang B, Zhao F, Ma C, et al.

Mol Ther, 2023 May 03;31(5):1365-1382.
PMID: 36733250 DOI: 10.1016/j.ymthe.2023.01.025

Mesenchymal stem cells regulate remote intercellular signaling communication via their secreted extracellular vesicles. Here, we report that menstrual blood-derived stem cells alleviate acute lung inflammation and injury via their extracellular vesicle-transmitted miR-671-5p. Disruption of this abundantly expressed miR-671-5p dramatically reduced the ameliorative effect of extracellular vesicles released by menstrual blood-derived stem cells on lipopolysaccharide (LPS)-induced pulmonary inflammatory injury. Mechanistically, miR-671-5p directly targets the kinase AAK1 for post-transcriptional degradation. AAK1 is found to positively regulate the activation of nuclear factor κB (NF-κB) signaling by controlling the stability of the inhibitory protein IκBα. This study identifies a potential molecular basis of how extracellular vesicles derived from mesenchymal stem cells improve pulmonary inflammatory injury and highlights the functional importance of the miR-671-5p/AAK1 axis in the progression of pulmonary inflammatory diseases. More importantly, this study provides a promising cell-based approach for the treatment of pulmonary inflammatory disorders through an extracellular vesicle-dependent pathway.

Matched MeSH terms: Protein-Serine-Threonine Kinases
Zerumbone targets the CXCR4-RhoA and PI3K-mTOR signaling axis to reduce motility and proliferation of oral cancer cells

Zainal NS, Gan CP, Lau BF, Yee PS, Tiong KH, Abdul Rahman ZA, et al.

Phytomedicine, 2018 Jan 15;39:33-41.
PMID: 29433681 DOI: 10.1016/j.phymed.2017.12.011

BACKGROUND: The CXCR4-RhoA and PI3K-mTOR signaling pathways play crucial roles in the dissemination and tumorigenesis of oral squamous cell carcinoma (OSCC). Activation of these pathways have made them promising molecular targets in the treatment of OSCC. Zerumbone, a bioactive monocyclic sesquiterpene isolated from the rhizomes of tropical ginger, Zingiber zerumbet (L.) Roscoe ex Sm. has displayed promising anticancer properties with the ability to modulate multiple molecular targets involved in carcinogenesis. While the anticancer activities of zerumbone have been well explored across different types of cancer, the molecular mechanism of action of zerumbone in OSCC remains largely unknown.
PURPOSE: Here, we investigated whether OSCC cells were sensitive towards zerumbone treatment and further determined the molecular pathways involved in the mechanism of action.
METHODS: Cytotoxicity, anti-proliferative, anti-migratory and anti-invasive effects of zerumbone were tested on a panel of OSCC cell lines. The mechanism of action of zerumbone was investigated by analysing the effects on the CXCR4-RhoA and PI3K-mTOR pathways by western blotting.
RESULTS: Our panel of OSCC cells was broadly sensitive towards zerumbone with IC50 values of less than 5 µM whereas normal keratinocyte cells were less responsive with IC50 values of more than 25 µM. Representative OSCC cells revealed that zerumbone inhibited OSCC proliferation and induced cell cycle arrest and apoptosis. In addition, zerumbone treatment inhibited migration and invasion of OSCC cells, with concurrent suppression of endogenous CXCR4 protein expression in a time and dose-dependent manner. RhoA-pull down assay showed reduction in the expression of RhoA-GTP, suggesting the inactivation of RhoA by zerumbone. In association with this, zerumbone also inhibited the PI3K-mTOR pathway through the inactivation of Akt and S6 proteins.
CONCLUSION: We provide evidence that zerumbone could inhibit the activation of CXCR4-RhoA and PI3K-mTOR signaling pathways leading to the reduced cell viability of OSCC cells. Our results suggest that zerumbone is a promising phytoagent for development of new therapeutics for OSCC treatment.

Matched MeSH terms: TOR Serine-Threonine Kinases/metabolism*
Fulltext A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma

Syafruddin SE, Rodrigues P, Vojtasova E, Patel SA, Zaini MN, Burge J, et al.

Nat Commun, 2019 03 11;10(1):1152.
PMID: 30858363 DOI: 10.1038/s41467-019-09116-x

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.

Matched MeSH terms: TOR Serine-Threonine Kinases/metabolism
Fulltext Induction of Endoplasmic Reticulum Stress Pathway by Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Activation of PERK/p-eIF2α/ATF4 and IRE1α

Md Nesran ZN, Shafie NH, Ishak AH, Mohd Esa N, Ismail A, Md Tohid SF

Biomed Res Int, 2019;2019:3480569.
PMID: 31930117 DOI: 10.1155/2019/3480569

Epigallocatechin-3-gallate (EGCG) is the most abundant bioactive polyphenolic compound among the green tea constituents and has been identified as a potential anticancer agent in colorectal cancer (CRC) studies. This study was aimed to determine the mechanism of actions of EGCG when targeting the endoplasmic reticulum (ER) stress pathway in CRC. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed on HT-29 cell line and normal cell line (3T3) to determine the EGCG toxicity. Next, western blot was done to observe the expression of the related proteins for the ER stress pathway. The Caspase 3/7 assay was performed to determine the apoptosis induced by EGCG. The results demonstrated that EGCG treatment was toxic to the HT-29 cell line. EGCG induced ER stress in HT-29 by upregulating immunoglobulin-binding (BiP), PKR-like endoplasmic reticulum kinase (PERK), phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2α), activating transcription 4 (ATF4), and inositol-requiring kinase 1 alpha (IRE1α). Apoptosis was induced in HT-29 cells after the EGCG treatment, as shown by the Caspase 3/7 activity. This study indicates that green tea EGCG has the potential to inhibit colorectal cancer cells through the induction of ER stress.

Matched MeSH terms: Protein-Serine-Threonine Kinases/metabolism*
Fulltext Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival

Nalairndran G, Hassan Abdul Razack A, Mai CW, Fei-Lei Chung F, Chan KK, Hii LW, et al.

J Cell Mol Med, 2020 Oct;24(20):12188-12198.
PMID: 32926495 DOI: 10.1111/jcmm.15876

Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome-wide lentiviral small-hairpin RNA (shRNA) library screen, we identified phosphoinositide-dependent kinase-1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock-down of endogenous human PDPK1 induced significant tumour-specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE-1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid-regulated kinase 3 (SGK3). Knock-down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock-down. Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.

Matched MeSH terms: Protein-Serine-Threonine Kinases/metabolism*
Fulltext Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, et al.

Oncotarget, 2016 10 25;7(43):69097-69110.
PMID: 27533245 DOI: 10.18632/oncotarget.10215

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.
METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.
RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).
CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics*

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