Ageing and the gut-brain axis: lessons from the Drosophila model.

The steady decline of physiological function and increased vulnerability to age-related disorders are two features of the complicated biological process of ageing. As a key organ for nutrient absorption, metabolism, and immunological regulation, the gut plays a major part in the ageing process. Drosophila melanogaster, a well-established model organism, has emerged as a significant tool for exploring the intricate rapport between the gut and ageing. Through the use of Drosophila models, the physiological and molecular elements of the gut-brain axis have been thoroughly explored. These models have also provided insights into the mechanisms by which gut health impacts ageing and age-related illnesses. Drosophila's gut microbiota experience dysbiosis with age which has been linked to age-related diseases. To prevent this and promote healthy ageing in Drosophila, gut microbiota modification methods, such as dietary restriction in tandem with time-restricted feeding, administration of pro-, pre- and synbiotics, as well as pharmaceutical interventions have been generated with positive impacts. The article also covers the drawbacks and difficulties of investigating the gut via the Drosophila. Thus, with an emphasis on the lessons discovered from Drosophila research, this review provides an extensive description of the current studies on the role of the gut-brain axis in ageing and health.

The differential roles of caspase family members in mediating PF4-induced breast cancer apoptosis.

INTRODUCTION: This study focused on PF4 effects on caspase-3,-6, -7, -8 and -9 which regulate the apopotosis process in breast cancer. MATERIALS AND METHODS: Breast tumours were induced in forty 21-day-old female Sprague Dawley rats (SDRs) using MNU until tumour size reached 14.5 mm (SD: 0.5 mm). The rats were then divided into two groups: Group 1 (control injected with 0.9% saline; n = 20), and Group 2 (platelet factor 4 (PF4); n = 20). PF4 was administered through focal intralesional injection at 20 µg/lesion dose. Following 5-day treatment, the SDRs were sacrificed. Subsequently, representative sections from the tumour were obtained for haematoxylin and eosin (H&E) staining. The expressions of caspase-3, -6, -7, -8 and -9 were evaluated using immunohistochemistry (IHC) staining. RESULTS: The majority of breast tumour specimens were of aggressive types [ncontrol = 13 (65%); nPF4 = 12 (60%)]. Invasive ductal carcinoma not otherwise specified (IDC-NOS) was the most commonly observed breast tumour histology for control and PF4 groups (n = 8 (40%) in respective groups). PF4-treated group exhibited significant differences in the caspase-3, -6 and -8 expression levels compared to the control group (all p < 0.001). There were no significant differences in caspase-7 (p = 0.347) and caspase-9 (p = 0.373) expression levels between both groups. CONCLUSION: This study found that PF4 acts via the caspase-mediated extrinsic apoptosis pathway without the involvement of the intrinsic pathway.

Scopoletin, an active principle of tree tobacco (Nicotiana glauca) inhibits human tumor vascularization in xenograft models and modulates ERK1, VEGF-A, and FGF-2 in computer model.

We recently reported the antineovascularization effect of scopoletin on rat aorta and identified its potential anti-angiogenic activity. Scopoletin could be useful as a systemic chemotherapeutic agent against angiogenesis-dependent malignancies if its antitumorigenic activity is investigated and scientifically proven using a suitable human tumor xenograft model. In the present study, bioassay-guided (anti-angiogenesis) phytochemical investigation was conducted on Nicotiana glauca extract which led to the isolation of scopoletin. Further, anti-angiogenic activity of scopoletin was characterized using ex vivo, in vivo and in silico angiogenesis models. Finally, the antitumorigenic efficacy of scopoletin was studied in human colorectal tumor xenograft model using athymic nude mice. For the first time, an in vivo anticancer activity of scopoletin was reported and characterized using xenograft models. Scopoletin caused significant suppression of sprouting of microvessels in rat aortic explants with IC50 (median inhibitory concentration) 0.06µM. Scopoletin (100 and 200mg/kg) strongly inhibited (59.72 and 89.4%, respectively) vascularization in matrigel plugs implanted in nude mice. In the tumor xenograft model, scopoletin showed remarkable inhibition on tumor growth (34.2 and 94.7% at 100 and 200mg/kg, respectively). Tumor histology revealed drastic reduction of the extent of vascularization. Further, immunostaining of CD31 and NG2 receptors in the histological sections confirmed the antivascular effect of scopoletin in tumor vasculature. In computer modeling, scopoletin showed strong ligand affinity and binding energies toward the following angiogenic factors: protein kinase (ERK1), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2). These results suggest that the antitumor activity of scopoletin may be due to its strong anti-angiogenic effect, which may be mediated by its effective inhibition of ERK1, VEGF-A, and FGF-2.

Effect of Er substitution on ultrasonic anomaly in Dy(0.5-x)Er(x)Ba(0.5)CoO3 cobaltates.

Rare-earth cobaltates Dy0.5-xErxBa0.5CoO3 (x=0, 0.03 and 0.05) have been systematically investigated to elucidate the effect of Er substitution on elastic as well as magnetic and transport properties. DC electrical resistance and AC susceptibility measurements showed that the x=0 sample exhibited an insulating behavior and an anti-ferromagnetic (AFM) transition, TN at 198 K as well as ferromagnetic (FM) transition, TC at 260 K. Increasing of Er content suppressed the FM and AFM state suggestively due to the increase in size disorder arising from the size mismatch between A-site cations as shown from our calculation of variance σ(2). On the other hand, both absolute longitudinal and shear velocities and related elastic moduli measured at 210 K decreased with Er content in conjunction with the declining in the FM domain indicating a weakening in elastic properties. A longitudinal velocity anomaly characterized by a drop in velocity upon cooling before hardening with further cooling was observed for all samples. This abnormal elastic anomaly can be attributed due to the Jahn-Teller (JT) distortion of intermediate-spin Co(3+) ions. Analysis of the elastic anomaly using the mean-field theory suggested that it is related to the JT effect which transformed from dynamic to static type with decreasing temperature. The elastic anomaly shifted to lower temperature from 129 K (x=0) to 124 K (x=0.05) with Er substitution indicating a weakening of the static JT effect.

Multistrategy self-organizing map learning for classification problems.

Multistrategy Learning of Self-Organizing Map (SOM) and Particle Swarm Optimization (PSO) is commonly implemented in clustering domain due to its capabilities in handling complex data characteristics. However, some of these multistrategy learning architectures have weaknesses such as slow convergence time always being trapped in the local minima. This paper proposes multistrategy learning of SOM lattice structure with Particle Swarm Optimisation which is called ESOMPSO for solving various classification problems. The enhancement of SOM lattice structure is implemented by introducing a new hexagon formulation for better mapping quality in data classification and labeling. The weights of the enhanced SOM are optimised using PSO to obtain better output quality. The proposed method has been tested on various standard datasets with substantial comparisons with existing SOM network and various distance measurement. The results show that our proposed method yields a promising result with better average accuracy and quantisation errors compared to the other methods as well as convincing significant test.

Crossed-pin versus lateral-pin fixation in pediatric supracondylar fractures.

A retrospective study was done on 56 patients treated with percutaneous pinning of displaced supracondylar fractures of the humerus in the Paediatrics Institute of Hospital Kuala Lumpur between November 1999 and October 2000, to ascertain whether there is any significance clinically in the stability of a crossed pinning medial compared with lateral pinning method. There was equal number of patients in each group (28 patients). The radiographs were evaluated for change in Baumann's angle and Lateral Humero-capitellar angle from immediate post-op until the last follow-up. The changes in the angles did not reveal any statistically significant difference in the ability to maintain reduction of the fractures. There were 3 instances of iatrogenic ulnar nerve injury in the crossed pinning group; the lateral pinning group had 1 case each of anterior interosseous nerve and radial nerve injury post operatively. No vascular injury was noted. Two cases of superficial pin tract infection were present in each group. The lateral percutaneous pinning technique of displaced supracondylar fractures of the humerus therefore offers a viable alternative to the crossed pinning group as it offers the same stability without the incipient risk of iatrogenic ulnar nerve injury.

Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF.

CTCF is a unique, highly conserved, and ubiquitously expressed 11 zinc finger (ZF) transcriptional factor with multiple DNA site specificities. It is able to bind to varying target sequences to perform different regulatory roles, including promoter activation or repression, creating hormone-responsive gene silencing elements, and functional block of enhancer-promoter interactions. Because different sets of ZFs are utilized to recognize different CTCF target DNA sites, each of the diverse DNA.CTCF complexes might engage different essential protein partners to define distinct functional readouts. To identify such proteins, we developed an affinity chromatography method based on matrix-immobilized purified recombinant CTCF. This approach resulted in isolation of several CTCF protein partners. One of these was identified as the multifunctional Y-box DNA/RNA-binding factor, YB-1, known to be involved in transcription, replication, and RNA processing. We examined CTCF/YB-1 interaction by reciprocal immunoprecipitation experiments with anti-CTCF and anti-YB-1 antibodies, and found that CTCF and YB-1 form complexes in vivo. We show that the bacterially expressed ZF domain of CTCF is fully sufficient to retain YB-1 in vitro. To assess possible functional significance of CTCF/YB-1 binding, we employed the very first identified by us, negatively regulated, target for CTCF (c-myc oncogene promoter) as a model in co-transfection assays with both CTCF and YB-1 expression vectors. Although expression of YB-1 alone had no effect, co-expression with CTCF resulted in a marked enhancement of CTCF-driven c-myc transcriptional repression. Thus our findings demonstrate, for the first time, the biological relevance of the CTCF/YB-1 interaction.

Synthesis, characterization and cytotoxicity of new platinum(IV) axial carboxylate complexes: crystal structure of potential antitumor agent [PtIV(trans-1R,2R-diaminocyclohexane)trans(acetate)2Cl2].

A series of new platinum(IV) complexes of the type [PtIV(DACH)trans(L)2Cl2] (where DACH = trans-1R,2R-diaminocyclohexane, and L = acetate, propionate, butyrate, valerate, hexanoate, or heptanoate) bearing the carboxylate groups in the axial positions have been synthesized and characterized by elemental analysis, IR, and 195Pt NMR spectroscopy. The crystal structure of the analogue [PtIV(DACH)trans(acetate)2Cl2] was determined by single crystal X-ray diffraction method. There were two crystallographically independent molecules, both of which lie on crystallographic two-fold axes. The bond lengths and bond angles of both the molecules were the same within the experimental error. The compound crystallizes in the monoclinic space group C2, with a = 11.180(2) A, b = 14.736(3) A, c = 10.644(2) A, beta = 112.38(3) degrees, Z = 4 and R = 0.0336, based upon a total of 1648 collected reflections. In this complex, the platinum had a slightly distorted octahedron geometry owing to the presence of a geometrically strained five-member ring. The two adjacent corners of the platinum plane were occupied by the two amino nitrogens of DACH, whereas the other two equatorial positions were occupied by two chloride ions. The remaining two axial positions were occupied by the oxygens of acetate ligands. The DACH ring was in a chair configuration. An intricate network of intermolecular hydrogen bonds held the crystal lattice together. These analogues were evaluated in vitro and demonstrated cytotoxic activity against the human ovarian 2008 tumor cell line (IC50 = 0.001-0.06 microM). Structure-activity study revealed that activity was highest for the analogue where L = butyrate.

Synthesis, characterization, and antitumor activity of new platinum(IV) trans-carboxylate complexes: crystal structure of [Pt(cis-1,4-DACH)trans-(acetate)2Cl2].

A series of novel platinum(IV) cisplatin analogues of the type [Pt(cis-1,4-DACH)trans-(L)2Cl2] (where cis-1,4-DACH = cis-1,4-diaminocyclohexane and L = acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, nonanoate, or decanoate) was synthesized and characterized by elemental analysis, IR, 13C-NMR, and 195Pt-NMR spectroscopy. The structure of [Pt(cis-1,4-DACH)trans-(acetate)2Cl2] (1) was determined by X-ray crystallography. The crystals were monoclinic, space group P2(1)/n (no. 14) with a = 10.193(2), b = 10.687(2), c = 14.265(3) A, beta = 99.67(3) degrees, Z = 4. The total reflections collected were 2556. The structure refinement converged to R1 = 0.0539 and wR2 = 0.1531. In this complex, platinum has distorted octahedral geometry, and cis-1,4-DACH is in a unique twist-boat configuration. cis-1,4-DACH forms a seven-member chelating ring with platinum, leading to considerable strain in bidentate DACH binding. The strain is evidenced by a large 126.5(9) degrees C-N-Pt angle. The N-Pt-N angle is expanded to 97.4(5) degrees owing to geometric constraints of the cis-1,4-DACH geometry. Three lower homologs of the cis-1,4-DACH-Pt(IV) series were tested in the murine L1210/0 leukemia model for antitumor activity. The results indicate that activity decreases in ascending the homologous series, and that the activity of two of the complexes is substantially better than that of cisplatin with respect to increase in life span and cures.

Chemical and biological studies on a series of novel (trans-(1R,2R)-, trans-(1S,2S)-, and cis-1,2-diaminocyclohexane)platinum(IV) carboxylate complexes.

A series of novel platinum(IV) complexes of the type DACH-PtIV-trans-(Y)2-cis-X (where DACH = trans-(1R,2R)-, trans-(1S,2S)-, or cis-1,2-diaminocyclohexane; X = diacetate, oxalate, malonate, methylmalonate, cyclobutanecarboxylate (CBCA), or 1,1-cyclobutanedicarboxylate (CB-DCA); and Y = acetate or trifluoroacetate) has been synthesized and characterized by elemental analysis, IR, and 195Pt-NMR spectroscopy. The compounds have been tested against cisplatin-sensitive L1210/0 leukemia, cisplatin-resistant L1210/DDP leukemia, and M5076 reticulosarcoma cell lines in vivo. Most of these analogs displayed reasonable activity against L1210/0 cells (%T/C = 135 to > 700). There were no gross differences in activity between analogs containing isomers of DACH. Selected compounds were evaluated against L1210/DDP tumor models in which they demonstrated reduced but significant activity compared with activity in the L1210/0 model. Interestingly, complex 20, PtIV(trans-1R,2R-DACH)-trans-(acetate)2-methylmalonate, was highly active against M5076, although it had no activity against the L1210 lines. The results demonstrate that specific combinations of axial and equatorial carboxylate ligands, together with the DACH carrier ligand, can favorably modulate the antitumor properties of platinum complexes and enhance circumvention of cisplatin resistance.

Synthesis, characterization, and antitumor activity of a series of novel cisplatin analogs with cis-1,4-diaminocyclohexane as nonleaving amine group.

A series of novel platinum(II) complexes of the type PtII(cis-1,4-DACH)X (where cis-1,4-DACH = cis-1,4-diaminocyclohexane and X = dichloro, sulfato, oxalato, malonato, methylmalonato, tartronato, or 1,1-cyclobutanedicarboxylato [CBDCA) ligand and novel platinum(IV) complexes of the types PtIV(cis-1,4-DACH)trans(Y)2Cl2 (where Y = chloro, hydroxo, acetato, propionato, or butyrato ligand) and PtIV(cis-1,4-DACH)trans(Cl)2(X) (where X = oxalato or CBDCA ligand) were synthesized and characterized by elemental analysis, infrared, and 195Pt NMR spectroscopic techniques. Platinum complexes had good in vitro cytotoxic activity against murine leukemia L1210/0 (IC50 = 0.0032-1.60 microM) and human ovarian A2780 (IC50 = 0.045-0.430 microM) cell lines.

Synthesis, antimicrobial, and antitumor activity of a series of palladium(II) mixed ligand complexes.

Mixed ligand complexes of cisdichloromethioninepalladium(II) with 2-mercaptopyrimidine and 2-aminopyrimidine were synthesized and characterized by elemental analysis, conductivity data, infrared, and 1H NMR and 13C NMR spectra. In these mixed ligand complexes methionine coordinates to palladium through amino nitrogen and sulphur, thus leaving a free carboxylic acid group. The pyrimidine ligand coordinates to metal ion through N3. Mixed ligand complexes of cisdichloroethioninepalladium(II) with cytosine and guanosine were synthesized and characterized earlier. All the above mixed ligand complexes were screened for antimicrobial activity against Vibrio parahaemolyticus, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli, Shigella flexnerri, Salmonella typhii, Klebsella pneumoniae, and Vibrio cholerae. It was found that complexes [Pd(meth)Cl2]: [Pd(meth)(2merpy)Cl]Cl; [Pd(meth)(2ampy)Cl]Cl; [Pd(ethio)Cl2]; [Pd(ethio)(cyt)Cl]Cl; and [Pd(ethio)(guo)Cl]Cl showed broad spectrum antimicrobial activity against all the human pathogens tested, however [Pd(meth)(2merpy)Cl]Cl eliminated plasmid with 100% frequency. These complexes have also been screened in vitro for antitumor activity against Hela (Epidermoid Carcinoma Cervix) and CHO cell lines. An excellent correlation between the antitumor activity of Pd(II) complexes and their ability to cure plasmids exists.