Hasan Mahmud Reza

Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action

Flavonoids are important natural compounds with diverse biologic activities. Citrus flavonoids constitute an important series of flavonoids. Naringin and its aglycone naringenin belong to this series of flavonoids and were found to display strong anti-inflammatory and antioxidant activities. Several lines of investigation suggest that naringin supplementation is beneficial for the treatment of obesity, diabetes, hypertension, and metabolic syndrome. A number of molecular mechanisms underlying its beneficial activities have been elucidated. However, their effect on obesity and metabolic disorder remains to be fully established. Moreover, the therapeutic uses of these flavonoids are significantly limited by the lack of adequate clinical evidence. This review aims to explore the biologic activities of these compounds, particularly on lipid metabolism in obesity, oxidative stress, and inflammation in context of metabolic syndrome.

L-Maf, a downstream target of Pax6, is essential for chick lens development

During lens development in vertebrates, the orchestration of multiple transcriptional regulators is essential for fate determination and terminal differentiation. In early development, Pax6, Sox2 and Six3 are expressed in the head ectoderm, while L-maf, Prox1 and crystallin genes are expressed at a later stage in the lens placode in a more restricted fashion. To uncover the genetic interactions among these factors during lens development, we examined the effects of dominant-negative molecules of Pax6 and L-Maf, which play decisive roles in lens formation. The two dominant-negative isoforms of Pax6 repress L-maf, Prox1 and delta-crystallin expression, resulting in failure of lens formation. These effects of dominant-negative Pax6 are fully rescued by co-expression with wild-type L-Maf. In addition, dominant-negative L-Maf inhibits the expression of Prox1 and delta-crystallin, while misexpression of L-Maf causes ectopic induction of these genes in a Sox-2-dependent fashion. Our results demonstrate that L-Maf is a downstream target of Pax6 and mediates Pax6 activity in developing lens cells.

Roles of Maf family proteins in lens development.

Lens provides a good model for studying developmental cues relevant to cellular and molecular interactions. Basic region/leucine zipper (bZIP) transcription factors have been found to play key roles during eye formation in various species, including human, mouse, rat, Xenopus, zebrafish, chick, and quail. Different ocular developmental anomalies associated with MAF mutation in human implicate its active role during eye development. Several members of the maf gene family with this bZIP motif participate directly in lens morphogenesis. One vital Maf protein, L‐Maf, is expressed in developing lens cells of chick embryos. Its homolog recently has been detected in lens placode of Xenopus embryos and regulates expression of lens fiber‐specific genes in this species. Ectopic expression of L‐Maf can induce lens‐specific genes in cultured retina cells and embryonic ectoderm. The dominant‐negative form of L‐Maf causes the suppression of crystallin expression and subsequently inhibits lens formation, indicating that L‐Maf plays a central role in chick lens development. Developmental Dynamics 229:440–448,

Umbilical Cord Lining Stem Cells as a Novel and Promising Source for Ocular Surface Regeneration

The stem cells involved in renewal of the corneal epithelium are located in the basal region of the limbus, a narrow transition zone surrounding the cornea. In many ocular surface disorders loss of these stem cells results in partial or complete vision loss. Conventional corneal transplant in these patients is associated with dismal results. Stem cell transplantation offers new hope to such patients. The umbilical cord is emerging as an important source of stem cells that may have potential clinical applications. There are advantages to the use of umbilical cord stem cells as these cells are less immunogenic, non-tumorigenic, highly proliferative and ethically acceptable. In this study, we have confirmed the expression of several putative limbal stem cell markers such as HES1, ABCG2, BMI1, CK15 as well as cell adhesion-associated molecules INTEGRIN-α6, -α9, -β1, COLLAGEN-IV and LAMININ in our recently characterized CLEC-muc population derived from human umbilical cord. Ex vivo expansion of these cells on a human amniotic membrane substrate formed a stratified cell sheet that similarly expresses some of these molecules as well as cornea-specific cytokeratins, CK3 and CK12. Transplantation of a bioengineered CLEC-muc sheet in limbal stem cell-deficient rabbit eyes resulted in regeneration of a smooth, clear corneal surface with phenotypic expression of the normal corneal-specific epithelial markers CK3, CK12 but not CK4 or CK1/10. Our results suggest that CLEC-muc is a novel stem cell that can be ex vivo expanded for corneal epithelial regeneration in the treatment of various eye diseases.

Hydroxycinnamic acid derivatives: A potential class of natural compounds for the management of lipid metabolism and obesity

Hydroxycinnamic acid derivatives are important class of polyphenolic compounds originated from the Mavolanate-Shikimate biosynthesis pathways in plants. Several simple phenolic compounds such as cinnamic acid, p-coumaric acid, ferulic acid, caffeic acid, chlorgenic acid, and rosmarinic acid belong to this class. These phenolic compounds possess potent antioxidant and anti-inflammatory properties. These compounds were also showed potential therapeutic benefit in experimental diabetes and hyperlipidemia. Recent evidences also suggest that they may serve as valuable molecule for the treatment of obesity related health complications. In adipose tissues, hydroxycinnamic acid derivatives inhibit macrophage infiltration and nuclear factor κB (NF-κB) activation in obese animals. Hydroxycinnamic acid derivatives also reduce the expression of the potent proinflammatory adipokines tumor necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor type-1 (PAI-1), and they increase the secretion of an anti-inflammatory agent adiponectin from adipocytes. Furthermore, hydroxycinnamic acid derivatives also prevent adipocyte differentiation and lower lipid profile in experimental animals. Through these diverse mechanisms hydroxycinnamic acid derivatives reduce obesity and curtail associated adverse health complications.

Effects of Antipsychotics on the Inflammatory Response System of Patients with Schizophrenia in Peripheral Blood Mononuclear Cell Cultures

Objective We investigated the effects of antipsychotics on immune-challenged peripheral blood mononuclear cell (PBMC) cultures. Methods Blood samples were collected from twelve patients with first-episode schizophrenia. The PBMCs were separated and cultures were prepared and stimulated with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly[I:C]), and then separately treated with a typical antipsychotic (haloperidol) or atypical antipsychotic (clozapine, quetiapine, or risperidone). Pro-inflammatory (interferon gamma [IFN-γ]) and anti-inflammatory (interleukin [IL]-4 and IL-10) cytokine levels were measured in the LPS- or poly(I:C)-stimulated PBMC cultures treated with antipsychotics. Results Haloperidol and quetiapine significantly increased the IL-4 levels (p<0.05) in LPS-stimulated PBMC cultures, while clozapine and quetiapine significantly enhanced the IL-4 levels (p<0.05) in poly(I:C)-stimulated PBMC cultures. Only treatment with haloperidol resulted in a significant increase in IL-10 production (p<0.05) in LPS-stimulated PBMC cultures, whereas clozapine, quetiapine, and risperidone treatment significantly increased IL-10 production (p<0.05) in poly(I:C)-stimulated PBMC cultures. All of the antipsychotics reduced the IFN-γ level significantly (p<0.05) in LPS- and poly(I:C)-stimulated PBMC cultures. Conclusion Antipsychotic treatment altered immune function by raising the levels of anti-inflammatory cytokines (IL-4 and IL-10) and suppressing the levels of pro-inflammatory cytokines (IFN-γ).

Cooperative action between L-Maf and Sox2 on δ-crystallin gene expression during chick lens development

Lens development is regulated by a variety of transcription factors with distinct properties. The lens-specific transcription factor, L-Maf, is essential for lens formation and induces lens-specific markers, such as the crystallin genes. In this study, we analyzed the mechanism by which L-Maf regulates delta-crystallin expression. Misexpression of L-Maf in the head ectoderm of lens placode-forming embryos by in ovo electroporation induced delta-crystallin only in the region surrounding the lens. To define this restricted expression, we misexpressed L-Maf together with other transcription factors implicated in delta-crystallin expression. Sox2 plus L-Maf expanded the delta-crystallin-inducible domain to the entire head ectoderm and simultaneously increased the quantity of delta-crystallin mRNA expressed. In contrast, co-expression of L-Maf with other factors such as Pax6, Six3 and Prox1 had little or no effect on delta-crystallin. We also observed that L-Maf and Sox2 cooperatively enhanced the transactivation of a reporter gene bearing the delta-crystallin enhancer in ovo, implying that L-Maf and Sox2 can induce delta-crystallin through the same enhancer. In conclusion, we report here that L-Maf and Sox2 cooperatively regulate the expression of delta-crystallin during chick lens development.

Transcription factors involved in lens development from the preplacodal ectoderm

Lens development is a stepwise process accompanied by the sequential activation of transcription factors. Transcription factor genes can be classified into three groups according to their functions: the first group comprises preplacodal genes, which are implicated in the formation of the preplacodal ectoderm that serves as a common primordium for cranial sensory tissues, including the lens. The second group comprises lens-specification genes, which establish the lens-field within the preplacodal ectoderm. The third group comprises lens-differentiation genes, which promote lens morphogenesis after the optic vesicle makes contact with the presumptive lens ectoderm. Analyses of the regulatory interactions between these genes have provided an overview of lens development, highlighting crucial roles for positive cross-regulation in fate specification and for feed-forward regulation in the execution of terminal differentiation. This overview also sheds light upon the mechanisms of how preplacodal gene activities lead to the activation of genes involved in lens-specification.

Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism

Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behavior in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600 mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2mg/kg) was given to the experimental group (VPA_AST, n=10) while saline was given to the control group (VPA, n=10) for 4 weeks. Behavioral test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p<0.05) improved the behavioral disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behavior in animal model of autism presumably by its antioxidant activity.

Characterization of a Novel Umbilical Cord Lining Cell with CD227 Positivity and Unique Pattern of P63 Expression and Function

Umbilical cord tissue is gaining attention as a novel source of multipotent stem cells because it is easily obtainable, ethically acceptable and the cells are immunologically naïve. In this study, we have isolated and characterized a new cell type expressing MUCIN1 (CD227) from human umbilical cord lining which we termed MUCIN-expressing Cord Lining Epithelial Cell (CLEC-muc). We found that CLEC-muc is highly proliferative and had significant clonogenic ability. These cells express embryonic stem cell markers OCT-4, NANOG, SSEA-4, REX1 and SOX2. Despite the abundant expression of epithelial cell marker MUCIN1 and cytokeratins, this population is also positive to the mesenchymal stem cell (MSC) marker CD166. CLEC-muc is unique in p63 expression that shuttles from the cytoplasm to the nucleus over time in culture. To understand p63 regulation and function in CLEC-muc, cells were treated with BMP4, a potent morphogen that plays a role in epidermal differentiation via p63 upregulation in ES cell and subsequent analyses were done. We found that BMP4 does not alter cytoplasmic expression of p63 that promotes cell proliferation. However, it increases nuclear p63 expression together with several other epithelial-associated genes such as GATA3, JAGGED1, NOTCH1, HES1 and IKKα. BMP4 has also been found to weakly induce deltaNp63 expression in CLEC-muc. Our results suggest that CLEC-muc is a novel stem cell-like population that can be further differentiated by BMP4 to generate specific cell-types probably destined to form non-keratinized epithelia.