Development of Galectin-3 Targeting Drugs for Therapeutic Applications in Various Diseases.

Galectin-3 (Gal3) is one of the most studied members of the galectin family that mediate various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Since Gal3 is pro-inflammatory, it is involved in many diseases that are associated with chronic inflammation such as cancer, organ fibrosis, and type 2 diabetes. As a multifunctional protein involved in multiple pathways of many diseases, Gal3 has generated significant interest in pharmaceutical industries. As a result, several Gal3-targeting therapeutic drugs are being developed to address unmet medical needs. Based on the PubMed search of Gal3 to date (1987-2023), here, we briefly describe its structure, carbohydrate-binding properties, endogenous ligands, and roles in various diseases. We also discuss its potential antagonists that are currently being investigated clinically or pre-clinically by the public and private companies. The updated knowledge on Gal3 function in various diseases could initiate new clinical or pre-clinical investigations to test therapeutic strategies, and some of these strategies could be successful and recognized as novel therapeutics for unmet medical needs.

Patterns of Common Dermatological Conditions among Children and Adolescents in Pakistan.

Background and Objectives: Dermatological disorders are highly prevalent among children in Pakistan. The present cross-sectional study aims to identify the spectrum of dermatological conditions among children and adolescents in Pakistan. Materials and Methods: A total of 582 patients (50.9% males; 49.1% females) were included in the study based on their age (5.7 ± 4.1 years), dermatological condition, and epidemiology. The youngest patient was aged ten days, whereas the eldest was seventeen. Age criteria were further stratified into three categories: infants and toddlers (≤5 years), children (≥5 to <12 years), and adolescents (≥12 to <18 years). Amongst them, the majority was from Punjab (81.6%), while the other regions included were Azad Jammu and Kashmir (14.4%), Islamabad (3.3%), and Khyber Pakhtunkhwa (0.7%). Results: Scabies was the highest reported skin condition with 281 (45.55%) patients, followed by 114 (19.6%) with eczema, 60 (10.3%) with dermatitis, 33 (5.7%) with tinea capitis, 17 (2.9%) with tinea corporis, 16 (2.7%) with impetigo, and 15 (2.6%) with folliculitis. Other conditions include urticaria, burns, infections, pediculosis, tinea inguinalis, tinea faciei, nappy rashes, alopecia, warts, tinea incognito, tinea cruris, and acne vulgaris. The chi-squared test showed a high prevalence of tinea corporis and acne among adolescents (12-17 years), whereas eczema, dermatitis, and impetigo were more prevalent among infants and toddlers. Conclusions: Pets or livestock and poor hygiene were found to be highly reported risk factors for many dermatological conditions like scabies and fungal infections. Dermatological conditions are common in younger individuals, but unfortunately, many children do not receive the desired medical assistance.

Safety of glucose-6 phosphate dehydrogenase deficient donors in living right lobe liver donation.

BACKGROUND: The literature lacks data on World Health Organization (WHO) class II and III deficient liver donors who underwent right hepatectomy during living donor liver transplantation (LDLT). METHODS: In this prospective cohort study, we compared the perioperative outcomes of 15 glucose-6 phosphate dehydrogenase (G6PD) deficient living liver donors with a matched cohort of 39 nondeficient living liver donors undergoing right lobe donation. RESULTS: Out of 15 G6PD deficient donors, four (26.67%) donors had class II, and 11 (73.34%) had class III G6PD deficiency. The mean postoperative trough hemoglobin level was significantly lower in the deficient group than the nondeficient group (9.38 ± 1.59 g/dL vs. 10.27 ± .91 g/dL, p = .046). The mean peak indirect bilirubin level was significantly higher in the deficient group than the nondeficient group (2.22 ± 1.38 mg/dL vs. 1.40 ± .89 mg/dL, p = .047), and a similar trend was observed in total serum bilirubin (3.99 ± 2.57 mg/dL vs. 2.99 ± 1.46 mg/dL, p = .038). Biochemical evidence of hemolysis was found only in three (20%) deficient donors, but none of them needed a blood transfusion. No mortality was observed in either group. All other parameters, including demographics, operative parameters, graft characteristics, and hospital stay were comparable between both groups (p > .05). CONCLUSION: G6PD deficiency with WHO class II and above should not be considered a contraindication for right lobe donation.

Melatonin and andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta-catenin signaling.

ß-catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating ß-catenin and inhibiting angiogenesis reduce CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anticarcinogenic, antioxidant, and antimetastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT-15). The viability and stemness were monitored (FDA propidium iodide staining and immunoblot for CD44, CD133, Nanog, Sox2, and Oct4). The drug combination synergistically diminished stemness via increased reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential and ATP level. MLT + AGP induced cell death by inhibiting ß-catenin expression and its downregulatory signals, Cyclin D1, c-Myc. MLT + AGP treated cells exhibited translocation of phospho-ß-catenin to the nucleus and dephosphorylated-ß-catenin. Downregulation of ß-catenin activation and its transcription factors (TCF4 and LEF1) and GTP binding/G-protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF messenger RNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT + AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and ß-catenin found increased apoptosis and downregulation of ß-catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/ß-catenin pathway. Our results provide a rationale for using MLT in combination with AGP for the inhibition of CRCs.

Phosphorylated Proteins from Serum: A Promising Potential Diagnostic Biomarker of Cancer.

Cancer is a fatal disease worldwide. Each year ten million people are diagnosed around the world, and more than half of patients eventually die from it in many countries. A majority of cancer remains asymptomatic in the earlier stages, with specific symptoms appearing in the advanced stages when the chances of adequate treatment are low. Cancer screening is generally executed by different imaging techniques like ultrasonography (USG), mammography, CT-scan, and magnetic resonance imaging (MRI). Imaging techniques, however, fail to distinguish between cancerous and non-cancerous cells for early diagnosis. To confirm the imaging result, solid and liquid biopsies are done which have certain limitations such as invasive (in case of solid biopsy) or missed early diagnosis due to extremely low concentrations of circulating tumor DNA (in case of liquid biopsy). Therefore, it is essential to detect certain biomarkers by a noninvasive approach. One approach is a proteomic or glycoproteomic study which mostly identifies proteins and glycoproteins present in tissues and serum. Some of these studies are approved by the Food and Drug Administration (FDA). Another non-expensive and comparatively easier method to detect glycoprotein biomarkers is by ELISA, which uses lectins of diverse specificities. Several of the FDA approved proteins used as cancer biomarkers do not show optimal sensitivities for precise diagnosis of the diseases. In this regard, expression of phosphoproteins is associated with a more specific stage of a particular disease with high sensitivity and specificity. In this review, we discuss the expression of different serum phosphoproteins in various cancers. These phosphoproteins are detected either by phosphoprotein enrichment by immunoprecipitation using phosphospecific antibody and metal oxide affinity chromatography followed by LC-MS/MS or by 2D gel electrophoresis followed by MALDI-ToF/MS analysis. The updated knowledge on phosphorylated proteins in clinical samples from various cancer patients would help to develop these serum phophoproteins as potential diagnostic/prognostic biomarkers of cancer.

Plasmodiophora brassicae in Its Environment: Effects of Temperature and Light on Resting Spore Survival in Soil.

Clubroot caused by Plasmodiophora brassicae is an important disease on cruciferous crops worldwide. Management of clubroot is challenging, largely because of the millions of resting spores produced within an infected root that can survive dormant in the soil for many years. This study was conducted to investigate some of the environmental conditions that may affect the survival of resting spores in the soil. Soil samples containing clubroot resting spores (1 × 107 spores/g soil) were stored at various temperatures for 2 years. Additionally, other samples were buried in soil or kept on the soil surface in the field. The content of P. brassicae DNA and the numbers of viable spores in the samples were assessed by quantitative PCR (qPCR) and pathogenicity bioassays, respectively. The results indicated that 4°C, 20°C, and being buried in the soil were more conductive conditions for spore survival than -20°C, 30°C, and at the soil surface. Most (99.99%) of the spores kept on the soil surface were nonviable, suggesting a negative effect of light on spore viability. Additional experiments confirmed the negative effect of ultraviolet light on spore viability because spores receiving 2 and 3 h ultraviolet light exhibited lower disease potential and contained less DNA content than the nontreated control. Finally, this work confirmed that DNA-based quantification methods such as qPCR can be poor predictors of P. brassicae disease potential because of the presence and persistence of DNA from dead spores.

Green Synthesis of CeO2 Nanoparticles from the Abelmoschus esculentus Extract: Evaluation of Antioxidant, Anticancer, Antibacterial, and Wound-Healing Activities.

Metal oxide nanoparticles synthesized by the biological method represent the most recent research in nanotechnology. This study reports the rapid and ecofriendly approach for the synthesis of CeO2 nanoparticles mediated using the Abelmoschus esculentus extract. The medicinal plant extract acts as both a reducing and stabilizing agent. The characterization of CeO2 NPs was performed by scanning electron microscopy (SEM), X-ray diffraction (XRD), ultraviolet-visible spectroscopy (UV-Vis), and Fourier transform infrared spectroscopy (FTIR). The in vitro cytotoxicity of green synthesized CeO2 was assessed against cervical cancerous cells (HeLa). The exposure of CeO2 to HeLa cells at 10-125 µg/mL caused a loss in cellular viability against cervical cancerous cells in a dose-dependent manner. The antibacterial activity of the CeO2 was assessed against S. aureus and K. pneumonia. A significant improvement in wound-healing progression was observed when cerium oxide nanoparticles were incorporated into the chitosan hydrogel membrane as a wound dressing.

The relationship between methionine synthase rs1805087 polymorphism and hematological cancers risk.

Background: The relationship between hematological cancer susceptibility and methionine synthase MTR A2756G (rs1805087) polymorphism is inconclusive based on data from past studies. Hence, this updated meta-analysis was conducted to investigate the relationship between methionine synthase reductase (MTR) rs1805087 polymorphism and hematological cancers. Method: We searched EMBASE, Google Scholar, Ovid and PubMed databases for possible relevant articles up to December 31, 2019. Results: The overall pooled outcome of our analysis showed lack of association between the risk of hematological malignancies and MTR A2756G polymorphism under the allele model (G vs A: odds ratio = 1.001, 95% CI: 0.944-1.061; p = 0.983), recessive model (GG vs GA + AA: odds ratio = 1.050, 95% CI: 0.942-1.170; p = 0.382). Conclusion: The findings in this study demonstrate a lack of relationship between hematological cancers and MTR A2756G.

The relationship between leukemia and TP53 gene codon Arg72Pro polymorphism: analysis in a multi-ethnic population.

Aim: Many studies have analyzed the relationship between Arg72Pro polymorphism of TP53 and leukemia; nevertheless, the findings continue to be indeterminate. We, therefore, performed an updated meta-analysis in multi-ethnic groups using specialized software for genome-wide association studies meta-analysis. Materials & methods: PubMed, EMBASE and Google Scholar were searched up to October 2018. An odds ratio (OR) with the corresponding 95% CI was used to evaluate the strength in the association. Results: This meta-analysis included 16 studies with 2337 cases and 9494 controls. In the overall population, significant relationship between Arg72Pro polymorphism of TP53 and leukemia susceptibility was found in two genetic models (recessive model: OR = 1.276, 95% CI = 1.102-1.476; p = 0.01; overdominant model: OR = 0.891, 95% CI = 0.802-0.988; p = 0.03). In stratified studies with ethnicity, a significant association was found in five ethnic groups, including Chinese, Americans, Africans, Japanese and Indians. Conclusion: We demonstrated that an association exist between leukemia risk and TP53 gene codon Arg72Pro polymorphism in the recessive and overdominant genetic models. Also, our findings show that the TP53 Arg72Pro polymorphism may influence leukemia development in different populations.

Selenium: A sole treatment for erosive oral lichen planus (Randomized controlled clinical trial).

Oral lichen planus (OLP) is a chronic disease with immune-mediated pathogenesis. Selenium (Se), an antioxidant, plays a role in modulating immunity. The aim of this clinical trial was to evaluate two Se forms (novel topical hydrogel and oral capsules), solely, in treating erosive OLP based on clinical evaluation and salivary oxidative stress markers. Patients were allocated into one of three groups: group I, topical corticosteroids; group II, topical Se; and group III, systemic Se. Treatment lasted for 6 weeks; patients were clinically evaluated at baseline, 6, and 12 weeks. Biochemical analysis for salivary malondialdehyde (MDA) and total antioxidant capacity (TAC) levels at baseline and 6 weeks was performed. There was a significant reduction in signs and symptoms in response to all treatment modalities. However, there was no significant difference among the three groups at 6 weeks. At 12 weeks, group II had significantly lower pain scores compared with group I. Salivary MDA levels showed a significant decrease in patients of group I and group III. TAC levels showed no significant difference in response to treatment. Selenium can be proposed as a treatment for OLP. Salivary MDA levels can be a biomarker for OLP disease severity.

Gradient Estimator-Based Amplitude Estimation for Dynamic Mode Atomic Force Microscopy: Small-Signal Modeling and Tuning.

Atomic force microscopy (AFM) plays an important role in nanoscale imaging application. AFM works by oscillating a microcantilever on the surface of the sample being scanned. In this process, estimating the amplitude of the cantilever deflection signal plays an important role in characterizing the topography of the surface. Existing approaches on this topic either have slow dynamic response e.g., lock-in-amplifier or high computational complexity e.g., Kalman filter. In this context, gradient estimator can be considered as a trade-off between fast dynamic response and high computational complexity. However, no constructive tuning rule is available in the literature for gradient estimator. In this paper, we consider small-signal modeling and tuning of gradient estimator. The proposed approach greatly simplifies the tuning procedure. Numerical simulation and experimental results are provided to demonstrate the suitability of the proposed tuning procedure.

Upregulation of RASSF1A in Colon Cancer by Suppression of Angiogenesis Signaling and Akt Activation.

BACKGROUND/AIMS: Silencing of tumor suppressor genes (TSGs) and promotion of angiogenesis are associated with tumor development and metastasis. However, little is known if angiogenic molecules directly control TSGs and vice versa. METHODS: A regulatory link between angiogenesis and down regulation of TSGs was evaluated using an anti-cancer agent, andrographolide (AGP) in cancer cells, mouse xenograft tissues and patient derived organoids through gene/protein expression, gene silencing, and immunohistochemical analyses. RESULTS: AGP treatment demonstrated significant expression of RASSF1A and PTEN TSGs in colon cancer and other cancer cells, mouse tissues and organoids. Depletion of RASSF1A with siRNA limited cyclin D1 and BAX expression. SiRNA depletion of PTEN, upstream regulator of RASSF1A resulted in a 50% reduction in RASSF1A expression. Histopathological analysis of the AGP treated tumor sections showed significant reduction in vessel size, microvascular density and tumor mitotic index suggesting suppression of angiogenesis. This was corroborated by protein analysis demonstrating significant reductions in angiogenesis signaling pathway molecules VEGF165, FOXM1, and pAkt, but significant elevation of the endogenous angiogenesis inhibitor Tsp-2. Treatment of cells with exogenous VEGF prevented the suppression of angiogenesis signaling by AGP, resulting in sustained expression of pAkt, an upstream down-regulator of RASSF1A. RASSF1A expression remained low in VEGF treated cells despite the addition of AGP. CONCLUSION: Our results demonstrate for the first time that AGP induces RASSF1A expression in colon cancer cells and is dependent on angiogenesis signaling events. Therefore, our research may facilitate novel therapeutic options for advanced colon cancer therapy.

Impact of demographic variables on women's economic empowerment: An ordered probit model.

The present study aimed to empirically examine the demographic variables that determine women's economic empowerment. A sample of 500 married women between 21 and 49 years old (Mage = 35.49, SD = 7.66) was conveniently selected from district Multan (Pakistan). Control over economic resources was used as a proxy for women's economic empowerment. Ordered probit regression was run to assess the demographic determinants (i.e., age, education, paid job, income, and property) of economic empowerment of the least empowered, moderately empowered, and highly empowered women. Paid job, age, income, and property appeared as positive and significant predictors of women's economic empowerment. Implications of the study were also discussed.

Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis.

Cancer metastasis and immune suppression are critical issues in cancer therapy. Here, we show that a ß-galactoside-binding lectin [galectin-3 (gal3)] that recognizes the Thomsen-Friedenreich disaccharide (TFD, Galß1,3GalNAc) present on the surface of most cancer cells is involved in promoting angiogenesis, tumor-endothelial cell adhesion, and metastasis of prostate cancer cells, as well as evading immune surveillance through killing of activated T cells. To block gal3-mediated interactions, we purified a glycopeptide from cod (designated TFD100) that binds gal3 with picomolar affinity. TFD100 blocks gal3-mediated angiogenesis, tumor-endothelial cell interactions, and metastasis of prostate cancer cells in mice at nanomolar levels. Moreover, apoptosis of activated T cells induced by either recombinant gal3 or prostate cancer patient serum-associated gal3 was inhibited at nanomolar concentration of TFD100. Because the gal3-TFD interaction is a key factor driving metastasis in most epithelial cancers, this high-affinity TFD100 should be a promising antimetastatic agent for the treatment of various cancers, including prostate adenocarcinoma.

On robustness of phase resetting to cell division under entrainment.

The problem of phase synchronization for a population of genetic oscillators (circadian clocks, synthetic oscillators, etc.) is considered in this paper, taking into account a cell division process and a common entrainment input in the population. The proposed analysis approach is based on the Phase Response Curve (PRC) model of an oscillator (the first order reduced model obtained for the linearized system and inputs with infinitesimal amplitude). The occurrence of cell division introduces state resetting in the model, placing it in the class of hybrid systems. It is shown that without common entraining input in all oscillators, the cell division acts as a disturbance causing phase drift, while the presence of entrainment guarantees boundedness of synchronization phase errors in the population. The performance of the obtained solutions is demonstrated via computer experiments for two different models of circadian/genetic oscillators (Neurospora׳s circadian oscillation model and the repressilator).

Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3.

Nicotine, a main addictive compound in tobacco smoke, has been linked to promotion and progression of lung, head and neck, pancreatic, and breast cancers, but the detailed mechanisms of cancer progression remain elusive. Here, we show that nicotine induces the expression of galectin-3 (an anti-apoptotic ß-galactoside-binding lectin) in breast cancer cell line and in primary tumors from breast cancer patients. Nicotine-induced up regulation of galectin-3 is due to an increased expression of α9 isoform of nicotinic acetylcholine receptor (α9nAChR), which activates transcription factor STAT3 that in turn, physically binds to galectin-3 (LGALS3) promoter and induces transcription of galectin-3. Intracellular galectin-3 increased mitochondrial integrity and suppressed chemotherapeutic-induced apoptosis of breast cancer cell. Moreover, nicotine-induced enrichment of side population cells with cancer stem cell-like properties was modulated by galectin-3 expression and could be significantly reduced by transient knock down of LGALS3 and its upstream signaling molecules STAT3 and α9nAChR. Thus, galectin-3 or its upstream signaling molecule STAT3 or α9nAChR could be a potential target to prevent nicotine-induced chemoresistance in breast cancer.

Investigating the confinement effects on masonry behavior based on friction interface.

As a material masonry is anisotropic in nature as it is constituted of various components that differ each other in many ways. Though, the ideas of modeling of concrete are also valid for masonry, still there are difficulties in determining the exact behavior of masonry. The micro modeling (simplified) approach has been adopted in this study for modeling masonry samples subjected to various nature of loadings. The brick masonry units were modeled as discrete elements and linked together by interface element. The coulomb friction model was used to describe the interface element as mortar joint. Damage was assumed to be governed by the compressive strength of both the constituents i.e., mortar and brick. The mechanical properties of the masonry samples were determined by means of variety of tests and those properties then served as input parameters in the constitutive model. The results clearly indicate that numerical model predicted the behavior of the experimentally tested samples, in compression as well as tension prims for both unconfined and confined cases. The proposed model is suitable for modeling any type of brick masonry walls.

Design and analysis of virtual impedance control scheme based on MESOGI for improving harmonic sharing of nonlinear loads.

Under the presence of nonlinear load, the most existing virtual impedance (VI) methods-based control solution performs poorly in reactive power sharing among droop-operated VSIs in microgrids (MGs). This may be due to the involved estimation techniques for extracting the current harmonics at selected frequencies, which suffer from either poor accuracy of the harmonic estimation and/or the effect of DC offset in the measurements. Such an issue may affect the performance of the virtual impedance control, hence, the system stability. To bridge this gap, the implementation of the virtual impedance based on multiple enhanced second-order generalized integrator (MESOGI) suitable for harmonics and DC-offset estimation/rejection, is proposed in this paper. The MESOGI can offer an accurate estimation of the current quadrature components free from DC offset at selected frequencies, required to implement the virtual impedance control. Therefore, it makes the designed virtual impedance-based control scheme robust to voltage distortions, immune to DC disturbance, and capable of sharing properly the power harmonics. As a result, this may contribute to improving the reactive and harmonic power-sharing between droop-controlled VSIs within an islanded MG. The modeling of the MESOGI scheme and its performance investigation is carried out. In addition, the mathematical model of the implemented virtual impedance is derived. Further, analysis based on the obtained model of the equivalent output impedance including virtual impedance is established to study its effect. Simulation and experimental tests are performed to prove the effectiveness of the control proposal in improving the reactive power sharing under nonlinear load operating conditions.

Synthesis of CuSe/PVP/GO and CuSe/MWCNTs for their applications as nonenzymatic electrochemical glucose biosensors.

Copper selenide (CuSe) is an inorganic binary compound which exhibits metallic behavior with zero band gap. CuSe has multiple applications in electrocatalysis, photothermal therapy, flexible electronic and solar cells. In the current study, copper selenide based nanocomposites CuSe/PVP/GO and CuSe/MWCNTs were synthesized by using the sol-gel method for application as a non-enzymatic glucose biosensor. Different characterization methods were employed, such as X-ray diffraction (XRD), photoluminescence (PL), Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible (UV-Vis) spectroscopy, and photoluminescence for determining various aspects of CuSe/PVP/GO and CuSe/MWCNTs nanocomposites including phase formation, functional group analysis, band gaps and morphology. Electrochemical impedance spectroscopy (EIS) showed that the resistances of modified electrode/bare electrode were 12.3 kΩ/17.3 kΩ and 6.3 kΩ/17.3 kΩ for CuSe/PVP/GO and CuSe/MWCNTs nanocomposites, respectively. Cyclic voltammetry showed that both CuSe/PVP/GO and CuSe/MWCNTs nanocomposites are promising biosensors for detection and monitoring of the glucose level in an analyte. The sensitivity and limit of detection are 2328 µA mM-1 cm-2/0.2 µM and 4157 µA mM-1 cm-2/0.3 µM for CuSe/PVP/GO and CuSe/MWCNTs, respectively. Chronoamperometry confirmed that our nanocomposite was the best sensor for glucose even in the presence of other interferents like ascorbic acid (AA), uric acid (UA) and dopamine (DA).

Correction: Synthesis of CuSe/PVP/GO and CuSe/MWCNTs for their applications as nonenzymatic electrochemical glucose biosensors.

[This corrects the article DOI: 10.1039/D3RA06713K.].