Macrophages as a Potential Immunotherapeutic Target in Solid Cancers.

The revolution in cancer immunotherapy over the last few decades has resulted in a paradigm shift in the clinical care of cancer. Most of the cancer immunotherapeutic regimens approved so far have relied on modulating the adaptive immune system. In recent years, strategies and approaches targeting the components of innate immunity have become widely recognized for their efficacy in targeting solid cancers. Macrophages are effector cells of the innate immune system, which can play a crucial role in the generation of anti-tumor immunity through their ability to phagocytose cancer cells and present tumor antigens to the cells of adaptive immunity. However, the macrophages that are recruited to the tumor microenvironment predominantly play pro-tumorigenic roles. Several strategies targeting pro-tumorigenic functions and harnessing the anti-tumorigenic properties of macrophages have shown promising results in preclinical studies, and a few of them have also advanced to clinical trials. In this review, we present a comprehensive overview of the pathobiology of TAMs and their role in the progression of solid malignancies. We discuss various mechanisms through which TAMs promote tumor progression, such as inflammation, genomic instability, tumor growth, cancer stem cell formation, angiogenesis, EMT and metastasis, tissue remodeling, and immunosuppression, etc. In addition, we also discuss potential therapeutic strategies for targeting TAMs and explore how macrophages can be used as a tool for next-generation immunotherapy for the treatment of solid malignancies.

Relationship of Major Depression with Body Mass Index and Salivary Cortisol.

Introduction Depression is one of the most incapacitating psychiatric diseases that disturb life of millions of people round the globe. Its major causes include stressful life events, bereavement, social abuses or certain biological and genetic factors with complex causal mechanisms. Higher salivary cortisol levels for a long period lead to dyslipidemias which increase body mass index (BMI), elevate adiposity and waist-to-hip ratio (WHR). Such individuals with high quartiles of BMI have considerably higher risk of major depressive disorder. The aim of this study was to establish a correlation between major depression, BMI and salivary cortisol. Methods This cross-sectional analysis was accomplished in the Physiology Department, Sheikh Zayed Federal Postgraduate Medical Institute, Lahore as well as in Punjab Institute of Mental Health, Lahore, Pakistan, over a period of six months. A total of 60 participants aged between 18 and 60 years were included in this study; they were divided equally into two groups as normal healthy individuals with no physical or mental illness and severely depressed groups. The patients were categorized as cases of severe depression on outdoor clinical assessment and further confirmed by ICD-10. Patient's BMI was estimated by measuring height in meters (m) and weight in kilograms (kg), and then dividing weight with square height. Early morning saliva samples were collected. Estimation of cortisol levels in saliva was done through ELISA. SPSS version 20.0 (IBM Corp., Armonk, NY) was used to analyze the data and p ≤ 0.05 was considered statistically significant. Results The mean BMI in normal healthy group was 22.02 ± 4.21, while the mean BMI in severely depressive group was 24.64 ± 3.58. The difference was statistically significant (p = 0.012). The mean salivary cortisol level was significantly raised in patients with major depression (2.23 ± 1.69 nmol/L) in contrast to healthy normal individuals (1.46 ± 0.91 nmol/L), with p-value = 0.031. Conclusion BMI and depression has a very noteworthy correlation and there is a remarkable link between raised salivary cortisol, greater BMI and development of major depression.

Comparison of Serum Brain-Derived Neurotrophic Factor Levels in Diabetic Patients With and Without Retinopathy.

Introduction Diabetes mellitus (DM) is a disease of carbohydrate, protein, and fats metabolism that results in hyperglycemia. It may also result from defects in the secretion of insulin from beta cells or in its action on target cells or both. Objective To determine the levels of brain-derived neurotrophic factor (BDNF) and glycated hemoglobulin (HbA1c) with the progression of retinopathy. Methodology The study was done on 80 patients who were divided into four groups (A, B, C, D), with 20 individuals each, on the basis of their diabetic status and fundoscopic findings. Serum BDNF levels were measured by using an enzyme-linked immunosorbent assay kit (Glory Science Co., Taichung City, Taiwan). Results On analysis, a significant decline was seen in serum BDNF levels in diabetics as compared with non-diabetics (p < 0.001), but a significant reduction in levels with the progression of retinopathy was observed (p < 0.001). Statistical analysis All the data were processed using the Statistical Package for the Social Sciences (SPSS) v20.0 (IBM Corp., Armonk, NY). Conclusion There is a significant decline in serum BDNF levels in type 2 diabetics with retinopathy in comparison with the healthy control group.

Vigilin protein Vgl1 is required for heterochromatin-mediated gene silencing in Schizosaccharomyces pombe.

Heterochromatin is a conserved feature of eukaryotic genomes and regulates various cellular processes, including gene silencing, chromosome segregation, and maintenance of genome stability. In the fission yeast Schizosaccharomyces pombe, heterochromatin formation involves methylation of lysine 9 in histone H3 (H3K9), which recruits Swi6/HP1 proteins to heterochromatic loci. The Swi6/HP1-H3K9me3 chromatin complex lies at the center of heterochromatic macromolecular assemblies and mediates many functions of heterochromatin by recruiting a diverse set of regulators. However, additional factors may be required for proper heterochromatin organization, but they are not fully known. Here, using several molecular and biochemical approaches, we report that Vgl1, a member of a large family of multiple KH-domain proteins, collectively known as vigilins, is indispensable for the heterochromatin-mediated gene silencing in S. pombe ChIP analysis revealed that Vgl1 binds to pericentromeric heterochromatin in an RNA-dependent manner and that Vgl1 deletion leads to loss of H3K9 methylation and Swi6 recruitment to centromeric and telomeric heterochromatic loci. Furthermore, we show that Vgl1 interacts with the H3K9 methyltransferase, Clr4, and that loss of Vgl1 impairs Clr4 recruitment to heterochromatic regions of the genome. These findings uncover a novel role for Vgl1 as a key regulator in heterochromatin-mediated gene silencing in S. pombe.

Combinatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurological Disorders.

Histone deacetylases (HDACs) regulate epigenetic gene expression programs by modulating chromatin architecture and are required for neuronal development. Dysregulation of HDACs and aberrant chromatin acetylation homeostasis have been implicated in various diseases ranging from cancer to neurodegenerative disorders. Histone deacetylase inhibitors (HDACi), the small molecules interfering HDACs have shown enhanced acetylation of the genome and are gaining great attention as potent drugs for treating cancer and neurodegeneration. HDAC2 overexpression has implications in decreasing dendrite spine density, synaptic plasticity and in triggering neurodegenerative signaling. Pharmacological intervention against HDAC2 though promising also targets neuroprotective HDAC1 due to high sequence identity (94%) with former in catalytic domain, culminating in debilitating off-target effects and creating hindrance in the defined intervention. This emphasizes the need of designing HDAC2-selective inhibitors to overcome these vicious effects and for escalating the therapeutic efficacy. Here we report a top-down combinatorial in silico approach for identifying the structural variants that are substantial for interactions against HDAC1 and HDAC2 enzymes. We used extra-precision (XP)-molecular docking, Molecular Mechanics Generalized Born Surface Area (MMGBSA) for predicting affinity of inhibitors against the HDAC1 and HDAC2 enzymes. Importantly, we employed a novel in silico strategy of coupling the state-of-the-art molecular dynamics simulation (MDS) to energetically-optimized structure based pharmacophores (e-Pharmacophores) method via MDS trajectory clustering for hypothesizing the e-Pharmacophore models. Further, we performed e-Pharmacophores based virtual screening against phase database containing millions of compounds. We validated the data by performing the molecular docking and MM-GBSA studies for the selected hits among the retrieved ones. Our studies attributed inhibitor potency to the ability of forming multiple interactions and infirm potency to least interactions. Moreover, our studies delineated that a single HDAC inhibitor portrays differential features against HDAC1 and HDAC2 enzymes. The high affinity and selective HDAC2 inhibitors retrieved through e-Pharmacophores based virtual screening will play a critical role in ameliorating neurodegenerative signaling without hampering the neuroprotective isoform (HDAC1).

Plant Derived Inhibitor Sulforaphane in Combinatorial Therapy Against Therapeutically Challenging Pancreatic Cancer.

Pancreatic cancer is one of the most aggressive human cancers and is expected to surpass breast cancer to become the third chief cause of cancer-related deaths in the United States. While conventional treatment approaches such as surgery and classic chemotherapy have slightly improved the relative five year survival rate to 8% yet it is the lowest survival rate for any major cancer. This emphasizes the serious need of more effective and well tolerated therapies to reverse the poor prognosis of the defined neoplasm. Aberrant expression of histone deacetylase (HDAC) enzymes has been implicated in pancreatic cancer signalling. The inhibitors of these enzymes namely HDAC inhibitors (HDACi) are the novel agents which are currently being tested. These inhibitors modulate both histone and nonhistone proteins and have shown multiple biological effects including cell cycle arrest, differentiation and apoptosis in several cancer models. This article focuses on plant-derived HDAC inhibitor Sulforaphane (SFN) as a promising antipancreatic cancer agent. Moreover, we discuss the distinct molecular mechanisms triggered by SFN to exert cytotoxic effect in the predefined cancer models. Finally we describe the combinatorial therapeutic strategy involving SFN with other anticancer agents. This novel approach circumvents herculean cancer chemoresistance and alleviates toxicity, the main drawbacks of monotherapy.

Role of Inner Nuclear Membrane Protein Complex Lem2-Nur1 in Heterochromatic Gene Silencing.

Heterochromatin in the fission yeast Schizosaccharomyces pombe is clustered at the nuclear periphery and interacts with a number of nuclear membrane proteins. However, the significance and the factors that sequester heterochromatin at the nuclear periphery are not fully known. Here, we report that an inner nuclear membrane protein complex Lem2-Nur1 is essential for heterochromatin-mediated gene silencing. We found that Lem2 is physically associated with another inner nuclear membrane protein, Nur1, and deletion of either lem2 or nur1 causes silencing defect at centromeres, telomeres, and rDNA loci. We analyzed the genome-wide association of Lem2 using ChIP sequencing and we found that it binds to the central core region of centromeres, in striking contrast to Chp1, a component of pericentromeric heterochromatin, which binds H3K9me-rich chromatin in neighboring sequences. The recruitment of Lem2 and Nur1 to silent regions of the genome is dependent on H3K9 methyltransferase, Clr4. Finally, we show that the Lem2-Nur1 complex regulates the local balance between the underln]Snf2/HDAC-containing repressor complex (SHREC) histone deacetylase complex and the anti-silencing protein Epe1. These findings uncover a novel role for Lem2-Nur1 as a key functional link between localization at the nuclear periphery and heterochromatin-mediated gene silencing.