Current Pharmaceutical Biotechnology - Volume 21, Issue 13, 2020

Aplastic Anemia (AA) is also known as idiopathic aplastic anemia (IAA) and the production of new blood cells ceases in AA, which leads to an abnormal hematological syndrome such as pancytopenia and suppression of hypo-cellular bone marrow. The pathophysiology of AA in most cases is immune-mediated and is stimulated by type 1 cytotoxic T cells. Reliable early diagnostic tests of IAA are not yet available, therefore most of the cases are identified in advanced stages. Recently, abnormal immune response and hematopoietic cell deficiencies are defined genetically, such as in target cells of telomere repair gene mutations and by the dysregulation of T-cell activation pathways. Importantly, anti-thymocyte globulins and cyclosporine-associated immunosuppression are successful treatments for restoring blood cell production in most of the cases, however, clonal hematologic diseases remain challenging. In the current review, we have discussed the common practices in the treatment, pathophysiology, diagnosis, and management of AA.

Parmelia that belongs to the Parmeliaceae Family is a foliose lichen combined with one or two groups of fungi in Phylum Ascomycota or Basidiomycota and algae, which might be green algae or blue-green algae (cyanobacteria). It is generally called “Stone Flower,” “Charila,” “Pattharphool,” or “Shilaaapushpa” in India. Lichen can be generally found growing on walls, old trees and spread largely across India, especially in the mountain area. It is a source of edible organisms for people residing in some regions of Nepal and it is also cultivated in hillsides of Kashmir. It has been found that lichen contains a lot of distinctive chemical compounds such as evernic acid, lecanoric acid, lobaric acid, norstictic acid, physodic acid, and salazinic acid. Some species of this lichen are recommended traditionally for controlling diseases such as boils, bronchitis, inflammations, excessive salivation, toothache, vomiting, etc. It has also applied as an indicator for biomonitoring, astringent, carminative, demulcent, bitter, resolvent, emollient, laxative, sporofic, sedative, diuretic and considered for treating sores, bronchitis, excessive salivation, vomiting, tooth-ache, boils and inflammations. It has been utilized for preparing traditional food and acts as a bioindicator for air pollution and radiation. It shows antibacterial, antioxidant, antimycobacterial and antifungal activities, including haemolytic, anaesthetic, spasmolytic and antispasmodic and antitumour activities. It also has several unique phytoconstituents that could be in charge of different therapeutic activities, but the majority of them are still unexplored. The review mainly focuses on various facets, such as common names, synonyms, traditional uses, botanical descriptions, and pharmacological activities of seven species of Parmelia.

Background: Mango peel is a major by-product of mango (Mangifera Indica L.) fruit that belongs to the Anacardiaceae family. It is a tropical or subtropical fruit and is a potent source of polyphenolic contents. In traditional medicines, mango peel extract has been commonly used, either singly or in combination with other plant extracts against different ailments since ancient times. Methods: An electronic database search for accepted articles in Pubmed, Google Scholar, Researchgate, Google, Scopus and Science Direct was used to review the scientific inputs by searching appropriate keywords. Some information was obtained from books and databases on medicinal plants used in different periods. Results: Numerous reports revealed that mango peel contains a wide spectrum of phytochemical compounds like polyphenolics and flavonoids. A mango peel is a potential source of antioxidant, antiinflammatory, antidiabetic, antibacterial and antiproliferative properties. This review suggests that mango peel could be a potential drug to treat various clinical conditions in the future. Conclusion: In this review, a number of phytochemicals have been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of mango peel against various diseases are also discussed.

Objective: Alkaline Carboxymethyl Cellulase (CMCase) is an attractive enzyme for the textile, laundry, pulp, and paper industries; however, commercial preparations with sufficient activity at alkaline conditions are scarce. Methods: High CMCase-producing bacterial isolate, SX9-4, was screened out from soil bacteria, which was identified as Flavobacterium sp. on the basis of 16S rDNA sequencing. Results: The optimum pH and temperature for CMCase reaction were 8.0 and 55°C, respectively. Alkaline CMCase was stable over wide pH (3.0-10.6) and temperature (25-55°C) ranges. Enzyme activity was significantly inhibited by the bivalent cations Mn²⁺ and Cu²⁺, and was activated by Fe²⁺. To improve the alkaline CMCase production of SX9-4, fermentation parameters were selected through onefactor- at-a-time and further carried out by response surface methodologies based on a central composite design. Conclusion: High CMCase production (57.18 U/mL) was achieved under the optimal conditions: 10.53 g/L carboxymethylcellulose sodium, 7.74 g/L glucose, 13.71 g/L peptone, and 5.27 g/L ammonium oxalate.

Background: Cardamom is the flavouring spices mainly cultivated all over the world. Apart from being used as the spice, it has many medicinal values. Therefore, the present study aimed to investigate the potential use of cardamom and its effects on the ability of learning, developmental, and various biochemical factors of Swiss-Webster mice offspring at different stages. Methods: In this method, Swiss-Webster mice offspring at different stages were used for the analysis of biochemical factors. After the administration of cardamom orally, the pups were subjected to various tests for determining social and defense behaviors of males and females, anxiety behavior; locomotor and neuromuscular activities, haemotological parameters, and hormonal factors of males and females. Results: The present findings indicate that the cardamom induced reduction in the social and defense behaviors of males and females, respectively, and also anxiety behavior. Interestingly, locomotor and neuromuscular activities decreased significantly. Discussion: In addition, the packed cell volume, red blood count, hemoglobin content, AChE in forebrain, the testosterone in males and progesterone in females were observed to increase significantly, whereas the blood platelets and total white blood count decreased non-significantly. Through perinatal exposure, cardamom can pass through the placenta or/and lactation and reaches the fetus. Care must be taken when using cardamom and especially during pregnancy and lactation. Conclusion: The administration of cardamom enhances the ability of social, developmental, and various biochemical factors of Swiss-Webster mice offspring at different stages.

Background: Developmental ethanol (EtOH) exposure can cause lifelong behavioral hyperactivity, cognitive deficits, emotional dysregulation, and more. However, co-treatment with lithium (Li) on the day of EtOH exposure prevents many of the impairments. Methods: Experimental groups of pregnant mice were exposed to EtOH (20% v/v solution at a dose of 2.5 g/kg) in their drinking water and the animals were treated with Li (15 and 30 mg/kg) through IP injection on gestational days14, 16, 18, and 20, and post-natal days (PD) 3, 5, 7, and 9. All treatments with EtOH and exposure to Li doses to pregnant mice started on gestational day 14 and continued until post-natal day 9 (PD9). The effects on some developing morphological indices, nerve reflexes during weaning age, and various cognitive dysfunctions at adolescent ages and biochemical changes in the brain tissue indices of below-mentioned neurotransmitters and oxidative stress in post-natal developing offspring at adolescent age, were studied. Results: Perinatal exposure to EtOH in pregnant mice resulted in several postnatal developing and morphological indices in the developing male pups during their weaning period, like gain in their body weight, delay in appearance of their body hair fuzz and opening of their eyes, and disruptions in their developing motor reflexes. Discussion: During adolescent age, a significant deficit in their learning capability and cognitive behavior, decline in the neurochemical DA and 5-HT in their brain and some indices of oxidative stress TBARS, GSH, GST, CAT, and SOD was observed. Conclusion: These results indicate that Li ameliorates significantly and dose-dependently EtOH induced developmental toxicities like morphological developments and dysfunctions in cognitive retention and oxidative stress on a long-term basis in brain tissue. However, further detailed studies are required for the clinical use of as an ameliorating agent for perinatal EtOH induced dysfunctions.

Background: Streptomyces sp. produces various antibiotic agents and the number of lead molecules from the genus Streptomyces increased rapidly in recent years. Drug resistance against various commercially available antibiotics is one of the important problems throughout the world. Streptomyces spp. produce various antimicrobials with potent activity against drug-resistant bacteria. Methods: Streptomyces sp. SA1 was isolated from the marine environment for the biosynthesis of antibiotics. The important variables influencing secondary metabolite biosynthesis were optimized to increase the biosynthesis of antimicrobial agents using the traditional method and statistical approach. Results: Streptomyces sp. SA1 produced novel antibiotics and the process variables were optimized by the traditional method (One-variable-at-a-time approach). Maltose showed maximum antimicrobial activity (220 U/mL). Analysis of the nitrogen, the effect of nitrogen sources revealed that beef extract incorporated culture medium showed rich antibacterial activity (188/mL). Among the ionic sources, KCl significantly influenced antibiotic production. Maltose, beef extract and KCl were considered as the most influencing medium components. Antimicrobial agent biosynthesis was achieved with maltose 1.22 g/L, beef extract 0.93 g/L and KCl 0.27 g/L in response surface methodology. Conclusion: Actinomycetes, especially Streptomyces, play an important role as a source for bioactive compounds that are used to treat infections, and many other diseases. The isolated Streptomyces sp. was a good producer of antibacterial agent, which required various nutritional supplements in the culture medium. The optimized medium components investigated in this study will be useful for future studies with the mass production of secondary metabolites.

An increase in the prevalence of Inflammatory Bowel Diseases (IBD) as a multifactorial intestinal chronic inflammation as well as the absence of a certain cure, has created an innovative era in the management of IBD by molecule/pathway-based anti-inflammatory approaches. There are credible documentations that demonstrate Mitogen-Activated Protein Kinases (MAPK) acts as IBD regulator. Upon the activation of MAPK signalling pathway, the transcription and expression of various encoding inflammatory molecules implicated in IBD are altered, thereby exacerbating the inflammation development. The current pharmacological management of IBD, including drug and biological therapies are expensive, possess temporary relief and some adverse effects. In this context, a variety of dietary fruits or medicinal herbs have received worldwide attention versus the development of IBD. Infact, natural ingredients, such as Flavaglines, Fisetin, Myricitrin, Cardamonin, Curcumin, Octacosanol and Mangiferin possess protective and therapeutic effects against IBD via modulation of different segments of MAPK signaling pathway. This review paper calls attention to the role of MAPK signaling triggered by natural products in the prevention and treatment of IBD.

Background: The last few decades have witnessed groundbreaking research geared towards immune surveillance mechanisms and have yielded significant improvements in the field of cancer immunotherapy. This approach narrows down on the development of therapeutic agents that either activate or enhance the recognitive function of the immune system to facilitate the destruction of malignant cells. The α -galactosylceramide derivative, KRN7000, is an immunotherapeutic agent that has gained attention due to its pharmacological ability to activate CD1d-restricted invariant natural killer T(iNKT) cells with notable potency against cancer cells in mouse models; a therapeutic success was not well replicated in human models. Dual structural modification of KRN7000 entailing the incorporation of hydrocinnamoyl ester on C6" and C4-OH truncation of the sphingoid base led to the development of AH10-7 which, interestingly, exhibited high potency in human cells. Objective/Methods: Therefore, to gain molecular insights into the structural dynamics and selective mechanisms of AH10-7 for human variants, we employed integrative molecular dynamics simulations and thermodynamic calculations to investigate the inhibitory activities of KRN7000 andAH10-7 on hTCR-CD1d towards activating iNKT. Results: Interestingly, our findings revealed that AH10-7 exhibited higher affinity binding and structural effects on hTCR-CD1d, as mediated by the incorporated hydrocinnamoyl ester moiety which accounted for stronger intermolecular interactions with ‘non-common’ binding site residues. Conclusion: Findings extracted from this study further reveal important molecular and structural perspectives that could aid in the design of novel α-GalCer derivatives for cancer immunotherapeutics.

Background: Semaphorin 3B (SEMA3B) is characterized as a strong suppressing factor of the proliferation of cancerous cells and also by its anti-angiogenic effect. However, the knowledge on the changes in the expression profile of SEMA3B under the influence of cisplatin in endometrial cancer remains fragmented. The aim of this work was to note the changes in expression of SEMA3B when under the influence of cisplatin in the endometrial cancer cell line. Methods: Ishikawa cell line cells were exposed to three different concentrations of cisplatin: 2.5μM; 5μM; 10μM for 12, 24 and 48 hours and were compared to cells untreated by the drug. Changes in the expression profile of SEMA3B were determined based upon RtqPCR (mRNA) alongside the ELISA assay (protein). The Statistica 13.0 PL program was used for statistical analysis (p<0.05). Results: Changes on the transcriptome level seem to be more dynamic than on the proteome level. Regardless of the concentration given or the exposition period, the expression of semaphorin 3B was, in fact, higher in cells exposed to cisplatin. Statistically substantial differences (p<0.05) in the expression of SEMA3B mRNA and protein were seen for all incubation periods at the given cisplatin level when compared to the control. Conclusion: Cisplatin causes a growth in the expression of SEMA3B in an endometrial cancer cell culture, this results in the restoration in the state of cell homeostasis and shows the effectiveness of pharmacotherapy, including a low risk of drug resistance.

Objective: Heart dysfunctions are the major complications of trastuzumab in patients with Human Epidermal growth factor Receptor-2 (HER2)-positive breast cancers. Methods: In this study, the cytotoxicity of trastuzumab on H9c2 cardiomyoblasts was demonstrated, and the proteome changes of cells were investigated by a tandem mass tagging quantitative approach. The Differentially Abundant Proteins (DAPs) were identified and functionally enriched. Results: We determined that carvedilol, a non-selective beta-blocker, could effectively inhibit trastuzumab toxicity when administrated in a proper dose and at the same time. The proteomics analysis of carvedilol co-treated cardiomyoblasts showed complete or partial reversion in expressional levels of trastuzumab-induced DAPs. Conclusion: Downregulation of proteins involved in the translation biological process is one of the most important changes induced by trastuzumab and reversed by carvedilol. These findings provide novel insights to develop new strategies for the cardiotoxicity of trastuzumab.

Background: The aim of this study was to explore the inhibitory effect of baicalin on myocardial apoptosis induced by Ischemia-Reperfusion (I/R). Methods: Sprague Dawley rats' heart and myocardial cells I/R model were established in vivo and vitro, then 100 mg/kg and 10 μmol/l baicalin were administrated, respectively. The experiment was randomly divided into 4 groups (n=10): Control; I/R; IR+DMEM; and I/R+baicalin groups. Postoperation, the Left Ventricular (LV) End-Diastolic Pressure (LVEDP), the maximum velocity of LV contraction (dP/dtmax) and the maximum velocity of LV diastole (dP/dtmin) were recorded by the transthoracic echocardiography; the myocardial apoptosis percentage was analyzed by Annexin VFITC/ PI and TUNEL staining, and the apoptosis gene and protein were detected by RT-PCR and western blot. Furthermore, the protein expression of the calcium-sensing receptor (CaSR) and ERK1/2 phosphorylation were observed by western blot and Fura-2-acetoxymethyl ester. Moreover, primary rats’ cardiomyocytes were cultured and ERK1/2 specific inhibitor PD98059 was added to the culture medium. The cell survival rate, vitality and apoptosis were detected by MTT, lactate dehydrogenase (LDH) and TUNEL staining assay Kit, respectively. Results: Our present study showed that baicalin significantly improved LV hemodynamic parameters and myocardial apoptosis in myocardial I/R injury rats. Furthermore, we found that baicalin could down-regulate the protein expression of CaSR, but up-regulate the protein expression of ERK1/2. Furthermore, when the cells were pretreated with ERK1/2 inhibitor PD98059, the cells survival rate significantly decreased, but LDH activity and apoptosis significantly increased. The results indicated that the effect of baicalin on myocardial I/R injury could be inhibited by ERK1/2 inhibitor. Conclusion: In conclusion, our data suggests that baicalin attenuates I/R-induced myocardial injury maybe through the suppression of the CaSR/ERK1/2 signaling pathway.

Background: Multiple Myeloma (MM) is a complex hematologic malignancy, driven by several genetic and epigenetic alterations. MiRNAs as biomarkers have become a rapidly growing research area in the last decade. Aim: The aim was to study the expression pattern of selected miRNAs and to explore the impact of cytogenetic aberrations in MM patients for therapeutic tools. Patients and Methods: Forty Egyptian adult patients were selected for the study with symptomatic newly diagnosed MM disease. Bone marrow samples were collected to investigate twelve miRNAs selected according to their relation to the most common cytogenetic aberrations with relevant prognostic value. The relative expression of the selected miRNAs was determined using a real-time PCR technique. Fluorescence In Situ Hybridization (FISH) technique was performed for cytogenetic analysis. Results: Eight miRNAs were down-regulated [miR-15a (p<0.001), miR214-3p (p<0.001), miR135b (p<0.001), miR19a-3p (p<0.001), miR19b-3p ((p=0.026), miR30e-5p (NS), miR133a (NS), miR146a- 5p (p<0.001)]. Four miRNAs were up-regulated [miR99b-5p (p=0.028), miR125a-3p (p=0.004), let7b- 5p (p<0.001), let7c-5p (p<0.001)]. Significant relation was observed between positive 14q32 rearrangement using the break apart re-arrangement probe for 14q32.33 locus and lower expression levels of miR15a (p= 0.014), 214-3p (p=0.046), 99b-5p (p=0.014), 146a-5p (p=0.041). A higher expression level of miR30e-5p was significantly related to positive 14q32 rearrangement. Conclusion: Deregulated miRNAs were identified and the association with 14q32 rearrangement and MM pathogenesis has been determined.

Objective: Osteosarcoma is considered as one of the most common types of bone tumors, which occurs among adolescents and children. Methods: Current therapy strategies still have limited effectiveness therefore, the development of new therapies is urgent. Morusin is a compound isolated from Morus australis (Moraceae). Many studies have reported its anti-tumor effect on several tumor types. However, its role in osteosarcoma is still unclear. Results: In this study, we determined that morusin significantly suppresses the proliferation and promotes the apoptosis of osteosarcoma cells. Furthermore, the migration and invasion of osteosarcoma were reduced after exposure to morusin. The deep mechanism was determined to be the inhibition of the PI3K/AKT signaling pathway. Conclusion: In conclusion, our study indicates morusin as a potential candidate for osteosarcoma therapy.