Molecularly targeted therapies for asthma: current development, challenges and potential clinical translation

Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs. New drug candidates with their putative targets that have shown promising results in the preclinical and/or clinical trials are summarised. Examples of these interventions include restoration of Th1/Th2 balance by the use of newly developed immunomodulators such as toll-like receptor-9 activators (CYT003-QbG10 and QAX-935). Clinical trials revealed the safety and effectiveness of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists such as OC0000459, BI-671800 and ARRY-502 in the restoration of Th1/Th2 balance. Regulation of cytokine activity by the use of newly developed biologics such as benralizumab, reslizumab, mepolizumab, lebrikizumab, tralokinumab, dupilumab and brodalumab are at the stage of clinical development. Transcription factors are potential targets for asthma therapy, for example SB010, a GATA-3 DNAzyme is at its early stage of clinical trial. Other candidates such as inhibitors of Rho kinases (Fasudil and Y-27632), phosphodiesterase inhibitors (GSK256066, CHF 6001, roflumilast, RPL 554) and proteinase of activated receptor-2 (ENMD-1068) are also discussed. Preclinical results of blockade of calcium sensing receptor by the use of calcilytics such as calcitriol abrogates cardinal signs of asthma. Nevertheless, successful translation of promising preclinical data into clinically viable interventions remains a major challenge to the development of novel anti-asthmatics

Andrographolide restores healthy airway function in toluene diisocyanate-induced occupational mouse asthma model through upregulation of heam oxygenase-1 and activation of Akt/Nrf-2 dependent pathway

Toluene diisocyanate (TDI) is a major cause of chemical-induced occupational asthma, which contributes about 15% of global asthma burden. Steroid resistance and compounded side effects that are associated with use of corticosteroid in management of asthma necessitate the search for alternative drugs. Andrographolide, a naturally occurring diterpene lactone was tested for control of cardinal occupational asthma features. BALB/c mice were dermally sensitized with 0.3% TDI or acetone olive oil (AOO) vehicle on day 1 and 8, followed by 0.01% TDI intranasal challenge on days 15, 18 and 21. Endpoints were evaluated via bronchoalveolar lavage fluid (BALF) cell analysis, 2′,7′-dichlorofluorescin diacetate (DCFH-DA) intracellular reactive oxygen species (ROS) assays, immunoblotting, immunohistochemistry and methacholine challenge tests. Decrease in BALF total and differential leukocyte counts was recorded in the andrographolide-treated animals. The compound dose-dependently (at 0.1mg/kg, 0.5mg/kg and 1mg/kg) reduced intracellular de-esterification of DCFH-DA. This suggests andrographolide’s role in the neutralization of intracellular BALF ROS surge. Mechanistically, the treatment prevented TDI-induced aberrant E-cadherin bronchial epithelial distribution at cell-cell contact site. Immunoblot analysis of lung samples shows significant up-regulation of heam oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor-2 (Nrf2) which may have possibly occurred through Akt dependent pathways. Methacholine triggered airway hyperresponsiveness was markedly suppressed following andrographolide administration (i.p). Collectively, these findings indicate that andrographolide exhibit protective function against TDI induced airway epithelial barrier dysfunction and oxidative lung damage, and that Akt dependent pathways may play a role in the restoration of normal airway functionality in chemical induced occupational asthma. To the best of our knowledge, the specific ability of andrographolide to control TDI-induced occupational asthma was not previously explored. Therefore, these data elucidate the therapeutic potential of the candidate compound in the control and management of chemical induced occupational asthma

SRS06, a new semisynthetic andrographolide derivative with improved anticancer potency and selectivity, inhibits nuclear factor-kB nuclear binding in the A549 non-small cell lung cancer cell line

Background: Andrographolide has been reported with anticancer and anti-inflammatory properties through the inhibition of the activity of signaling molecules such as v-Src, nuclear factor-κB (NF-κB), STAT3, and PI3K. NF-κB has been proven to promote cancer cell survival, and targeting this pathway will halt the growth of cancer cells. Efforts have been made to produce semisynthetic derivatives of andrographolide with improved anticancer potency and selectivity. Subsequently, the effect of a selected derivative, 3,14,19-tripropionylandrographolide (SRS06), was tested for its action against NF-κB. Methods: Screening against 60 US National Cancer Institute (NCI) human cancer cell lines representing leukemia and non-small cell lung (NSCL), colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers was performed to determine the tumor type selectivity and potency of SRS06. Microculture tetrazolium, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and sulforhodamine B assays were used to determine the in vitro anticancer activity, while Western blot studies were performed to ascertain the inhibitory effect of SRS06 on the NF-κB signaling cascade. The TransAM™ p65 assay kit was used to determine NF-κB p65 DNA binding activity in the NSCL cancer cell line A549. Results: From the NCI screening, SRS06 was found to exhibit potent growth-inhibitory effects on multiple cancer cell lines with 10-fold lower 50% growth inhibition (GI50) compared with andrographolide. It was also discerned that the compound preferentially targeted melanoma, CNS, renal, colon, ovarian, prostate, and NSCL cancer cell lines. The DNA fragmentation assay indicated that the main mode of cell death of SRS06-treated A549 cells was via apoptosis. At 5 µmol/l the compound decreased NF-κB protein expression and caused a significant reduction in the nuclear p65 DNA binding activity. Conclusion: SRS06 displayed improved anticancer selectivity and potency when compared with andrographolide. We alluded its anticancer activity to its effect of inhibiting NF-κB nuclear binding

Mechanisms of oral bacterial virulence factors in pancreatic cancer

Pancreatic cancer is a highly lethal disease, and most patients remain asymptomatic until the disease enters advanced stages. There is lack of knowledge in the pathogenesis, effective prevention and early diagnosis of pancreatic cancer. Recently, bacteria were found in pancreatic tissue that has been considered sterile before. The distribution of flora in pancreatic cancer tissue was reported to be different from normal pancreatic tissue. These abnormally distributed bacteria may be the risk factors for inducing pancreatic cancer. Therefore, studies on combined effect of multi-bacterial and multi-virulence factors may add to the knowledge of pancreatic cancer pathogenesis and aid in designing new preventive and therapeutic strategies. In this review, we outlined three oral bacteria associated with pancreatic cancer and their virulence factors linked with cancer

Glycyrrhizic acid: a natural plant ingredient as a drug candidate to treat COVID-19

The total number of cumulative cases and deaths from the COVID-19 pandemic caused by SARS-CoV-2 is still increasing worldwide. Although many countries have actively implemented vaccination strategies to curb the epidemic, there is no specific efficient therapeutic drug for this virus to effectively reduce deaths. Therefore, the underappreciated macromolecular compounds have become the spotlight of research. Furthermore, the medicinal compounds in plants that provide myriad possibilities to treat human diseases have become of utmost importance. Experience indicates that Traditional Chinese medicine effectively treats SARS and has been used for treating patients with COVID-19 in China. As one of the world’s oldest herbal remedies, licorice is used for treating patients with all stages of COVID-19. Glycyrrhizic acid (GA), the main active compound in licorice, has been proven effective in killing the SARS virus. Meanwhile, as a natural plant molecule, GA can also directly target important protein structures of the SARS-CoV-2 virus and inhibit the replication of SARS-CoV-2. In this review, we summarized the immune synergy of GA and its potential role in treating COVID-19 complications. Besides, we reviewed its anti-inflammatory effects on the immune system and its positive effects in cooperation with various drugs to fight against COVID-19 and its comorbidities. The purpose of this review is to elucidate and suggest that GA can be used as a potential drug during COVID-19 treatment

36th Malaysian Society of Pharmacology and Physiology Annual Scientific Meeting 2023

The 36th Malaysian Society of Pharmacology and Physiology (MSPP) Annual Scientific Meeting was hosted in collaboration with the Faculty of Medicine and Health Sciences, Universiti Putra Malaysia from the 7th to 8th of August 2023 at Bangi Resort Hotel in Bangi, Malaysia. The event focused on the theme "Pharmacology & Physiology Post-Millenial Era: Challenges & Opportunities". This platform is one of the suitable avenues to facilitate the exchange of scientific endeavors and enhance networking among scientists, academicians, clinicians, and postgraduate students involved in the fields of pharmacology and physiology, as well as multidisciplinary areas such as drug discovery, omics approaches, stem cells, and regenerative medicine. The primary objective of the special issue is to revitalize recent advances and breakthroughs in pharmacology and physiology to enhance opportunities and vanquish challenges in the post-millenial era, especially in the wake of the COVID-19 pandemic. In light of this, the special issue compiles the conference proceeding, to provide opportunities for knowledge integration of research and innovations

Molecular and immunomodulatory actions of new antiasthmatic agents: exploring the diversity of biologics in Th2 endotype asthma

Asthma is a major respiratory disorder characterised by chronic inflammation and airway remodelling. It affects about 1–8% of the global population and is responsible for over 461,000 deaths annually. Until recently, the pharmacotherapy of severe asthma involved high doses of inhaled corticosteroids in combination with β-agonist for prolonged action, including theophylline, leukotriene antagonist or anticholinergic yielding limited benefit. Although the use of newer agents to target Th2 asthma endotypes has improved therapeutic outcomes in severe asthmatic conditions, there seems to be a paucity of understanding the diverse mechanisms through which these classes of drugs act. This article delineates the molecular and immunomodulatory mechanisms of action of new antiasthmatic agents currently being trialled in preclinical and clinical studies to remit asthmatic conditions. The ultimate goal in developing antiasthmatic agents is based on two types of approaches: either anti-inflammatory or bronchodilators. Biologic and most small molecules have been shown to modulate specific asthma endotypes, targeting thymic stromal lymphopoietin, tryptase, spleen tyrosine kinase (Syk), Janus kinase, PD-L1/PD-L2, GATA-3, and CD38 for the treatment and management of Th2 endotype asthma

An Andrographis paniculata Burm. Nees extract standardized for three main Andrographolides prevents house dust mite-induced airway inflammation, remodeling, and hyperreactivity by regulating Th1/Th2 gene expression in mice

Ethnopharmacological relevance: Andrographis paniculata Burm. Nees (AP) is an herb used traditionally in Indian and Chinese traditional medicine for the treatment of various inflammatory and respiratory tract diseases. However, the anti-inflammatory potential of standardized Andrographis paniculata 50% ethanol extract (APEE50) in the murine model of asthma has not been investigated. Aim of the study: This study aimed to evaluate the protective anti-inflammatory potential and better understand the underlying mechanism of action of APEE50 in a clinically-relevant mouse asthma model. Thereafter, develop the ethanolic extract of AP as a supplement for asthma prophylaxis. Materials and method: APEE50 was prepared and standardized for AGP, NAG, and DDAG using a high-performance liquid chromatography system. Asthma was induced according to a 14-day house dust mite (HDM) induction protocol. The prophylactic potential of APEE50 (50 mg/kg – 200 mg/kg) was determined by assessing cardinal asthma features, which included BALF leukocyte and differential cell count, BALF cytokine assay, histology, gene expression, and airway hyperreactivity study. Results: APEE50 significantly inhibited HDM-induced airway eosinophilia and neutrophilia. In addition to decreased levels of IL-4, IL-5, IL-13, and eotaxin in bronchoalveolar fluid, APEE50 abrogated HDM-induced airway mucus over-secretion and airway hyper-responsiveness. Administration of APEE50 downregulated HDM-induced upregulation of the oxidative stress enzyme Duox1 (dual oxidase 1) and marginally induced Nfe2l2 (nuclear factor erythroid 2-related factor 2) gene expressions. Similarly, Th2-related (Serpinb2, Clca3a1, Il4 and Il13) and Muc5ac gene expression were significantly downregulated. Conclusion: Prophylactic administration of APEE50 prevented the progression of HDM-induced asthmatic responses by down-regulating Th2 cytokine gene expression and oxidative stress level

Melanoma metastasis: what role does melanin play? (review)

Melanoma is an extremely aggressive form of skin cancer that can spread to the lungs, brain, and liver, among other vital organs. Melanoma cells, unlike any other cancer cells, can produce significant amounts of melanin by a process known as melanogenesis, causing them to become heavily pigmented. Melanogenesis, specifically the melanin pigment, is well known for its ability to protect the skin from the harmful effects of UV light, which can lead to the development of skin cancer. Nevertheless, uncontrolled melanogenesis plays a role in the advancement of melanotic melanoma, and melanin pigments can reduce the effectiveness of radiotherapy and immunotherapy. Therefore, studies are being performed that focus on inhibiting melanogenesis to prevent melanoma metastasis. However, it is worth noting that, in addition to its UV‑protective function, melanin also plays a role in preventing melanoma metastasis. Microphthalmia‑associated transcription factor (MITF) and melanin have been demonstrated to attenuate the aggressiveness of melanoma by suppressing numerous essential metastatic processes. Eumelanin and pheomelanin (two types of melanin), which cause oxidative stress, can also prevent melanoma progression in the early stages. Hence, it is vital to explore the role of inducing melanogenesis rather than inhibiting melanogenesis in preventing melanoma metastasis

Pharmacological modulation of apoptosis and autophagy in pancreatic cancer treatment

Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles. This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC. Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords. Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas