Current Molecular Pharmacology - Volume 16, Issue 3, 2023

Mycobacterium tuberculosis causes a contagious pulmonary disease with a high mortality rate in developing countries. However, the recommendation of DOTS (approved by WHO) was effective in treating tuberculosis, but nowadays, resistance from the first line (MDR-TB) and the second line (XDR-TB) drugs is highly common. Whereas, the resistance is a result of factors like poor patient constancy due to the long duration of therapy and co-infection with HIV. The approval of bedaquiline under an accelerated program for the treatment of MDR-TB has revealed its effectiveness in clinical trials as a therapeutic novel molecule. BDQ selectively inhibits the ATP synthase of bacterium and reduces ATP production. Additionally, the poor pharmacokinetic properties raised provocations in the MDR therapy, but the use of targeted drug delivery can solve the hurdles. While the preclinical and clinical studies included in this review are strongly suggesting the usefulness of BDQ in MDR-TB and XDR-TB, the repurposing of different drug classes in resistant TB is opening new opportunities to manage the disease conditions. In this review, we have summarized the examples of pipeline drugs and repurposed molecules with preclinical formulation developments.

Background: Alzheimer's disease (AD), the primary cause of dementia, escalating worldwide, has no proper diagnosis or effective treatment. Neuronal cell death and impairment of cognitive abilities, possibly triggered by several brain mechanisms, are the most significant characteristic of this disorder. Methods: A multitude of pharmacological targets have been identified for potential drug design against AD. Although many advances in treatment strategies have been made to correct various abnormalities, these often exhibit limited clinical significance because this disease aggressively progresses into different regions of the brain, causing severe deterioration. Results: These biomarkers can be game-changers for early detection and timely monitoring of such disorders. Conclusion: This review covers clinically significant biomarkers of AD for precise and early monitoring of risk factors and stages of this disease, the potential site of action and novel targets for drugs, and pharmacological approaches to clinical management.

Background: The treatment of cancer is a current challenge for public health, causing high rates of morbidity and mortality worldwide. Doxorubicin (DOX) and cisplatin (CP) are two well-known chemotherapeutic agents approved by the Food and Drug Administration to treat cancer patients. However, there are two problems associated with DOX and CP: drug resistance and adverse impact. Resveratrol (Res) belongs to the stilbene class and possesses various health-promoting effects, such as antioxidant, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective effects. Objective: The present review aims to give special attention to the therapeutic impacts of Res in potentiating DOX and CP’s antitumor activities and reducing their side effects. Methods: PubMed, Science Direct, and Google Scholar were used to search articles for the current manuscripts. Results: Co-administration of Res can prevent chemoresistance and potentiate the induction of apoptosis and cell cycle arrest in cancer cells. Res can enhance the sensitivity of cancer cells to DOX and CP chemotherapy by inhibiting the migration and metastasis of cancer cells. Simultaneously, Res, due to its therapeutic actions ameliorates the adverse impacts of DOX and CP on normal cells and organs, including the liver, kidney, brain, and testes. As Res suffers from poor bioavailability, nanoformulations have been developed with promising results to improve its antitumor activity and protective effects. Conclusion: Based on preclinical studies, it is obvious that Res is a promising adjsuvant for CP and DOX chemotherapy, and its benefits can be utilized in the clinical course.

Effective and better-tolerated agents for the treatment of most of psychiatric disorders are one of the main challenges. Recently, anti-inflammatory, antioxidants and neuroprotective agents as adjuvant therapy have been shown to be able to play a role against the degenerative mechanisms commonly related to psychiatric conditions. Berberine, a biologically active alkaloid derived from various plants, represents many pharmacological impacts, such as antimicrobial, antidiabetic, anticancer, antioxidant and anti-inflammatory activities. This compound also protects neurons and improves the survival, growth and action of nerve cells due to its high potential for crossing the blood-brain barrier. Ample evidence reported that berberine had been associated with CNS-related disorders, including Alzheimer's, cerebral ischemia, mental depression, schizophrenia and anxiety. Thus, in this review, we aimed to indicate the effectiveness of berberine on mental disorders

Osteoporosis is becoming more prevalent in the ageing society, however, its treatment is still a problem for both society and individuals. Traditional Chinese Medicine (TCM) has a long history in treating osteoporosis and is receiving increasing attention. Multiple formulas of TCM showed satisfactory effects in treating osteoporosis in both animal models and clinical patients. However, because TCM usually consists of multiple plant and/or animal products, it is difficult to clarify the mechanism of TCM according to the requirements of Western medicine regarding purity, efficacy, dosage, and safety. With increasing researchers have started to investigate the TCM using modern scientific tools such as bioinformatics and network pharmaceutics in osteoporosis and the addition of TCM in the latest version of International Statistical Classification of Diseases and Related Health Problems (ICD-11 version, 2019) by WHO, TCM is showing large potential in treating osteoporosis although there is still a long way. The review aimed to summarize recent advancements of TCM treating osteoporosis.

In the present study, the health-protective and therapeutic properties of MET have been discussed, focusing on the effect of MET on the Nrf2 expression in patients with different pathological conditions. Metformin (MET) regulates high blood glucose, thus being an integral part of the antidiabetic medications used to treat type 2 diabetes mellitus. It belongs to biguanide class medications that are administered through the oral route. Moreover, the agent is widely known for its anti-cancer, anti-oxidant, anti-inflammatory, and neuroprotective effects. The MET modulates the nuclear factor erythroid-2 related factor-2 (Nrf2) signaling pathway, which in turn yields the above-mentioned medical benefits to patients. The Nrf2 signaling pathways are modulated in multiple ways described subsequently: 1) MET acts on the cancer cells and inactivates Raf-ERK signaling, thus reducing Nrf2 expression, 2) MET obstructs the expression of proteins that are involved in apoptosis of tumor cells and also prevents tumor cells from oxidation through an AMPK-independent pathway; 3) MET carries out Keap1-independent mechanism for reducing the levels of Nrf2 protein in cancer cells; 4) MET upregulates the Nrf2-mediated transcription to stimulate the anti-oxidant process that prevents oxidative stress in cells system and consequently gives neuroprotection from rotenone and 5) MET downregulates p65 and upregulates Nrf2 which helps improve the angiogenesis impairment stimulated by gestational diabetes mellitus. This article presents an analysis of the health-protective properties of MET and also sheds light on the effect of MET on the Nrf2 expression in patients with different pathological conditions.

Acute liver injury (ALI) is a critical and fatal disorder associated with excessive Although considerable advances have been made in the early diagnosis and treatment of breast cancer, it is still one of the major causes of global cancer-related death in women over the last several decades. Phytochemicals have been shown to be promising agents in the prevention and treatment of breast cancer. Resveratrol is an important plant-derived polyphenolic compound with a variety of potent biological activities. It has been suggested that resveratrol can be used to prevent and treat various types of cancer, including breast cancer. Resveratrol can affect numerous signaling pathways in vitro, leading to the induction of cell cycle arrest and apoptosis, suppression of proliferation, reduction of inflammatory responses, and the inhibition of angiogenesis and metastasis. Nevertheless, studies of resveratrol in animal models of breast cancer have so far been disappointing.

Background and Objective: Hydroxychloroquine (HCQ) is a molecule derived from quinacrine; it displays a wide range of pharmacological properties, including anti-inflammatory, immunomodulatory, and antineoplastic. However, little is known about this molecule’s role in lung injury. This study aimed to identify HCQ’s regulatory role of HCQ in sepsis-induced lung injury and its molecular mechanism. Methods: To test the protective properties of HCQ, we established an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice. The extent of the injury was determined by evaluating histopathology, inflammatory response, oxidative stress, and apoptosis. Mechanistically, conventional nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) knockout mice were employed to investigate whether HCQ exerted pulmonary protection by inhibiting NLRP3-mediated pyroptosis. Results: Our findings revealed that HCQ pretreatment significantly mitigated LPS-induced lung injury in mice in terms of histopathology, inflammatory response, oxidative stress, and apoptosis, while inhibiting LPS-induced NLRP3 inflammasome activation and pyroptosis. Additionally, the indicators of lung injury, including histopathology, inflammatory response, oxidative stress, and apoptosis, were still reduced drastically in LPS-treated NLRP3 (-/-) mice after HCQ pretreatment. Notably, HCQ pretreatment further decreased the levels of pyroptosis indicators, including IL-1β, IL-18 and Cle-GSDMD, in LPS-treated NLRP3 (-/-) mice. Conclusion: Taken together, HCQ protects against lung injury by inhibiting pyroptosis, maybe not only through the NLRP3 pathway but also through non-NLRP3 pathway; therefore, it may be a new therapeutic strategy in the treatment of lung injury.

Background: Curcumin has been isolated from the rhizomes of Curcuma longa. Over the years, it has shown outstanding therapeutic potential in various human disorders, including cancers. Objective: The aim is to study curcumin’s effects on the apoptosis signaling pathway in the head and neck squamous cell carcinoma (HNSCC) cell line HN5. Methods: The cytotoxicity of curcumin on HN5 cells were assessed. In addition, HN5 cells were also treated with curcumin to evaluate its effect on the caspase-8, -9, Bcl-2, Bax, and Stat3 gene expressions. Results: The results exhibited that cell viability reduced following curcumin treatment in a concentration- dependent manner. Curcumin treatment caused decreased expression of Bcl2, with simultaneous upregulation of the Bax/Bcl2 ratio. Curcumin increased caspase-9 expression, did not affect caspase-8, and decreased Stat3 expression. The induction of the mitochondria-dependent apoptosis pathway of curcumin happened by modulating the expression of Bcl2 and Bax genes, resulting in the caspase-9 activation. Furthermore, curcumin decreased the expression of the Stat3 in HN-5 cells. Conclusions: In conclusion, curcumin showed marked anticancer effects in the HN-5 cell line by modulating Stat-3; Bax/Bcl-2 expression in vitro.

Background: An imbalance in the levels of arachidonic acid (ARA) metabolites in cardiovascular disorders and drug-induced cardiotoxicity have been previously described. Aims: This study aimed to investigate the influence of cyclooxygenase-2 (COX-2) selective inhibitors on the gene expression of ARA-metabolizing genes and beta1 gene in the hearts and kidneys of experimental mice. Methods: Thirty-five balb/c mice were divided into five groups with seven mice per group. The groups were then given two distinct types of COX-2 selective inhibitors, rofecoxib and celecoxib, in two different doses equivalent to those used in human treatment for 30 days. The mRNA expression of beta1, ace2, and ARA-metabolizing genes, coxs, lipoxygenases (aloxs), and cytochrome p450 (cyp450s) in mice heart and kidneys were assessed. Genes were analyzed using real-time polymerase chain reaction analysis. In addition, rofecoxib-induced histological alterations were examined. Results: It was found that only the high dose of rofecoxib (5 mg/kg) caused toxicological alterations, a finding that was indicated by a significant increase (P < 0.05) in the relative weight of the mouse hearts and increase in the ventricle wall thickness as observed through pathohistological examination. This increase was associated with a significant increase in the mRNA expression level of the beta1 receptor in both the heart and kidneys of the mice (53- and 12-fold, respectively). The expression of both cox1 and 2 genes was increased 4-fold in the kidneys. In addition, the expression of the alox12 gene increased significantly (by 67-fold in the heart and by 21-fold in the kidney), while alox15 gene expression was upregulated in the heart by 8-fold and 5-fold in the kidney. The genes responsible for synthesizing 20- Hydroxyeicosatetraenoic acid (cyp4a12 and cyp1a1) were significantly upregulated (P < 0.05) in the hearts of high-dose rofecoxib-treated mice by 7- and 17 -fold, respectively. In addition, the expression of epoxyeicosatrienoic acid-synthesizing genes, cyp2c29 and cyp2j5, was increased significantly (P < 0.05) in the hearts of high-dose rofecoxib-treated mice by 4- and 16-fold, respectively. Conclusion: Rofecoxib caused upregulation of the mRNA expression of the beta 1 gene in association with increased expression of ARA-metabolizing genes in mouse hearts and kidneys. These findings may help us understand the molecular cardiotoxic mechanism of rofecoxib.

Background and Objective: This investigation explores the neuroprotective effect of PIASA, a newly designed peptide, VCSVY, in in-silico and in opposition to rotenone stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in an SH-SY5Y cellular model. Methods: Docking and visualization of the PIASA and rotenone were progressed against mitochondrial respiratory complex I (MCI). The in-silico analysis showed PIASA to have interaction with the binding sites of rotenone, which may reduce the rotenone interaction and its toxicity too. The SH-SY5Y cells were segregated into four experimental groups: Group I: untreated control cells; Group II: rotenone-only (100 nM) treated cells; Group III: PIASA (5 μM) + rotenone (100 nM) treated cells; and Group IV: PIASA-only (5 μM) treated cells. Results: We evaluated the cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), apoptosis (dual staining technique), nuclear morphological changes (Hoechst staining technique), the expressions of BAX, Bcl-2, cyt c, pro-caspase 3, and caspase 3, -6, -8, -9, and cleaved caspase 3 by western blot analysis. In SH-SY5Y cells, we further observed the cytotoxicity, oxidative stress and mitochondrial dysfunction in rotenone-only treated cells, whereas pretreatment of PIASA attenuated the rotenone-mediated toxicity. Moreover, rotenone toxicity is caused by complex I inhibition, which leads to mitochondrial dysfunction, increased BAX expression, while downregulating the Bcl-2 expression and cyt c release, and then finally, caspases activation. PIASA pretreatment prevented the cytotoxic effects via the normalization of apoptotic marker expressions influenced by rotenone. In addition, pre-clinical studies are acceptable in rodents to make use of PIASA as a revitalizing remedial agent, especially for PD in the future. Conclusion: Collectively, our results propose that PIASA mitigated rotenone-stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in rotenone-induced SH-SY5Y cells.

Background: The activity of the amiloride-sensitive epithelial sodium channel (ENaC) in the tight epithelia of the lung is regulated by proteolytic activation and ubiquitination. Pathophysiology of lung diseases is directly related to changes in one or both of these mechanisms. Methods: In this study, we investigated the impact of ubiquitination and cathepsin-mediated proteolytic activation mechanisms on the functional regulation of ENaC in lung cancer A549 cells using the patch-clamp technique. Results: Our findings suggest that inhibiting the proteasome (polyubiquitination) with MG132 improves ENaC activity, whereas altering the pH of the lysosome (monoubiquitination inhibition) with NH4Cl has no effect on ENaC activity. In A549 cells, inhibition of cathepsin B (CSTB) decreased the ENaC current, open probabilities (NPo and Po), and the number of active channels. Conclusion: These findings delineate novel modes of ENaC degradation and proteolytic activation of functional channels in A549 cells. Our findings indicate that both proteolytic activation and ubiquitination of ENaC significantly affect channel function and add new insights into the endogenous ENaC processing which might help to further understand the pathophysiology of the lung disease.

Background: Acute liver injury (ALI) is a critical and fatal disorder associated with excessive oxidative stress and inflammation, ultimately leading to the death of hepatocytes. Myricetin is a bioflavonoid in some berries, including blueberries and strawberries, with anti-inflammatory, antioxidant and anti-apoptotic properties. Objective: In the current research, the hepatoprotective potential of myricetin was studied in the LPS/D-GalN model of ALI in C57BL/6 mice. Methods: For inducing liver injury, D-GalN (400 mg/kg) and LPS (50 g/kg) were injected via intraperitoneal route and myricetin was orally administered (25 or 100 mg/kg/day) for two days before inducing injury. Functional indices of liver dysfunction along with hepatic apoptotic, autophagic, oxidative stress and inflammatory factors were measured. Results: Myricetin (100 mg/kg) reduced the fatality rate of animals and pathological liver changes and suitably lowered serum levels of total bilirubin, 8-OH-dG, ALT, AST and ALP in addition to decreasing apoptotic, oxidative and inflammatory factors, NOX, NLRP3, caspase 3, MPO and enhancing some antioxidants. Besides, myricetin improved the hepatic level and activity of sirtuin 1 and reversed inappropriate alterations of autophagic parameters, including LC3 II, Beclin 1, and P62. The beneficial effects of myricetin were attenuated after co-treatment with the autophagy inhibitor 3- methyladenine. Conclusion: This study indicates the hepatoprotective potential of myricetin that can be ascribed to its down-regulation of oxidative, apoptotic, and inflammatory factors and upregulation of antioxidants besides its partial regulation of sirtuin 1 and autophagic pathway.