Molecular Medicine Communications is a biannual, peer-reviewed, open-access journal that publishes studies investigating the cellular and molecular aspects of medicine, especially related to pharmacology, pathology, genetics, neurosciences, infectious diseases, and molecular medicine in general. Animal studies investigating molecular mechanisms of disease diagnosis, pathogenesis, and treatment, as well as investigational new compounds using in vitro, in vivo, and in silico tools for mechanistic insights, are also welcomed.
The JAK/STAT Signaling Pathway in Lung Cancer: Mechanisms, Clinical Implications, and Therapeutic Opportunities
Lung cancer remains the leading cause of cancer-related mortality worldwide, with persistently poor survival outcomes despite advances in targeted therapies and immunotherapy. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway have emerged as a central regulator of lung cancer pathogenesis, integrating extracellular cytokine and growth factor signals into transcriptional programs that drive tumor progression. This review provides a comprehensive overview of the molecular mechanisms underlying JAK/STAT activation and dysregulation in lung cancer, with particular emphasis on the dominant oncogenic role of STAT3. Aberrant pathway activation arises through multiple converging mechanisms, including cytokine-driven stimulation from the tumor microenvironment, oncogenic receptor signaling, and epigenetic silencing of negative regulators. Functionally, JAK/STAT signaling promotes tumor cell proliferation, survival, epithelial–mesenchymal transition (EMT), metastasis, and immune evasion, notably through upregulation of programmed death-ligand 1 (PD-L1) and modulation of the tumor immune microenvironment. Therapeutically, targeting the JAK/STAT axis has shown promise in preclinical models, particularly in overcoming resistance to tyrosine kinase inhibitors and enhancing immunotherapy responses. Early-phase clinical studies highlight the potential of combination strategies, including JAK inhibitors with immune checkpoint blockade, demonstrating encouraging response rates and durable clinical benefit in selected patient populations. However, clinical translation remains challenged by pathway complexity, limited efficacy of monotherapies, and safety concerns. Future directions should focus on the development of isoform-selective inhibitors, identification of predictive biomarkers, and rational combination regimens to optimize therapeutic outcomes. Overall, the JAK/STAT pathway represents a critical and actionable target in lung cancer, with significant potential to advance precision oncology.
Copyright (c) 2025 Muhammad Bilal Anwar https://creativecommons.org/licenses/by/4.0
Molecular Mechanisms of FDA-Approved Drugs for the Treatment of Alzheimer's Disease: A Comprehensive Review
Alzheimer’s disease (AD) is characterized by progressive degeneration of neurons. It is a complex and multifactorial disorder. Symptomatic modulation of neurotransmitter pathways and disease-modifying treatments are the current therapeutic approaches in molecular medicine. The efficacy of Food and Drug Administration (FDA)-approved medications for AD has improved over time. Among the classes of drugs, cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate receptor (NMDAR) antagonists are used for symptom management. The combination of these treatments improves understanding about neurotransmitter abnormalities in AD. Although their processes differ, they complement each other in terms of effectiveness. The mechanistic evidence remains underexplored for these interactions. With time, treatment advancement introduced anti-amyloid monoclonal antibodies. This shifted the therapeutic focus toward targeted intervention. These drugs selectively target pathogenic amyloid plaques and clear them from brain tissues, which further clears amyloid in the bloodstream. The immune-mediated process provided by this class of drugs differs in both efficacy and downstream biological pathways. These steps in the mechanism are critical; emerging observations need to inquire regarding their treatment specificity, biological variability, and safety mechanisms in neural and cellular safety signaling pathways. In this review, therapeutic classes with distinct mechanisms are explored at the molecular level, where immune activation, aggregated protein clearance, and symptomatic modulation intersect. The review discusses a combination of these molecular-level understandings of AD pathology and how treatments interact with biological systems across conventional and innovative therapeutic options.
Copyright (c) 2025 Aimen Shahid, Uzair Ahmad https://creativecommons.org/licenses/by/4.0
Plant-Derived Psychoactive Drugs: Mechanisms, Addiction, and Health Consequences
Plant-derived substances such as cocaine and nicotine are widely abused drugs with diverse pharmacological effects, including psychedelic, stimulant, hypnotic, euphoric, and anticholinergic actions. Each plant source confers distinct characteristics that generate both beneficial and harmful outcomes, primarily affecting the brain but also influencing multiple organ systems. Chronic use often results in addiction due to alterations in neural pathways, with detrimental effects on vital organs such as the heart, lungs, kidneys, and muscles. The impact of these substances depends on the drug type, target organ, and mode of administration. Genetic predisposition and stress substantially influence vulnerability to addiction. Withdrawal symptoms emerge upon cessation as a result of physiological dependence. Addiction not only induces behavioral and neurobiological changes but also appears to accelerate biological aging, reflected in telomere attrition aggravated by oxidative stress. This article provides a comprehensive overview of drug addiction and its consequences for individuals and society. It examines psychoactive substances including cannabis, cocaine, morphine, and nicotine, highlighting their mechanisms of action, physiological effects, and implications for aging. These substances act on specific brain receptors, initially eliciting desired effects but ultimately promoting addiction through receptor desensitization and altered neural function. Addiction arises from the complex interplay of genetics, environment, and substance exposure. Addressing this challenge requires integrated strategies encompassing prevention, effective therapies, and strong support systems.
Copyright (c) 2025 Asad Abbas, Hussain Ahmed, Syed Mohammad Usman, Haadia Surtaj, Aisha Naeem, Muhammad Jawad Khan https://creativecommons.org/licenses/by/4.0
Antiplatelet, Analgesic, and Anti-inflammatory Effects of Piperine are Mediated Through Several Different Mechanisms
Piperine is a phytocompound found in black and long pepper (Piper nigrum and Piper longum, respectively). It has several important pharmacological properties. The current study aimed to evaluate piperine for analgesic, anti-inflammatory, and anti-platelet activities. The analgesic and anti-inflammatory effects were assessed in mice and rats respectively using acetic acid and formalin-induced nociception, and carrageenan-induced rat paw edema tests. The intraperitoneal (i.p.) administration of the Piperine (10, 50, and 100 µg/kg) produced significant inhibition (P\0.01) of the acetic acid-induced writhing in mice and suppressed formalin-induced licking response of animals. Piperine (10, 50, and 100 µg/kg) produced a marked anti-inflammatory effect in carrageenan-induced rat paw edema assay comparable to diclofenac and produced a dose-dependent (1,5, and 10µM) inhibitory effect against arachidonic acid and adenosine diphosphate-induced platelet aggregation. However, piperine was less potent against the platelet aggregation induced by the platelet-activating factor and epinephrine. These data suggest that piperine possesses peripheral analgesic and anti-inflammatory properties, with potent antiplatelet effects against arachidonic acid and adenosine diphosphate.
Copyright (c) 2025 Fawad Ali, Syed Majid Shah, Manzoor Ahmad https://creativecommons.org/licenses/by/4.0
Gut Microbiota Composition and Its Association with Hydroxyurea Response in Beta Thalassemia Major Patients
Hydroxyurea (HU), a fetal hemoglobin (HbF) inducer, effectively alleviates symptoms in beta-thalassemia patients; however, its efficacy varies among individuals, potentially due to differences in HU metabolism and gut microbiota composition. Previous research has suggested that both factors can significantly impact drug metabolism and disease progression, including in thalassemia. This study aimed to establish a link between the gut microbiota and HU response in beta-thalassemia major patients. Stool samples were collected from a total of 45 beta-thalassemia patients aged 5-20 years and classified into three groups with 15 patients in each group: responders, non-responders, and those not using HU-based therapy on the basis of transfusion requirement. Notably, HU users tested negative for the Xmn-1 mutation. Sequencing was performed on the V3-V4 hyper-variable region of the 16SrRNA gene. The analysis uncovered noteworthy distinctions in the gut microbiota among the three groups at both the genus and species levels. The response to HU was associated with butyrate-producing bacteria from the phylum Firmicutes. Responders exhibited an enrichment of butyrate-producing bacteria such as Faecalibacterium, Butyrivibrio, Oscillobacter, Gemmiger, and Eubacterium. Non-responders, on the other hand, had higher levels of Prevotella, Mitsuokella, and Treponema. Non-users were characterized by an abundance of Succinivibrio, followed by Bacteroides and Megasphaera. These findings suggest that altered gut microbiota may contribute to inter-individual variation in HU response, highlighting specific microbes that could potentially serve as biomarkers for thalassemia or predict HU efficacy.
Copyright (c) 2024 Ayesha Khan, Saeed Khan, Saqib Hussain Ansari, Ayaz Ahmed, Asif Iqbal Khan, Muniza Omair https://creativecommons.org/licenses/by/4.0
Variations in Genes and Their Influence on Atorvastatin's Effectiveness: Tailoring Hyperlipidemia Therapy
Hyperlipidemia, characterized by elevated levels of lipoproteins in the blood, is a significant public health concern due to its association with cardiovascular diseases like coronary artery disease (CAD) and stroke. Lipid-lowering agents mitigate the risks associated with hyperlipidemia, with statins, specifically 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, being the frontline treatment. Atorvastatin is one of the most widely prescribed drugs of this class. However, the safety and efficacy of Atorvastatin vary among individuals. Despite the widespread use of statins, adherence to the regimen remains a challenge, with up to 50% of patients discontinuing treatment within the first year. Statin intolerance, often due to musculoskeletal symptoms, is a significant reason for nonadherence. Genetic factors play a substantial role in statin disposition and adverse events, adding to the complexity of treatment response. This review article will explore the pharmacogenetics of statins with particular emphasis on Atorvastatin, i.e., genetic polymorphisms in APOE, HMGCR, cytochrome P450 enzymes (CYP3A4, CYP3A5, and CYP2D6), CETP, LDLR, PCSK9, ABCB1, ABCG5/8, SLCO1B1, and KIF6, and the influence on its hypolipidemic outcomes. Understanding the impact of genetic polymorphisms can aid in predicting individual responses to statin therapy, optimizing treatment outcomes, and preventing adverse effects. By tailoring hyperlipidemia treatment based on genetic profiles, personalized medicine can be achieved, bringing us closer to optimal management and control of hyperlipidemia-related health risks
Copyright (c) 2024 Fawad Ali https://creativecommons.org/licenses/by/4.0
Clinical Pharmacokinetics of Brivaracetam: A Systematic Review
Brivaracetam (BRV) is an antiepileptic drug (AED) used to treat focal seizures. It can be administered through oral and intravenous (IV) routes. In this review, the main objective is to present a thorough analysis of reported pharmacokinetics (PK) information on BRV in humans. Five electronic databases were used to execute a systematic literature search i.e. Google Scholar, EBSCO, Science Direct, Cochrane, and PubMed. All articles containing information on the PK of BRV in humans were searched. This review process is officially filed in the PROSPERO database under the registration number CRD42023451328. Thirteen papers were finally included in this systematic review after applying eligibility criteria to 1508 publications from all included databases. A dose-dependent increase in Cmax and AUC0-∞ was seen after oral application of BRV. A slight increase in the AUC0-∞ of BRV was observed in severe renal impaired patients as compared to healthy control. The co-administration of BRV with carbamazepine and rifampicin resulted in a significant rise in oral clearance (CL/F) from 0.92 ml/min to 1.30 ml/min and 0.80 ml/min to 1.45 ml/min respectively, emphasizing the importance of medication interactions in clinical settings. The bioavailability and serum half-life (t1/2) of BRV were reduced when administered with drugs. This comprehensive overview not only improves our understanding of the drug's PK behavior but also provides valuable insights for researchers and clinicians to optimize BRV therapy. The presented results may help clinicians understand the PK parameters (AUC0-∞, Cmax, and t1/2) of BRV in foreseeing its adverse drug reactions and drug-drug interactions.
Copyright (c) 2024 Muhammad Fawad Rasool, Attia Qayyum, Ammara Zamir, Imran Imran https://creativecommons.org/licenses/by/4.0
Association of Human Leukocyte Antigen (HLA) Class II Alleles of DQB1 (DQB1*03:02) (DQB1*06:02) and DRB1 (DRB1*04:01) with Type-1 Diabetes Patients of Khyber Pakhtunkhwa, Pakistan
Type-1 diabetes (T1D), an autoimmune disease, significantly impacts global health, with varying prevalence across different geographies. This study investigates the association of specific Human Leukocyte Antigen (HLA) Class II alleles, namely DQB1*03:02, DQB1*06:02, and DRB1*04:01, with T1D in the Khyber Pakhtunkhwa (KP) population of Pakistan. Conducted as a 1:1 matched case-control study, this research involved 33 T1D patients and an equal number of age- and gender-matched healthy controls. Our findings reveal a weak association of alleles DRB1*04:01 and DQB1*03:02 with T1D (OR = 2.065 and 1.393, respectively, p > 0.05). DQB1*06:02 allele, which is considered to have a protective effect against T1D was more prevalent in control as compared to cases (93.9% vs 90.9%), however, the association was non-significant (OR 0.645, p > 0.05). These insights contribute to understanding genetic influences on T1D in the KP region and underscore the need for further research with larger, diverse cohorts to refine the genetic markers of T1D risk and protection
Copyright (c) 2024 Qudsia Hina, Zakiullah, Haji Bahadar, Haseenullah Shah, Mohammad Sajjad Afridi, Sobia Kulsoom Awan, Maqsood Ali, Kiran Ijaz, Hira Siyar, Aiman Begaum https://creativecommons.org/licenses/by/4.0
Pyrotinib: A promising Tyrosine Kinase Inhibitor for treating Breast Cancer
Globally breast cancer is the second leading cause of mortality in women. The past two decades have seen tremendous progress in understanding and treating the disease, leading to more efficient and less toxic regimens. Anti-HER2 cancer drugs, particularly for metastatic breast cancer (MBC), are key for effective treatment. Lapatinib and neratinib are Food and Drug Administration (FDA) approved, while pyrotinib, a novel and potentially safer HER2-targeted drug, shows promise in treating HER2-positive MBC. Phase I and II trials demonstrated pyrotinib's safety and efficacy, particularly when combined with capecitabine. Compared to lapatinib, pyrotinib achieved significantly higher overall response rates and prolonged progression-free survival (PFS) in patients with HER2-positive MBC previously treated with standard therapies. Notably, pyrotinib also exhibited anti-tumor activity against brain metastases, a common challenge in HER2-positive MBC. In addition to performing well, pyrotinib is more tolerable, with manageable side effects, than the standard treatment, like trastuzumab. While conditionally approved in China, further research is needed to fully establish pyrotinib's safety and efficacy profile. Ongoing phase IV trials in China and a phase I trial in the USA are crucial steps. Overall, pyrotinib offers a promising new option for HER2-positive breast cancer treatment, potentially with a better safety and efficacy profile than existing drugs.
Copyright (c) 2024 Nida Saleem, Qudsia Rehman, Abdul Qayyum Khan, Hamza Hussain Bangash https://creativecommons.org/licenses/by/4.0
Potential Inhibition of Human Neutrophil Elastase Enzyme to Attenuate Emphysema; A Molecular Docking Study
Chronic Obstructive Pulmonary Disease (COPD), also referred to as chronic bronchitis and emphysema, is a major threat to global health. It is an essential part of the Rehabilitation 2030 initiative of the World Health Organization (WHO). It is more common in nations with enhanced smoking habits. The latter is associated with the damage of the elastin protein of the lung parenchyma as a result of the enhanced protease activity of human neutrophil elastase (HNE). This leads to impaired gaseous exchange and air entrapment in the lungs. Among symptomatic pharmacotherapy, anti-proteases such as alpha-1 antitrypsin could be used to counter the effect of proteases, but the treatment costs too much and is not easily available. This study aims to explore and discover potential drug compounds for lessening the progression of protease-induced lung parenchymal damage in emphysema. Molecular docking and ADMET analysis investigated the anti-HNE activity of several compounds and newly designed analogs of Sivelestat, a drug molecule that has been approved as Sivelestat Sodium Hydrate in Japan as well as in the Republic of Korea for the management of acute lung injury. The software used in this study were PyRx, BIOVIA Discovery Studio Visualizer v17.2.0.16349, and DataWarrior V5.5.0. All the potential drug molecules demonstrated binding with the active residues of HNE, i.e., Ser 195, His 57, and Ser 214, and showed potentially promising results in terms of their binding energies and poses. Subsequent in vitro and in vivo studies are recommended to support the findings of this study
Copyright (c) 2024 Ahsan Ibrahim, Muhammad Arslan, Muhammad Hamza https://creativecommons.org/licenses/by/4.0
A Comprehensive Review of Antimicrobial Resistance against Colistin and Countermeasures
In times of increasing antimicrobial resistance (AMR), colistin is used as a last resort against numerous gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Unfortunately, recent studies have shown that some species of gram-negative bacteria are becoming resistant to colistin. This has led to an increase in antimicrobial burden and limited treatment options against bacterial infections. This review highlights emerging studies aimed at optimizing the use of colistin. The frequent use of colistin for the treatment of infections has led to colistin resistance. Resistance patterns include intrinsic and acquired resistance mechanisms. The intrinsic resistance mechanism encompasses genetic modification of Lipopolysaccharide (LPS), whereas the acquired resistance mechanism involves modifications of PmrAB and PhoPQ, which alter the LPS membrane. Mutations in the CrrB, ramA, romA, ramR, and KpnEF genes, transfer of the MCR gene via plasmids, activation of efflux pumps, and capsule formation all accentuate colistin resistance. Various methods have been developed to detect resistance. Different combinatorial therapies and supramolecular traps have also been reported to be efficacious. Moreover, newer strategies and methods are required to prevent this global dilemma. This review comprehensively explains colistin resistance, its mechanisms, detection techniques, and future implications.
Copyright (c) 2024 Muhammad Usama Shahzad, Laraib Badar, Usman Shareef https://creativecommons.org/licenses/by/4.0
Elucidating the Potential Compounds Targeting OPNL1W Through Virtual Screening for the Treatment of Color Blindness
Partial blindness occurs and a patient is unable to differentiate colors in a typical manner. It is otherwise called variety lack generally acquired, however, can likewise be brought about by eye sicknesses, drugs, and aging. Color visual impairment frequently happens when somebody cannot recognize specific colors and at least one of the variety cone cells is missing, not working, or there is an unexpected variety in comparison to the typical and normal. Partial blindness is more normal in males and influences around 8% of males and 0.5% of females around the world. In current efforts, the molecular docking approach was applied to screen the novel compounds from the ZINC compound database that may show effectiveness against color blindness. Various computational strategies including homology modeling, threading, and ab initio methods were applied for the 3D structure prediction of the target protein OPN1LW. The 3D structures of OPN1LW were additionally evaluated and their efficacy was calculated. It was observed that the overall quality of the predicted structure was 95.88%. Ramachandran plot showed reliable results as the conserved residues were falling in the most favored region. After structure evaluation the energy of the top-picked structures was minimized and molecular docking analyses were performed against the FDA database from the ZINC compounds database. The suitable docked compounds were analyzed and ADMET analyses were performed. After analyzing the molecular docking and ADMET results concluded that the screened compound (ZINC000000005560) with interacting residues Thr-118, Glu-122, Ile-189, Tyr-191, Met-207, Phe-212, Trp-265, Tyr-268, Ala-269, Ala-272, can be used against color blindness and may prove reliable results.
Copyright (c) 2024 Hassan Bin Waseem, Kashif Shahid, Azhar Iqbal, Ayesha Zafar, Sidrah Hafeez, Ayesha Afzal, Muhammad Jahangir Shafi, Ayman Rashid, Keziah Shaheen, Rabbia Allah Rakha, Noel Shamaun, Muhammad Mumtaz Tahir https://creativecommons.org/licenses/by/4.0
Pembrolizumab Plus Trastuzumab and Chemotherapy for HER2-Positive Gastric or Gastro-oesophageal Junction Adenocarcinoma
he combination of pembrolizumab, and trastuzumab chemotherapy has long been investigated in the treatment of HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. HER2-positive gastric or gastroesophageal junction adenocarcinoma refers to cancers that overexpress the human epidermal growth factor receptor 2 (HER2), which is associated with more aggressive tumor behavior. Pembrolizumab is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor, a checkpoint protein on immune cells. By blocking PD-1, pembrolizumab helps unleash the immune system to target and attack cancer cells. Trastuzumab is another monoclonal antibody that specifically targets HER2-positive cancer cells. It has been a standard treatment for HER2-positive breast cancer and has been explored in HER2-positive gastric and gastroesophageal junction cancers. Janjigian and colleagues revealed the interim analysis of a randomized, phase 3 KEYNOTE-811 trial which involved 168 medical centers in 20 countries worldwide. They found that compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumors with a PD-L1 combined positive score of 1 or more. They stated that the overall survival follow-up is ongoing and will be reported at the final analysis. Lancet. 2023 Dec 9;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0.
Copyright (c) 2023 Editorial Staff https://creativecommons.org/licenses/by/4.0
Lactate dehydrogenase (LDH) is an enzyme that plays a key role in cellular metabolism by converting pyruvate to lactate during anaerobic glycolysis. LDH has been implicated in various cancer types, including breast cancer, where increased LDH activity is associated with tumor growth, invasion, and resistance to therapy. LDH inhibitors are being investigated as potential therapeutic agents in cancer treatment, including breast cancer. Khajah and colleagues investigated the role of LDH inhibitors in both estrogen receptor (ER)+ and ER‑ breast cancer cell lines and in normal breast epithelial cells. A significant reduction in extracellular lactate level, cell proliferation, motility, and invasion was observed after treatment with LDH inhibitors. Subsequently, changes in the levels of vimentin, E‑cadherin, p38 MAPK, ERK1/2, and AKT were also observed. Cancer cell proliferation was preferentially blocked compared with normal epithelial cell inhibition by LDH inhibitors such as quercetin and lonidamine. These results further highlight the role of lactate in breast cancer progression and indicate the practical use of various commercially available LDH inhibitors as promising therapeutic agents to oppose the processes leading to cancer progression. While LDH inhibitors show promise, challenges include achieving selectivity for cancer cells and minimizing toxicity to normal tissues. The development of specific LDH inhibitors with favorable pharmacokinetic properties is an ongoing area of research. Mol Med Rep. 2024 Jan;29(1):12. doi: 10.3892/mmr.2023.1313.
Role of ZAKα-Mediated Metabolic Decline in Obesity and Aging
It has been known that there exists a connection between oxidative stress, ribosomal dysfunction, and the metabolic decline observed in conditions such as obesity and aging. The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and ZAKα sense stalling and/or collision of ribosomes. ZAKα, also known as MAP3K20, is a mitogen-activated protein kinase kinase kinase (MAP3K) that plays a role in cellular signaling pathways. Snieckute and colleagues show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. They also found that ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis, stressing the role of the RSR in metabolic regulation. Their study revealed the hallmarks of metabolic aging in animals after ZAK ablation. Understanding these molecular pathways could provide insights into the cellular mechanisms contributing to metabolic dysfunction in these conditions and may potentially lead to the development of targeted interventions or therapies. Science 2023 Dec 8;382(6675):eadf3208. doi: 10.1126/science.adf3208.
Financial Incentives for COVID-19 Vaccines Help
Cash incentives for COVID-19 vaccination involve offering individuals a financial reward as an encouragement to get vaccinated against the coronavirus. This strategy has been implemented by various governments, organizations, and businesses as part of their efforts to increase vaccination rates. Duch and colleagues randomly assigned about 700 residents of several villages in Ghana to four groups in a cluster-controlled trial. The results show that participants assigned to the cash incentive treatments had an average rate of 81% (1,733 of 2,168) compared to 71% (1,895 of 2,669) for those in the placebo treatment arm. For self-reported vaccinations, the average rate for participants in the cash treatment was 3.5% higher than for participants in the placebo treatment (95% confidence interval (CI): 0.001, 6.9; P = 0.045): 40% (602 of 1,486) versus 36.3% (672 of 1,850). These results suggest that cash incentives help in vaccination uptake but paradoxically, low cash incentives resulted in higher vaccine uptake compared to high cash incentives. We found that cash incentives motivate individuals who may be hesitant or reluctant to receive the COVID-19 vaccine. Financial rewards can serve as an additional motivator for those who may be on the fence about getting vaccinated. Trial identifier: AEARCTR-0008775. Nat Med. 2023 Nov 27. doi: 10.1038/s41591-023-02670-4.
Primaquine Reduces P vivax Parasitemia Risk
In areas where both P falciparum and P vivax are co-endemic, and a patient is diagnosed with P falciparum malaria, the standard practice is to treat the acute infection with an appropriate antimalarial, often an Artemisinin-based combination therapy (ACT). Primaquine is not typically used for treating the acute P falciparum infection. However, adding primaquine to ACT could help reduce their risk of subsequent P vivax parasitemia. Thriemer and colleagues performed a multicenter clinical trial across Bangladesh, Indonesia, and Ethiopia. The primary endpoint was the incidence risk of P vivax parasitemia on day 63. This trial was registered at ClinicalTrials.gov, NCT03916003. The trial recruited 500 patients and the results suggest that there were very few serious adverse effects while 143 mild adverse effects were also reported. The incidence risk of P vivax parasitemia at day 63 was 11·0% (95% CI 7·5–15·9) in the standard care arm (low dose primaquine) compared with 2·5% (1·0–5·9) in the intervention (high dose primaquine) arm (hazard ratio 0·20, 95% CI 0·08–0·51; p=0·0009). These results suggest that high-dose short-course primaquine can reduce P vivax parasitemia risk within 63 days by fivefold. Lancet. 2023 Dec 2;402(10417):2101-2110. doi: 10.1016/S0140-6736(23)01553-2.
Editor's Summaries of the Articles Published in This Issue of Molecular Medicine Communications
In this issue, Amanat and colleagues reviewed the pharmacogenomics of 5-fluorouracil (5-FU) in oesophageal carcinoma chemotherapy, Khan and colleagues investigated predominant genotypes and viral load of HIV and HCV in Karachi, Pakistan, Waseem, and colleagues used a hybrid approach of molecular docking studies and virtual screening to test compounds from ‘Zinc database library’ that may be effective against Alzheimer’s disease, Zubair and colleagues investigated the relationship between single nucleotide polymorphism (SNP) (rs1544410 G>A) of the vitamin D receptor (VDR) gene with postmenopausal women who have osteoporosis in a Pakistani cohort, and Naudhani, and colleagues reported two Pakistani families with symptoms of diabetes, hyperphagia, seizures, and obesity, and containing interesting genetic polymorphisms.
Challenges with Newly Approved CRISPR Gene Technologies
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology is a powerful gene-editing tool that allows for precise modification of DNA. While CRISPR has shown immense potential in laboratory and preclinical studies, the development of CRISPR-based therapies for human use is still in the early stages. However, on December 08, the Food and Drug Administration (FDA) of the United States of America approved two milestone treatments, Casgevy and Lyfgenia, representing the first cell-based gene therapies for the treatment of sickle cell disease (SCD) in patients 12 years and older. Several CRISPR-Cas9 therapies that work on the same principle are in clinical trials as treatments for a range of diseases. However, there are still significant concerns with the use of this new technology. One major concern with CRISPR technology is the potential for off-target effects, where unintended changes may occur in locations other than the target gene. The introduction of CRISPR components into the body may also trigger an immune response. Several laboratories are investigating ways to mitigate immune reactions and improve the delivery of CRISPR components. The method of delivering CRISPR components into cells is also important for safety. Further research into different delivery methods, such as viral vectors or nanoparticles, would help optimize efficiency while minimizing potential side effects. The long-term effects of CRISPR-based interventions are an area of ongoing research. Understanding the stability of CRISPR-induced changes over time and potential consequences is crucial for assessing safety. Ethical considerations are important to discussions about CRISPR use, particularly when it comes to editing the human germline (sperm, eggs, embryos), as changes made in these cells would be heritable. The potential for unintended consequences and ethical implications necessitates careful consideration. It is important to consider that although CRISPR holds great promise, the technology is relatively young, and research is ongoing to address safety concerns. The scientific community and regulatory bodies are actively working to ensure that CRISPR technologies are developed and implemented responsibly. Continuous advancements, ongoing research, and open communication will be essential to addressing safety challenges associated with CRISPR.
Copyright (c) 2023 Sagheer Ahmed https://creativecommons.org/licenses/by/4.0
Genotype Variation of HIV/HCV Co-infections in Karachi, Pakistan
Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) are among major health issues that affect a large section of the world's population. While HCV affects around 170 million people worldwide, HIV affects 3% of the global population, with 10 million HCV cases documented in Pakistan alone. Co-infection with HIV and HCV results in a variety of genotypic patterns, with significant global heterogeneity in the incidence of spontaneous resolution of hepatitis C and the distribution of HCV genotypes among co-infected individuals. Co-infection is usually transmitted by sexual contact, contaminated blood supplies, and mother-to-child transmission, with high-risk populations like intravenous drug users (IDUs), and men who have sex with men (MSM) having increased vulnerability. This study, conducted in Karachi, Pakistan, aimed to explore the predominant genotypes and viral load of HIV and HCV. The genetic features of the HIV Gag and HCV NS5b genes were examined using genotyping techniques and phylogenetic methodology. The study revealed that out of the 150 individuals examined, 70 were diagnosed with HIV alone, 55 with HCV only, and 25 had both HIV and HCV infections concurrently. Furthermore, genetic analysis demonstrated that HIV-1 subtype A1 was the predominant genotype, with subtype C closely following. In the case of HCV, genotype 3a was the most prevalent in both mono- and co-infected individuals. Notably, individuals with dual infections exhibited limited genotypic variability for each virus. In the case of HIV co-infection, there was an elevation in viral load, while HCV demonstrated lower viremia relative to mono-infection. In conclusion, the study revealed the predominance of HIV-1 subtype A1 and HCV genotype 3a, as well as an elevated level of HIV and a lowered level of HCV in co-infection.
Copyright (c) 2023 Asif Iqbal Khan, Saeed Khan, Muhammad Asif Qureshi, Bilal Ahmed Khan, Maria Zahid, Ikram Din Ujjan, Amanullah Lail, Mohammad Rafiq Khanani, Iqra Iqbal Akbar, Abdul Sami Khatri https://creativecommons.org/licenses/by/4.0
Pharmacogenomics of 5-Fluorouracil in Oesophageal Carcinoma: Association of Single Nucleotide Polymorphisms with Efficacy & Adverse Effects
Esophageal carcinoma (EC) is a highly fatal cancer. The usual therapy for localized squamous cell carcinoma has traditionally been surgically removing the tumor from its main location. However, recent clinical advancements have led to the development of new therapeutic options. The available choices encompass chemotherapy which involves continuous administration of 5-fluorouracil (5-FU), cisplatin, and simultaneous radiation treatment. To enhance clinical outcomes, future advancements would have to improve the integration of new anticancer medications, the administration of cisplatin, or 5-FU, guided by pharmacokinetics, and the identification of potential responders through genetic profiling of patients before treatment initiation. This review provides a comprehensive summary of the information about the genetic variation in ABCB1, ERCC!, TYMS, XPD, and DYPD genes that most likely contribute to the pharmacokinetic or genotype-guided administration of 5-FUfor the treatment of oesophageal cancer. The review aims to facilitate personalized treatment strategies for this condition in the future.
Copyright (c) 2023 Amanat Ali, Syed Irfan Raza, Zarafshan Bader, Syed Furqan Ali Shah https://creativecommons.org/licenses/by/4.0
Association of Vitamin D Gene Receptor Polymorphism with Osteoporosis in Postmenopausal Women
Osteoporosis is a critical and complicated systemic musculoskeletal disorder that encompasses low bone density (LBD) and weakening of osseous tissue at a microarchitectural level. This predisposes to increased bone fragility and subsequent risk of fractures. It is frequently encountered in postmenopausal women and has also been seen in elderly men. Vitamin D synchronizes bone and calcium homeostasis in the body by modifying the transcription of target genes through the Vitamin D receptor (VDR) and thus aids calcium uptake and bone-forming proteins. The main objective of the present research was to study the relationship of single nucleotide polymorphisms (SNP) (rs1544410 G>A) of the VDR gene with postmenopausal women who have osteoporosis in a Pakistani cohort. A total of 100 postmenopausal women, 50 without osteoporosis to be in the control group, and 50 with osteoporosis as cases, were enrolled in this study. The patients had no immediate family connections with each other. All the patients underwent BMD measurements at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry scan for their diagnosis of osteoporosis based on World Health Organization (WHO) criteria (T score < -2.5 SD). A total of 25 participants had at least one allele of rs1544410, of which 14 were cases and 11 controls. The number of heterozygous and homozygous were present with similar ratios in both groups (p=0.973). Age was noted to be correlated with osteoporosis (OR: 1.06; 95%CI: 1.004-1.12), (P<0.031). It was also observed that cases had a notably lower weight than the control group (P<0.0001) and the overall body mass index of cases was significantly low in comparison to control (P<0.0001). Moreover, average BMD of femoral and BMD lumbar were notably greater among the control group (P<0.0001) as compared to cases. The SNP (rs1544410) is not significantly associated with BMD but significantly correlated with age which was identified as a risk factor while body mass index was found to be a protective factor for osteoporosis
Copyright (c) 2023 Muhammad Zubair, Saeed Khan, Akhtar Ali, Farina Hanif, Uzair Abbas, Bilal Ahmed, Safia Mehmood, Fatima Khan https://creativecommons.org/licenses/by/4.0
In silico Elucidation of Potent Therapeutic Targets against Alzheimer’s by Targeting CAPNS2
Alzheimer’s disease (AD) is considered one of the common types of dementia in which brain cell gradually deteriorate, leading to memory loss. Approximately 50 million people are afflicted by AD. There is no permanent solution for this malady; however, early detections may help slow down the disease prognosis. In the current study, a hybrid approach of molecular docking studies and virtual screening is taken to test compounds from ‘Zinc database library’ that may be effective against AD by targeting CAPNS2. The top-ranked four compounds were reported by molecular docking analysis on the basis of their binding affinity by targeting CAPNS2. Molecular docking analyses revealed that Lys-5, Ala-4, Leu-3, Tyr-56, Ile-48, Ala-52, Gln-55, Cys-56, Ala-152, Ala-54, and Ala-53 are the interacting residues from the selected target protein. In addition, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were performed to assess the drug-like properties of the selected compounds. After extensive in silico analyses, the present study deduced that the top four scrutinized compounds might be potent against AD by targeting CAPNS2.
Copyright (c) 2023 Hassan Bin Waseem, Mustafa Mubeen, Muhammad Talal Rahim, Muhammad Kazim, Ayman Rashid, Muhammad Shoaib Amir, Ayesha Afzal, Sehrish Naz https://creativecommons.org/licenses/by/4.0
Identification of MC4R and VCP Genetic Variants in Two Pakistani Families Showing Symptoms of Diabetes, Hyperphagia, Seizures, and Obesity
Variations in the melanocortin 4 receptor (MC4R) are most commonly associated with serious early-stage monogenic obesity. The valosin-containing protein (VCP) gene, also referred to as p97, produces the ubiquitous, crucial, and multifunctional protein VCP, involved in a wide range of cellular processes, including endoplasmic reticulum-associated degradation (ERAD), degradation of lysosomal protein, and degradation of the proteasome-mediated protein. In the present study, we investigated two Pakistani families enrolled from Sibi, Pakistan, for variation in MC4R and VCP genes. Clinical symptoms involved obesity, hyperphagia, and diabetes in Family 1. Obesity with autism spectrum disorder (ASD), hyperphagia, diabetes, seizure, gastrointestinal, and sleep disorders were found in Family 2. Additionally, blood samples were collected and DNA extraction was performed. Subsequent molecular analysis was conducted to identify mutations. Clinical and genetic results were analyzed, and the segregation of MC4R and VCP gene variants in the families helped to make the diagnosis of the disease. For the identification of variations, we conducted whole exome sequencing (WES) and confirmed the findings through target sequencing. We divulged two previously reported heterozygous missense variations. Notably, WES revealed variants (c.307G>A, rs2229616) in the MC4R and (c.1360-35A>G, rs2258240) in the VCP genes in both families separately. The chromatogram illustrated homozygous unaffected siblings and parents, as well as heterozygous individuals with the disease. Both families segregate with the obesity disorder in an autosomal dominant manner. In Family 1, the change from ‘G’ to ‘A’ in the MC4R gene depicts the mutant allele ‘A’ segregating dominantly from one generation to another. Similarly, the change from ‘A’ to ‘G’ in the VCP gene illustrates the mutant allele ‘G’ segregating dominantly in Family 2.
Copyright (c) 2023 Sara Naudhani, Fariya Khan Bazai, Mehmood Ul Hassan, Akram Ali, Hani Tayyab, Sara Mannan, Muhammad Tariq, Shakeela Daud https://creativecommons.org/licenses/by/4.0
In this issue Yusuf and colleagues investigated the association of association of fat, mass and obesity (FTO) gene polymorphism with diabetes and prediabetes in Pakistani population, Mannan and colleagues did a variant analysis of FOXE1 gene in non-syndromic cleft lip and palate in Peshawar, Pakistan, Zaib et al determined the frequency of p53 mutations and Epstein-Barr virus in Pakistani gastric cancer patients and investigated their association with the tumor grade, Rehman and her colleagues made an analysis of comparative effectiveness & renoprotective effects of hypoglycemic drugs for type 2 diabetes mellitus, and Ain et al reviewed the sources and mechanisms of chemoresistance in hepatocellular carcinoma.
Study of the Human Microbiota Under Physiological Conditions
Profiling the human intestinal environment under physiological conditions involves characterizing the various components and factors in the gut to understand its normal functioning. This profiling can encompass multiple aspects, including the microbiome, host immune response, metabolites, and the physical environment of the intestine. Shalon and colleagues developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. The collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins, and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched, and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in the stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins, and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease. Nature. 2023 May;617(7961):581-591. doi: 10.1038/s41586-023-05989-7.
Study of Human Microglia Phenotypes via an In Vivo Neuroimmune Organoid Model
Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, Schafer and colleagues developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Developing an in vivo neuroimmune organoid model to study human microglia phenotypes would involve creating a three-dimensional structure that mimics the complexity of the human brain and immune system. Such a model could provide a valuable tool to investigate the behavior and function of microglia, the resident immune cells of the central nervous system, in a more physiologically relevant context. Data from Schafer and colleagues show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, they demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly. Cell. 2023 May 11;186(10):2111-2126.e20. doi: 10.1016/j.cell.2023.04.022.
Small Molecules for Chemically Induced Pluripotency Inception
Harnessing endogenous transcription factors directly by small molecules for chemically induced pluripotency inception refers to using specific small molecules to activate endogenous transcription factors to reprogram adult cells into induced pluripotent stem cells (iPSCs). This approach aims to bypass the use of viral vectors or genetic manipulation to introduce exogenous factors, making it a potentially safer and more efficient method for generating iPSCs. Jin and colleagues show that small molecule CD3254 activates endogenous existing transcription factor RXRα to significantly promote mouse chemical reprogramming. Mechanistically, the CD3254-RXRα axis can directly activate all the 11 RNA exosome component genes (Exosc1-10 and Dis3) at the transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30, which is identified as a new barrier for cell-fate determination. In turn, MMVL30-mediated inflammation (IFN-γ and TNF-α pathways) is reduced, promoting successful reprogramming. Collectively, their study provides conceptual advances for translating environmental cues into pluripotency inception, particularly identifies that the CD3254-RXRα-RNA exosome axis can promote chemical reprogramming and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine. Proc Natl Acad Sci USA. 2023 May 23;120(21):e2215155120. doi: 10.1073/pnas.2215155120.
Cardiomyocyte Maturation During Regeneration
The interplay between calcium signaling and sarcomeres plays a crucial role in directing cardiomyocyte maturation during cardiac regeneration. During cardiac regeneration, various processes occur to restore damaged or lost cardiac tissue, including the proliferation and differentiation of precursor cells into functional cardiomyocytes. These newly formed cardiomyocytes undergo a maturation process to acquire the structural and functional characteristics of adult cardiomyocytes. Nguyen and colleagues found that the cardiac dyad, a structure that regulates calcium handling and excitation-contraction coupling, played a key role in the redifferentiation process. A component of the cardiac dyad called leucine-rich repeat-containing 10 (Lrrc10) acted as a negative regulator of proliferation, prevented cardiomegaly, and induced redifferentiation. They found that its function was conserved in mammalian cardiomyocytes. Their study highlights the importance of the underlying mechanisms required for heart regeneration and their application to the generation of fully functional cardiomyocytes. Science. 2023 May 19;380(6646):758-764. doi: 10.1126/science.abo6718.
L1 Retrotransposition in Normal Colorectal Epithelium
Somatic L1 retrotransposition refers to the process in which long interspersed nuclear elements (LINE-1 or L1 elements), which are a type of transposable element, move within the DNA of somatic cells. These elements can have the ability to "copy and paste" themselves into different genomic locations, potentially leading to genetic alterations. While L1 retrotransposition has been extensively studied in the context of cancer, it is still a topic of ongoing research to determine its prevalence and significance in normal tissues, including the colorectal epithelium. Colorectal epithelium refers to the tissue lining the colon and rectum, and abnormalities in this tissue can contribute to the development of colorectal cancer. Nam and colleagues explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. They found 1,708 somatic L1 retrotrans position events that were enriched in the colorectal epithelium and showed a positive relationship with age. Analysis of matched cancers further suggested that the somatic L1 retrotransposition rate is substantially increased during colorectal tumorigenesis. They concluded that L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime. Nature. 2023 May;617(7961):540-547. doi: 10.1038/s41586-023-06046-z.