Pharmaceutical Approaches Research Articles

Pharmaceutical Approach to Develop Novel Photosensitizer Nanoformulation: An Example of Design and Characterization Rationale of Chlorophyll α Derivative.

In this study, we described physico-chemical properties of novel nanoformulation of photosensitizer-pyropheophorbide α 17-diethylene glycol ester (XL) (chlorophyll α derivative), revealing insights into antitumor activity and maintaining quality, meeting the pharmaceutical approach of new nanoformulation design. Our formulation, based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles, increased XL solubility and selective tumor-targeted accumulation. In our research, we revealed, for the first time, that XL binding to polyvinyl alcohol (PVA) enhances XL photophysical activity, providing the rationale for PVA application as a stabilizer for nanoformulations. Results of FTIR, DSC, and XRD revealed the physical interactions between XL and excipients, including PVA, indicating that the encapsulation maintained XL binding to PVA. The encapsulated XL exhibited higher photophysical activity compared to non-encapsulated substance, which can be attributed to the influence of residual PVA. Gamma-irradiation led to degradation of XL; however, successful sterilization of the samples was achieved through the filtration. Importantly, the encapsulated and sterilized XL retained cytotoxicity against both 2D and 3D tumor cell models, demonstrating the potential of the formulated NP-XL for photodynamic therapy applications, but lacked the ability to reactivate epigenetically silenced genes. These findings provide valuable insights into the design and characterization of PLGA-based nanoparticles for the encapsulation of photosensitizers.

Current perspective of vaccination in Spain for dogs and cats from a pharmaceutical approach.

Current perspective of vaccination in Spain for dogs and cats from a pharmaceutical approach.

Progress in the applications of biocompatible ionic liquids: renewable commodity production, catalytic and pharmaceutical approaches – a review

This review addressed the recent advances of biocompatible ionic liquids that include the production of renewable commodities and approaches in catalysis and the pharmaceutical field. Likewise, patents and future perspectives are discussed.

Development of an in vivo syngeneic mouse transplant model of invasive intestinal adenocarcinoma driven by endogenous expression of Pik3caH1047R and Apc loss.

Preclinical models that replicate patient tumours as closely as possible are crucial for translational cancer research. While in vitro cancer models have many advantages in assessing tumour response therapy, in vivo systems are essential to enable evaluation of the role of the tumour cell extrinsic factors, such as the tumour microenvironment and host immune system. The requirement for a functional immune system is particularly important given the current focus on immunotherapies. Therefore, we set out to generate an immunocompetent, transplantable model of colorectal cancer suitable for in vivo assessment of immune-based therapeutic approaches. Intestinal tumours from a genetically engineered mouse model, driven by expression of a Pik3ca mutation and loss of Apc, were transplanted into wild type C57BL/6 host mice and subsequently passaged to form a novel syngeneic transplant model of colorectal cancer. Our work confirms the potential to develop a panel of mouse syngeneic grafts, akin to human PDX panels, from different genetically engineered, or carcinogen-induced, mouse models. Such panels would allow the in vivo testing of new pharmaceutical and immunotherapeutic treatment approaches across a range of tumours with a variety of genetic driver mutations.

Using the Values of Integrative Medicine to Create the Future of Healthcare.

The ideal future state of health for the world's populations requires a cohesive model that considers the synergistic roles of communities, public health and healthcare.This future state reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic and lifestyle approaches, healthcare professionals and disciplines to achieve optimal health and healing.This is the definition of Integrative Medicine. We are far from this idealistic future. Healthcare costs continue to escalate while life expectancy declines. We train our future healthcare professionals in our current disease-based model that prioritizes siloed pharmaceutical and interventional approaches over whole person prevention focused care. As healthcare professionals, we disregard our capacity to influence the leading risk factors for disease-related death and disability which include health behaviors, social, economic and environmental drivers. Burnout is high and rising. Rapid shifts are expected in the coming years as the current system's cost becomes untenable. We need a sustainable future for healthcare. That means we must figure out how to re-center on the patient, on a full spectrum of prevention and treatment, and how to influence public and community health. The future model must focus on health behaviors at its foundation, use systems thinking, be environmentally sustainable, and approach health from a population lens. The future will require an ability to consider complex systems approaches to health and wellbeing that include a focus on both the patient and the healthcare team. Research strategies must not only consider effectiveness but also reach, implementation and institutionalization in a multi-dimensional capacity that looks at whole person health as an outcome while looking at individuals in the context of where they live and work. The Integrative Medicine community has an opportunity to help lead the way to a sustainable and health focused future.

Cell Type-Specific Expression of Molecular Players in Morphine Action

Hidden drug abuse has become a concerning issue in Hong Kong, despite an overall decrease in reported cases. The opioid epidemic, fueled by substances like heroin and fentanyl, continues to be a global problem. Understanding the molecular mechanisms of morphine addiction is crucial for developing effective treatments to combat this problem. This study investigates the gene expression patterns of key players in morphine addiction in the Nucleus Accumbens (NAc) region of the mesolimbic dopamine system, a key area in drug-associated reward. The RNA transcripts produced in mice NAc under acute morphine treatment can reveal transcriptional changes that alter the regulation of gene expression related to its molecular mechanisms. By analyzing publicly available single-cell RNA sequencing data, we identified gene expression patterns in specific cell types for genes like BDNF, ΔFosB, CREB, and Npy, all of which were previously studied to be relevant to morphine addiction. The study also highlights novel differentially expressed genes in response to morphine treatment. These findings provide insight into new and relevant genes as well as their cell type-specific expression patterns to glean the pathways that they influence. Understanding these molecular processes can inform personalized pharmaceutical approaches and aid in the development of new therapies.

Insight of Chinese Herbal Medicine in Treating Osteoporosis: Achievements from 2013 to 2023.

Osteoporosis is the most common bone metabolic disease, and it is becoming increasingly common as the global population ages. Osteoporosis and its complications, such as fractures and pain, negatively affect patient quality of life and easily lead to disability, placing enormous burdens on society. Although several anti-osteoporosis drugs are currently available, many adverse reactions have been observed during the long-term application of these drugs. Therefore, safer and more useful medications are urgently needed to replace those currently available. Chinese herbal medicine has been extensively used to treat osteoporosis, and the current literature confirms that such medicines have anti-osteoporosis effects, are safe, and have minimal side effects. Thus, Chinese herbal medicines are natural alternatives to pharmaceutical approaches to treating osteoporosis, and these medicines must be further developed and utilized. In this article, we review the mechanisms underlying the anti-osteoporosis effects of single herbal extracts and traditional Chinese medicine (TCM) formulas that have been elucidated since 2013, providing key evidence and support for future research on the anti-osteoporosis effects of Chinese herbal medicines. In addition, due to the complexity of the ingredients in Chinese herbal medicine, more thorough investigations are needed to determine the specific ingredients that are effective in osteoporosis treatment. Therefore, identifying the effective ingredients of Chinese herbal medicines will be a necessary focus in laboratory research and clinical application.

Tolerability of Current Treatments for Dry Eye Disease: A Review of Approved and Investigational Therapies.

Dry eye disease (DED) is a common, multifactorial ocular disease impacting 5% to 20% of people in Western countries and 45% to 70% in Asian countries. Despite the prevalence of DED and the number of treatment approaches available, signs and symptoms of the disease continue to limit the quality of life for many patients. Standard over-the-counter treatment approaches and behavior/environmental modifications may help some cases but more persistent forms often require pharmacological interventions. Approved and investigational pharmaceutical approaches attempt to treat the signs and symptoms of DED in different ways and tend to have varying tolerability among patients. While several pharmacological approaches are the standard for persistent and severe disease, mechanical options provide alternate treatment modalities that attempt to balance efficacy and comfort. Newer approaches target the causes of DED, utilizing novel delivery methods to minimize irritation and adverse events. Here, we review approved and investigational approaches to treating DED and compare patient tolerability.

Pharmaceutical Cocrystals: A Novel Systematic Approach for the Administration of Existing Drugs in New Crystalline Form

ABSTRACT: Poor physicochemical properties like solubility, dissolution profile, stability, etc. of drugs remain as an obstacle to formulation development. In the last two decades, pharmaceutical cocrystal gaining lots of interest from researchers as these physicochemical, mechanical, and pharmacokinetic properties can be altered without compromising the therapeutic effect. The multi-component systems wherein one component is essentially the Active Pharmaceutical Ingredient and another may be either one more drug or coformer are termed as pharmaceutical cocrystal. Cocrystal is a novel, promising, and emerging approach to encountering such problems and improving the performance of pharmaceuticals. The present article describes the types, rationale of design, synthesis methods, and characterization of pharmaceutical cocrystals. In addition to this, challenges before and after synthesizing cocrystal along with currently approved formulations based on the pharmaceutical cocrystal approach and cocrystals under clinical investigation are highlighted.

Pharmaceutical Intervention at Community Level: Report of a Clinical Case Due to Lychee Intoxication

We present a clinical case of a 3-year-old male patient with signs and symptoms of a diagnosis of unidentified food poisoning. In this scenario the community pharmacist's job consisted of collaboratively work with the doctor, to ensure that the patient's medication was safe, with the aim of detecting drug-related problems or interactions with food, and avoiding negative outcomes associated with medication. The pharmacist applied the methodology described by DADER, for the pharmaceutical care approach and through the intervention, it was possible to establish that the poisoning was due to the intake of lychees. To date, in Mexico there are no reports of litchi poisoning in children, on the other hand, the community pharmacy is an emerging area, hence these types of interventions are scarce.

A Review Article on Migrane

Migrane are a neurological disorder characterized by recurrent, moderate to severe headache. They are often accompanied by symptoms such as nausea, vomiting, sensitivity to light and sound and in some cases, visual disturbances migraines can significantly impact a person’s quality of life and may require a combination of lifestyles changes, medication and other therapies for effective management. Migraine is the sixth most prevalent disease globally, a major cause of disability, and it imposes an enormous personal and socio-economic burden. Migraine treatment is often limited by insufficient therapy response, leading to the need for individually adjusted treatment. In this review, we analyse historical and current pharmaceutical development approaches in acute and chronic migraine based on comprehensive and systematic analysis of Food and Drug Administration (FDA)-approved drugs and those under investigation. The development of migraine therapeutics has significantly intensified during the last 3 years, as shown by our analysis of the trends of drug development between 1970 and 2020. The spectrum of drug targets has expanded considerably, which has been accompanied by an increase in the number of specialised clinical trials. This review highlights the mechanistic implications of FDA approved and currently investigated drugs and discusses current and future therapeutic options based on identified drug classes of interest.

Обоснование применения метода «садовой терапии» для коррекции и профилактики девиантного поведения

The problems of correction and prevention of deviant behaviour are one of the main issues and challenges for modern society. Such deviant behaviour as aggression, drug addiction, crime, sexual deviation and other antisocial manifestations has a negative impact on various spheres of people's lives, including family, education, work and society as a whole. Various pharmaceutical and non-pharmaceutical approaches are examined to manage or reduce deviant behaviour.
 The purpose of this research, based on our own findings, as well as on a number of results of national and foreign experience, is to substantiate the possibility of wider application of "Horticultural therapy" as an interdisciplinary non-pharmacological method of correction and prevention of deviant behaviour.
 The authors based their research on the methods of interdisciplinary studies at the intersection of biology, botany, social sciences and psychology, as well as on the study of the experience of "Horticultural therapy" in more than 200 botanical gardens and their analogues in 32 countries of the world, the practice of application to children and adolescents requiring special methods of upbringing, as well as convicted persons detained in the institutions of the Federal Service for the Execution of Punishments.
 Research results and practical experience revealed that "Horticultural therapy" as a non-pharmacological method has a significant potential in working with persons with deviant behaviour. Its applicability is due to the fact that regular participation in special horticultural sessions contributes to the development of skills to overcome stress, cope with life challenges, strengthens self-regulation and self-control skills, develops patience, diligence and constancy. This enables participants to develop disciplined and responsible behaviour, communication skills and abilities to cooperate, skills of constructive social interaction. The possibility of applying "Horticultural therapy" for people with special causes of deviant behaviour, including participants and veterans of war, and members of their families, is substantiated.
 The authors make a conclusion about the perspectives and possibility of its use for adaptation and rehabilitation of this category of persons, who are assisted in finding positive and healthy ways to cope with post-traumatic and life challenges.

Pharmaceutical management of acute radiation dermatitis in the German speaking radiation oncology community.

Radiation dermatitis (RD) remains the most common side effect in radiation therapy (RT) with various pharmaceutical options available for prevention and treatment. We sought to determine pharmaceutical management patterns of radiation dermatitis among radiation oncology professionals. We conducted a survey on RD among the German-speaking community of radiation oncologists inquiring for their opinion on preventive and therapeutic pharmaceutical approaches for acute RD. 244 health professionals participated. Dexpanthenol lotion is the agent most widely used both for prevention (53.0%) and treatment (76.9%) of RD, followed by urea (29.8%) for prevention and corticosteroids (46.9%) for treatment. A wide range of substances is used by participants, though the overall experience with them is rather limited. 32.5% of participants do generally not recommend any preventative treatment. 53.4% of participants recommend alternative medicine for RD management. While seldomly used, corticosteroids were considered most effective in RD therapy, followed by dexpanthenol and low-level laser therapy. A majority of participants prefers moist over dry treatment of moist desquamation and 43.8% prescribe antiseptics. Pharmaceutical management of RD in the German-speaking radiation oncology community remains controversial, inconsistent, and partially not supported by evidence-based medicine. Stronger evidence level and interdisciplinary consensus is required amongst practitioners to improve these care patterns.

Effects Of Health Promotion Through Animation Video In Reducing Anxiety Among Hypertension Patients: A Literature Review

Introduction: Anxiety is a state of unease or apprehension that arises from the expectation of potential harm, frequently without a clear or identifiable cause. An individual undergoing anxiety might induce a rise in blood pressure. Anxiety exacerbates hypertension by causing vasoconstriction, resulting in elevated blood pressure. Regarding the correlation between anxiety and hypertension, it is crucial to address anxiety in individuals with hypertension. There are multiple methods available to address this anxiety, including both pharmaceutical and non-pharmacological approaches. Material and Methods: This study is a review of existing literature. The researchers aimed to locate scholarly literature about the use of animated movies as a means of alleviating anxiety in individuals diagnosed with hypertension. Articles about the specified theme were chosen from 2018 to 2023 using electronic databases such as Science Direct, PubMed, and Google Scholar and open knowledge maps during the article search. The researchers employed the PRISMA methodology to analyze the literature review studies. Results: 174 articles were chosen using the keywords Health Promotion, Animation Video, Anxiety, and Hypertension. The research underwent a comprehensive review encompassing its aims, samples, methods, and results. Based on the literature review findings, there needs to be more participants or samples that align with the focus of this study. Researchers did not discover any instances of anxiousness in individuals with hypertension through the examination of samples. However, researchers conducted studies on various topics, including the impact of using animated videos to promote health in reducing anxiety among postpartum patients, preoperative anxiety in children, and hypertension. These findings are presented in Table 1. Nevertheless, scholars might engage in discussions regarding the impacts of animated videos. The researchers selected and evaluated only ten publications despite their lack of relevance to the research area of this literature review. Conclusion: Out of the 10 articles examined, many employed animated videos as interventions. However, researchers did not discover any studies specifically focused on investigating the impact of using animated videos for health promotion in reducing anxiety among hypertensive patients. The researchers discovered an independent subject. Consequently, researching this topic can contribute innovatively to future investigations.

Manual Lymph Drainage for Post-COVID-19 Related Cough, Breathlessness, and Fatigue; Two Case Reports

Background: Persistent symptoms after SARS CoV-2 infection such as fatigue, shortness of breath, and cognitive dysfunction that cannot be explained by an alternative diagnosis have been termed long COVID and present a significant emerging public health problem. Current approaches include rehabilitation and symptom management involving multiple health disciplines and as yet there are no pharmaceutical approaches other than routine symptom management. Manual lymph drainage (MLD) has been used to support recovery during pulmonary rehabilitation and reduce chronic inflammation including symptoms associated with long COVID. Case description and outcomes: Two adult females who had reported long-COVID symptoms more than 10 weeks after the resolution of the acute infection were treated with MLD by Remedial Therapists trained in the Dr Vodder method of MLD. Respiratory function (Peak Flow Meter) and blood oxygen levels (Oximeter) were recorded before and after a one-minute sit-to-stand test prior to the treatment. The Dyspnea-12 Questionnaire, the Revised Piper Fatigue Scale, and Likert scales were used to collect client-reported outcomes. Six 45-min treatments were applied weekly, with a follow-up review and treatment at three months. In both cases, all outcomes improved after the third treatment with further improvement noted at three months. Conclusions: MLD may offer a non-invasive, non-pharmaceutical approach to the resolution of long-COVID symptoms such as cough, breathlessness, and fatigue.

CRISPR-Cas9 gene editing in pharmaceuticals : Current applications and future prospects

CRISPR-Cas9 gene editing has emerged as a transformative tool in pharmaceuticals, revolutionizing the understanding and treatment of genetic diseases. This review explores the current landscape and future potential of CRISPRCas9 technology in the pharmaceutical domain. Examining its fundamentals, including the CRISPR-Cas9 system and mechanisms, reveals unparalleled precision in disease modeling, drug discovery and targeted therapies. Challenges like offtarget effects and regulatory complexities are addressed alongside advancements in CRISPR technology beyond Cas9, offering enhanced precision and expanded therapeutic horizons. The significance of CRISPR-Cas9 in shaping the future of pharmaceuticals is evident in its potential applications for rare diseases, complex disorders and its integration with other pharmaceutical approaches, promising groundbreaking therapies. Ethical considerations and regulatory frameworks necessitate responsible innovation while predicting a profound impact on personalized medicine. The future of CRISPR-Cas9 in pharmaceuticals lies in refining delivery methods, addressing ethical concerns and exploring synergies with emerging technologies. This article underscores the ongoing evolution and immense potential of CRISPR-Cas9 in revolutionizing healthcare and therapeutics.

Restriction of dietary protein slows the development and progression of Alzheimer’s disease in 3xTg mice

AbstractBackgroundCaloric restriction (CR) promotes health and longevity in diverse species and has been successful in ameliorating Alzheimer’s disease (AD) pathology in mouse models and non‐human primates. However, CR may be difficult to adhere to, which makes the reduction of specific macronutrients without restricting calories an attractive alternative. Low protein intake is associated with healthy aging and reduced mortality in humans, and protein restriction (PR) extends the lifespan and healthspan of many mouse models. In this study, we examined the effects of PR on metabolic health and AD pathology in the 3xTg mouse model of AD.MethodWe placed male and female 3xTg mice as well as non‐transgenic (NTg) controls on either a Control diet (21% of calories from protein) or a PR diet (7% of calories from protein) starting at 6 months of age. We assessed the effect of PR on metabolic health, cognition, and AD neuropathology along with targeted metabolomics on plasma samples to identify the abundance of metabolites and dysregulated metabolic pathways.ResultWe found that a long‐term PR diet had substantial metabolic benefits for both male and female 3xTg and NTg mice, promoting leanness and glycemic control. We also found that consumption of low protein diet significantly improved cognitive performance and reduced multiple aspects of AD neuropathology including tau phosphorylation, Aß plaques and gliosis. Phosphorylation of the mTORC1 substrate S6K1 was decreased and the major autophagy cargo receptor P62 was increased in PR‐fed 3xTg mice, which suggests that reduced mTORC1 signaling may mediate the beneficial effects of PR on AD pathology. Targeted metabolomics revealed that several metabolites involved in nucleic acid metabolism and amino acid metabolism were altered between control fed and PR fed mice in a sex specific manner.ConclusionOur findings suggest that lowering dietary protein may be a novel way to slow or even prevent AD. In addition, drugs that mimic the effects of PR may be an effective pharmaceutical approach to combat AD pathology.

Qpctl Inhibition, By Targeting the Inflammatory Tumor Microenvironment, Constitutes a Novel Therapeutic Approach for Diffuse Large B-Cell Lymphoma

We have previously described that diffuse large B-cell lymphomas (DLBCL) harboring an inflammatory and immunosuppressive microenvironment (i.e., IN-LME) carry independent poor prognosis while proof-of-principle experiments modifying the composition of the LME were sufficient to induce lymphoma regression in mice models ( Kotlov, Cancer Discovery 2021). However, identification of pharmaceutical approaches that by modifying the LME will induce an anti-lymphoma effect while being suitable for short-term human translation remains challenging. The IN-LME is characterized by the presence of pro-inflammatory and immunosuppressive chemokines and cytokines that frequently undergo post-translational modifications. QPCTL (glutaminyl-peptide cyclotransferase-like) is an intracellular enzyme that mediates a N-terminal pyroglutamylation of CD47 and several chemokines, including CCL2 and CCL7, ultimately resulting in their sustained expression and/or secretion. SC-2882 is a first-in-class specific QPCTL inhibitor that induces secondary proteolytic degradation of the monocyte chemoattractants CCL2 and CCL7 ( da Silva, Nature Immunology 2022) and inactivation of the “do-not-eat-me” signal CD47 ( LogtenbergNature Medicine 2019). In a dataset of 470 DLBCL patients we found that the expression of QPCTL correlates negatively with overall survival and progression free survival (0.019 and <0.001, respectively). To determine whether QPCTL could be a potential target in DLBCL, we investigated its expression along with its targets CCL2, CCL7 and CD47 in additional 216 DLBCL cases categorized by LME. We found that while QPCTL and CD47 are expressed at similar levels in all DLBCL cases regardless their COO class and LME category, CCL2 was highly expressed in DLBCL harboring a IN-LME (p <0.05 vs. other LME categories), that also correlate with higher presence of tumor-associated macrophages (TAMs) and exhausted CD8+PD1 HIGH T cells (p <0.01 and p<0.001, vs. other LME categories, respectively). CCL7 was not expressed at detectable levels in majority of LMEs in DLBCL. In preclinical models, murine and human DLBCL cell lines expressed baseline QPCTL and CD47 while CCL2 and CCL7 expression (qPCR) and secretion (ELISA) increased at higher levels upon culturing these cells for 24 h embedded in splenic extracellular matrix 3D cultures. Exposure of a panel of 3 murine and 5 human DLBCL cells to increasing concentrations of SC-2882 (vs. vehicle) for up to 72 h and up to a 10 micromolar dose had no noticeable decrease in cell viability or proliferation. However, SC-2882 (vs. vehicle) at nanomolar concentrations increased anti-Cd20-dependent lymphoma cell phagocytosis by in vitro differentiated macrophages (from splenic monocytes in mice and THP1 cells in humans) in 3D co-cultures (p < 0.05, for all conditions). To further test the anti-lymphoma effect of SC-2882 we used a murine GCB-DLBCL model by implanting GEMM-derived aggressive Ezh2 mutant (EZH2 Y646equivalent) + BCL2 amplified lymphoma cells in the spleen of immunocompetent C57BL/mice (n=14). After implantation, mice were randomized to receive SC-2882 by oral gavage (n=7) or vehicle (n=14) for 14 days. Tumor burden was followed by luciferase imaging (Caliper), and spleens were analyzed at sacrifice by multiparametric imaging, flow-cytometry, and spatial transcriptomics. Oral SC-2882 (vs. vehicle) induced a significant decrease in tumor growth (p=0.0079, Figure 1) without evidence of systemic toxicity by body weight, blood cell count and chemistry panel. Analysis of the LME in remnant splenic tumors showed in SC-2882 (vs. vehicle) treated mice a significant decrease in lymphoma cells and Ki67+ cells (p<0.001) as well as F480+ TAMs (p<0.01) while there was an increase of CD3+ T cell infiltration (p<0.001). We also found a decrease in Cd4+Foxp3+ Tregs and increase in Cd8+Gzb+ cells in SC-2882 treated mice by flow-cytometry. These changes mirrored the findings in the spatial transcriptomics. Additional analysis of LME cell subpopulations by SC-RNA-seq is ongoing. Overall, these data indicate that QPCTL is a potential target in DLBCL, and that QPCTL inhibition exhibits potent anti-lymphoma effects primarily by targeting the IN-LME.

Synergistic Effects of Type I PRMT1 and Type II PRMT5 Inhibitors Against Multiple Myeloma

Multiple myeloma (MM) is a plasma cell malignancy characterized by the extensive expansion of monoclonal aberrant plasma cells in the bone marrow and the second most prevalent hematological malignancies worldwide. Despite the promising outcomes of advanced therapies, relapsed/refractory (RR) diseases remain incurable, highlighting an unmet clinical need to identify novel therapeutic targets. An emerging field of investigation is the role of aberrant post-translational modifications in multiple myeloma pathology. Arginine methylation is one of the most predominant post-translational modifications in cells, catalyzed by protein arginine methyltransferases (PRMTs) that plays a crucial role in multiple cellular processes. Type I PRMTs catalyze mono- (MMA) and asymmetric demethylation (ADMA) of arginine; Type II PRMTs catalyze mono- and symmetric demethylation (SDMA) of arginine on proteins; Type III PRMT mediates MMA only. Aberrant expression of PRMTs is strongly associated with poor prognosis of solid cancers and hematologic malignancies. Recently, we identified PRMT1 as a novel therapeutic vulnerability in MM cells. Among PRMTs, PRMT1 is the highest expressed gene in MM cell lines and patient cells. The elevation of PRMT1 expression is strongly associated with relapsed/refractory patients and poor clinical outcomes. Deletion of PRMT1 and suppression of the PRMT1's enzymatic activity exhibited a strong anti-MM in vitro via suppressing cell cycle and elevating the apoptosis. We also found that inhibition of PRMT1 boosts the T cell activation in the co-culture setup, indicating a potential enhancement of immunotherapy. Using a subcutaneous xenograft model, we showed that suppressing PRTM1 in vivo by either genetic or pharmaceutical approaches robustly inhibits MM tumor growth and extends survival of tumor-bearing mice. Our findings demonstrated that PRMT1 is indispensable in MM. PRMT5, a PRMT type II, is prognostically relevant and a known druggable target in MM. PRMT1 and PRMT5 inversely regulate post-transcription and have been implicated in human cancers. Recent studies in solid tumor showed a strong anti-tumor effect in vivo using the combinational inhibition of PRMT1 and PRMT5. We hypothesize that PRMT1 and PRMT5 might have a complementary function in MM cells. The combinational inhibition PRMT1 and PRTM5 will exhibit a synergistic anti-MM effect. To address this hypothesis, we treated MM cell lines with two clinical trial inhibitors: GSK3368715 (GSK) and EPZ 015666 (EPZ), suppressing PRMT type I and type II inhibitor, respectively. We first performed dose-dependent cell viability inhibition and selected effective doses for drug combination treatments in three different MM cell lines. The combination of GSK and EPZ demonstrated a strong synergistic effect in suppressing the viability of MM cells. Using the SynergyFinder algorithm, we found that the synergistic indexes (>10, synergism) for 3 MM cell lines JJN3, MM1S, and KMS11 were 33.5, 32.8, and 14.3, respectively. We next assessed the effects of combined treatment on the cell cycle and apoptosis of MM cells. We found that combination of GSK and EPZ strikingly elevated the apoptosis and suppressed cell cycle of MM cell lines compared single treatment and untreated control. Intriguingly, the combination treatment of two inhibitors significantly decreased MMA, SDMA, and ADMA, suggesting a robust suppression of global arginine methylation. Of note, we found a similar anti-MM effect when treating bortezomib-resistant MM cells with GSK and EPZ, indicating that PRMT type I and type II inhibitors potentially have a substantial clinical impact on relapsed MM. Of note, the same dose of GSK and EPZ that exhibits the synergistic anti-MM effect, didn't suppress the viability of healthy peripheral blood cells. In summary, our preliminary data suggest that suppression of both PRMT type I and type II might provide a potential effective combination treatment for both newly diagnosed and relapsed MM patients. We're currently investigating the underling mechanisms of how PRMTs regulate MM pathology and validating the in vivo efficacy of combination treatment using patient-derived xenograft.

Immunosenescence and cancer: Opportunities and challenges.

As individuals age, cancer becomes increasingly common. This continually rising risk can be attributed to various interconnected factors that influence the body's susceptibility to cancer. Among these factors, the accumulation of senescent cells in tissues and the subsequent decline in immune cell function and proliferative potential are collectively referred to as immunosenescence. Reduced T-cell production, changes in secretory phenotypes, increased glycolysis, and the generation of reactive oxygen species are characteristics of immunosenescence that contribute to cancer susceptibility. In the tumor microenvironment, senescent immune cells may promote the growth and spread of tumors through multiple pathways, thereby affecting the effectiveness of immunotherapy. In recent years, immunosenescence has gained increasing attention due to its critical role in tumor development. However, our understanding of how immunosenescence specifically impacts cancer immunotherapy remains limited, primarily due to the underrepresentation of elderly patients in clinical trials. Furthermore, there are several age-related intervention methods, including metformin and rapamycin, which involve genetic and pharmaceutical approaches. This article aims to elucidate the defining characteristics of immunosenescence and its impact on malignant tumors and immunotherapy. We particularly focus on the future directions of cancer treatment, exploring the complex interplay between immunosenescence, cancer, and potential interventions.