Antimetabolic Drugs Research Articles

Impact of V9302, a Competitive Antagonist of Transmembrane Glutamine Flux on Reversal of Resistance in Breast Cancer Cell Lines.

Chemotherapy is a known treatment modality that improves the long-term survival of breast cancer patients. However, due to the resistance to numerous anticancer drugs, alternative chemotherapeutic strategies are required. Regarding antimetabolic drugs, several compounds have proven anticancer properties, such as statins. The present study aimed to investigate the in vitro effects of V9302, a competitive antagonist of glutamine flux, on different subtypes of breast cancers (estrogen, progesterone, and HER2 receptor-positive or negative, and Pgp-negative and Pgp-overexpressing). The interactions of V9302 with standard chemotherapeutic drugs (doxorubicin and cisplatin) were also determined by MTT staining on breast cancer cell lines. Furthermore, the influence of V9302 on the cell cycle of MCF-7 and its Pgp-overexpressing counterpart KCR was monitored by flow cytometry. It was shown that V9302 exerted synergistic interactions with doxorubicin in all breast cancer cell lines. In cell cycle analysis, the KCR cell line was more sensitive to V9302. After 48 h, cell proliferation was completely blocked, and elevated G1, suppressed S, and decreased G2/M could be detected. Inhibition of glutamate transport can be assumed to block resistance related to Pgp.

Transcriptional regulation of hexokinase 2 by BRD4 drives perivascular adipose tissue meta-inflammation in cardiometabolic disease

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Holcim Stiftung SwissLife Stiftung Background/Introduction BRD4 is an epigenetic reader that modulates inflammatory transcriptional programmes implicated in cancer. The therapeutic potential of BRD4 modulation in cardiometabolic disorders remains elusive. Purpose We investigate BRD4-related transcriptional programmes and therapeutic modulation in mouse and human models of cardiometabolic disease. Methods Small arteries (100-300 μM) from healthy subjects (n=16) and patients with obesity and hypertension (n=16) were dissected from visceral fat biopsies and mounted on a pressurised myograph to assess ex-vivo vascular function. Vasorelaxation to acetylcholine and acetylcholine+L-NAME was evaluated at baseline and after incubation with the BRD4 inhibitor RVX-208 and with selective anti-inflammatory and anti-metabolic drugs. Vasorelaxation was assessed in the presence or in the absence of perivascular adipose tissue (PVAT). An experimental mouse model of cardiometabolic disease (high-fat diet+L-NAME supplementation) was orally administered RVX-208 (150 mg/kg) or vehicle for 10 days (n=6 each group) to test in vivo effect of chronic BRD4 inhibition on endothelial and PVAT functions. Vascular and PVAT levels of cytosolic and mitochondrial ROS and nitric oxide were assessed by confocal microscopy; protein and gene expression were measured by Western blot and qPCR. Transcriptional changes upon BRD4 inhibition were investigated by a custom PCR array and confirmed by ChIP, qPCR and Western blot and further characterised by metabolomics, lipidomics and mitochondrial swelling assays. Results Endothelial-dependent vasorelaxation and tissue levels of TNF-α, IL-1β and IL-6 were altered in the vessel wall and PVAT from cardiometabolic patients and mice. RVX-208 substantially attenuated ex-vivo vascular dysfunction. Distinct ex-vivo modulation of well-established inflammatory pathways showed that the effect observed with BRD4 inhibition was stronger than with anti-IL-1β, anti-IL-6 receptor and anti-TNF-α. The effect was more pronounced in vessels with intact PVAT, suggesting a restoration of the PVAT anti-contractile phenotype. (Figure 1). Gene expression profiling in PVAT from cardiometabolic mice unveiled hexokinase-2 (HK2) - a glycolytic enzyme implicated in mitochondrial dysfunction and inflammation - as the top downregulated gene by RVX-208 treatment. Increased binding of BRD4 to HK2 promoter in PVAT samples from cardiometabolic mice was confirmed by ChIP assays. Metabolomics assays further validated the findings, showing a PVAT glycolytic shift in condition of disease. Finally, ex-vivo selective inhibition of HK2 restored vascular dysfunction (Figure 2). Conclusions Targeting the deleterious BRD4-HK2 interplay restores cardiometabolic-related vascular dysfunction reversing the PVAT meta-inflammatory shift. Epigenetic modulators of meta-inflammatory pathways might represent a promising strategy to prevent and vascular dysfunction, key signature of cardiometabolic disease.Figure 1Figure 2

Systematic review and network meta-analysis on the efficacy and safety of parmacotherapy for hand osteoarthritis.

Hand osteoarthritis poses a significant health challenge globally due to its increasing prevalence and the substantial burden on individuals and the society. In current clinical practice, treatment options for hand osteoarthritis encompass a range of approaches, including biological agents, antimetabolic drugs, neuromuscular blockers, anti-inflammatory drugs, hormone medications, pain relievers, new synergistic drugs, and other medications. Despite the diverse array of treatments, determining the optimal regimen remains elusive. This study seeks to conduct a network meta-analysis to assess the effectiveness and safety of various drug intervention measures in the treatment of hand osteoarthritis. The findings aim to provide evidence-based support for the clinical management of hand osteoarthritis. We performed a comprehensive search across PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials was conducted until September 15th, 2022, to identify relevant randomized controlled trials. After meticulous screening and data extraction, the Cochrane Handbook's risk of bias assessment tool was applied to evaluate study quality. Data synthesis was carried out using Stata 15.1 software. 21 studies with data for 3965 patients were meta-analyzed, involving 20 distinct Western medicine agents. GCSB-5, a specific herbal complex that mainly regulate pain in hand osteoarthritis, showed the greatest reduction in pain [WMD = -13.00, 95% CI (-26.69, 0.69)]. CRx-102, s specific medication characterized by its significant effect for relieving joint stiffness symptoms, remarkably mitigated stiffness [WMD = -7.50, 95% CI (-8.90, -6.10)]. Chondroitin sulfate displayed the highest incidence of adverse events [RR = 0.26, 95% CI (0.06, 1.22)]. No substantial variation in functional index for hand osteoarthritis score improvement was identified between distinct agents and placebo. In summary, GCSB-5 and CRx-102 exhibit efficacy in alleviating pain and stiffness in HOA, respectively. However, cautious interpretation of the results is advised. Tailored treatment decisions based on individual contexts are imperative.

The application of Global Trigger Tool in monitoring antineoplastic adverse drug events: a retrospective study.

This study aimed to establish an antineoplastic drugs trigger tool based on Global Trigger Tool (GTT), to examine the performance by detecting adverse drug events (ADEs) in patients with cancer in a Chinese hospital (a retrospective review), and to investigate the factors associating with the occurrence of antineoplastic ADEs. Based on the triggers recommended by the GTT and those used in domestic and foreign studies and taking into account the scope of biochemical indexes in our hospital, some of them were adjusted. A total of 37 triggers were finally developed. Five hundred medical records of oncology patients discharged in our hospital from 1 June 2020 to 31 May 2021 were randomly selected according to the inclusion and exclusion criteria. These records were reviewed retrospectively by antineoplastic drugs trigger tool. The sensitivity and specificity of the triggers were analyzed, as well as the characteristics and risk factors for the occurrence of ADEs. Thirty-three of the 37 triggers had positive trigger, and the sensitivity rate was 91.8% (459/500). For the specificity, the positive predictive value of overall ADEs was 46.0% (715/1556), the detection rate of ADEs was 63.0% (315/500), the rate of ADEs per 100 admissions was 136.0 (95% CI, 124.1-147.9), and the rate of ADEs per 1,000 patient days was 208.33 (95% CI, 201.2-215.5). The top three antineoplastic drugs related to ADEs were antimetabolic drugs (29.1%), plant sources and derivatives (27.1%), and metal platinum drugs (26.3%). The hematologic system was most frequently involved (507 cases, 74.6%), followed by gastrointestinal system (89 cases, 13.1%). Multivariate logistic regression analysis showed that the number of combined drugs (OR = 1.14; 95% CI, 1.07-1.22; P < 0.001) and the previous history of adverse drug reaction (ADR) (OR = 0.38; 95% CI, 0.23-0.60; P < 0.001) were the risk factors for ADEs. The length of hospital stay (OR = 0.40; 95% CI, 0.14-1.12; P < 0.05) and the previous history of ADR (OR = 2.18; 95% CI, 1.07-4.45; P < 0.05) were the risk factors for serious adverse drug events (SAE). The established trigger tool could be used to monitor antineoplastic drugs adverse events in patients with tumor effectively but still needs to be optimized. This study may provide some references for further research in order to improve the rationality and safety of antineoplastic medications.

TRANSCRIPTIONAL REGULATION OF HEXOKINASE-2 BY BRD4 DRIVES PERIVASCULAR ADIPOSE TISSUE META-INFLAMMATION IN CARDIOMETABOLIC DISEASE

Objective: To investigate BRD4-related transcriptional programmes and therapeutic modulation in mouse and human models of cardiometabolic disease. Design and method: Small arteries (0.1-0.3 mm) from healthy subjects (n=16) and patients with obesity and hypertension (n=16) were dissected from visceral fat biopsies and mounted on a pressurised myograph to assess the ex-vivo effects of BRD4 inhibition on vascular function. Vasorelaxation to acetylcholine and acetylcholine+L-NAME was evaluated, in the presence or in the absence of perivascular adipose tissue (PVAT), at baseline and after incubation with the BRD4 inhibitor RVX-208 and with selective anti-inflammatory and anti-metabolic drugs. A cardiometabolic mouse (high-fat diet+L-NAME supplementation) was orally administered RVX-208 (150 mg/kg) to test in vivo effect of chronic BRD4 inhibition. ROS and nitric oxide were assessed by confocal microscopy; protein and gene expression were measured by Western blot and qPCR. Transcriptional changes upon BRD4 inhibition were investigated by a custom qPCR array, confirmed by ChIP, qPCR and Western blot and further characterised by metabolomics, lipidomics and mitochondrial swelling assays. Results: Endothelial-dependent vasorelaxation and tissue levels of TNF-alpha, IL-1beta, and IL-6 were altered in the vessel wall and PVAT from cardiometabolic patients and mice. RVX-208 substantially attenuated ex-vivo vascular dysfunction, with an impact greater when compared to anti-IL-1beta, anti-IL-6 receptor and anti-TNF-alpha. The effect was more pronounced in vessels with intact PVAT, suggesting a restoration of the PVAT anti-contractile phenotype. Gene expression profiling in PVAT from cardiometabolic mice unveiled hexokinase-2 (HK2) - a glycolytic enzyme implicated in mitochondrial dysfunction and inflammation - as the top downregulated gene by RVX-208 treatment. Increased binding of BRD4 to HK2 promoter in PVAT samples from cardiometabolic mice was confirmed by ChIP assays. Metabolomics assays further validate the findings, showing a PVAT glycolytic shift in condition of disease. Finally, ex-vivo selective inhibition of HK2 restored vascular dysfunction. Conclusions: Targeting the deleterious BRD4-HK2 interplay restores cardiometabolic-related vascular dysfunction reversing the PVAT meta-inflammatory shift. Epigenetic modulators of meta-inflammatory pathways might represent a promising strategy to prevent and reverse vascular dysfunction, key signature of cardiometabolic disease.

Transcriptional regulation of Hexokinase-2 by BRD4 drives perivascular adipose tissue meta-inflammation in cardiometabolic disease

Aim: To investigate BRD4-related transcriptional programmes in mouse and human models of cardiometabolic disease. Methods: Small arteries (0.1-0.3 mm) dissected from visceral fat biopsies from healthy subjects (n=16) and patients with obesity and hypertension (n=16) were mounted on a pressurized myograph to assess the acute ex-vivo effects of BRD4 inhibition on vascular function. Vasorelaxation to acetylcholine and acetylcholine+L-NAME was evaluated, in the presence or in the absence of perivascular adipose tissue (PVAT), at baseline and after incubation with the BRD4 inhibitor RVX-208 and with selective anti-inflammatory and anti-metabolic drugs. A cardiometabolic mouse (high-fat diet+L-NAME supplementation) was orally administered RVX-208 (150 mg/kg) to test in vivo effect of chronic BRD4 inhibition. ROS and nitric oxide were assessed by confocal microscopy; protein and gene expression by Western blot and qPCR. Transcriptional changes upon BRD4 inhibition were investigated by a custom PCR array, confirmed by ChIP, and characterised by metabolomics, lipidomics and mitochondrial swelling. Results: Endothelial-dependent vasorelaxation and vascular and perivascular TNF-alpha, IL-1beta, IL-6 were altered in cardiometabolic patients and mice. RVX-208 substantially attenuated ex-vivo vascular dysfunction, with an impact greater than anti-IL-1beta, anti-IL-6 receptor and anti-TNF-alpha. The effect was more pronounced in vessels with intact PVAT, suggesting a restoration of the PVAT anti-contractile phenotype. Gene expression profiling in PVAT unveiled hexokinase-2 (HK2) - a glycolytic enzyme implicated in mitochondrial dysfunction and inflammation - as the top downregulated gene by RVX-208 treatment. Increased binding of BRD4 to HK2 promoter in PVAT samples from cardiometabolic mice was confirmed by ChIP assays. Metabolomics assays further validated the findings by demonstrating a glycolytic shift in PVAT under disease conditions. Finally, ex vivo selective inhibition of HK2 rescued vascular dysfunction. Conclusion: Targeting the deleterious BRD4-HK2 interplay restores cardiometabolic vascular dysfunction via reversal of the PVAT meta-inflammatory shift, highlighting a novel potential target to fight cardiometabolic pandemics.

Clinical Characteristics and Outcomes of Unvaccinated Kidney Transplant Recipients Infected with the SARS-CoV-2 Omicron Variant: A Case Series

ABSTRACT Background: Due to their chronic immunocompromised status, kidney transplant (KT) recipients face escalated risks from coronavirus disease 2019 (COVID-19), which may be exacerbated by lower vaccination rates. However, there is a paucity of information regarding the clinical traits of unvaccinated KT recipients with COVID-19. We aimed to investigate the clinical characteristics and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron infection in unvaccinated KT recipients. Methods: In this retrospective study, we analyzed the clinical outcomes of 36 unvaccinated KT recipients diagnosed with SARS-CoV-2 Omicron infection, as confirmed by reverse transcription polymerase chain reaction. Clinical characteristics, laboratory tests, treatment regimens, and outcomes were examined, and 2-month follow-up assessments were conducted. Results: KT recipients had a high incidence of severe infection, with 66.7% classified as having severe/critical illness. Factors associated with severe/critical illness included age; diabetes mellitus; lung infection computed tomography score; and elevated serum D-dimer, interleukin-6, C-reactive protein, procalcitonin, and ferritin levels. The patients in the severe/critical group also had significantly lower blood lymphocyte counts and serum albumin levels. Treatment strategies included discontinuation of antimetabolic drugs, reduction or discontinuation of calcineurin inhibitor drugs, antiviral therapy, and early patient-tailored nutritional support. Acute kidney injury was observed in 19.4% of patients. Four (11.1%) patients died during the observation period, with two (5.6%) succumbing hospitalization and two (5.6%) during the 2-month follow-up period due to infection. The remaining patients did not report any significant symptoms and are still undergoing follow-up. Conclusion: Early diagnosis, personalized treatment, and vigilant monitoring are all crucial aspects of the clinical management of unvaccinated KT recipients with COVID-19. These findings contribute to the understanding of the clinical characteristics and management of COVID-19 in patients undergoing KT.

Regulation of metabolism in pancreatic ductal adenocarcinoma via nanotechnology-enabled strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with insidious onset and early distal metastasis. Metabolic reprogramming, the autonomous changes in cellular bioenergetics driven by aberrant genetic events and crosstalk between cancer and non-cancer cells in the desmoplastic microenvironment, is pivotal for the rapid progression of PDAC. As an attractive therapeutic target, nucleoside metabolism is regulated by various anti-metabolic drugs for the clinical treatment of PDAC. Despite various challenges, such as poor drug delivery efficiency and off-target side effects, metabolic modification and intervention are emerging as promising strategies for PDAC therapy, enabled by the rapid development of nanotechnology-based drug delivery strategies. In this review, we discuss the metabolic characteristics of PDAC and highlight how the development of nanomedicine has boosted the development of new therapeutics for PDAC by modulating critical targets in metabolic reprogramming.

Colostrum Proteins in Protection against Therapy-Induced Injuries in Cancer Chemo- and Radiotherapy: A Comprehensive Review.

In this article, we review the benefits of application of colostrum and colostrum-derived proteins in animal models and clinical trials that include chemotherapy with antimetabolic drugs, radiotherapy and surgical interventions. A majority of the reported investigations was performed with bovine colostrum (BC) and native bovine or recombinant human lactoferrin (LF), applied alone, in nutraceutics or in combination with probiotics. Apart from reducing side effects of the applied therapeutics, radiation and surgical procedures, BC and LF augmented their efficacy and improved the wellness of patients. In conclusion, colostrum and colostrum proteins, preferably administered with probiotic bacteria, are highly recommended for inclusion to therapeutic protocols in cancer chemo- and radiotherapy as well as during the surgical treatment of cancer patients.

Ultrahigh-Resolution NMR with Water Signal Suppression for a Deeper Understanding of the Action of Antimetabolic Drugs on Diffuse Large B-Cell Lymphoma.

Ultrahigh-resolution NMR has recently attracted considerable attention in the field of complex samples analysis. Indeed, the implementation of broadband homonuclear decoupling techniques has allowed us to greatly simplify crowded 1H spectra, yielding singlets for almost every proton site from the analyzed molecules. Pure shift methods have notably shown to be particularly suitable for deciphering mixtures of metabolites in biological samples. Here, we have successfully implemented a new pure shift pulse sequence based on the PSYCHE method, which incorporates a block for solvent suppression that is suitable for metabolomics analysis. The resulting experiment allows us to record ultrahigh-resolution 1D NOESY 1H spectra of biofluids with suppression of the water signal, which is a crucial step for highlighting metabolite mixtures in an aqueous phase. We have successfully recorded pure shift spectra on extracellular media of diffuse large B-cell lymphoma (DLBCL) cells. Despite a lower sensitivity, the resolution of pure shift data was found to be better than that of the standard approach, which provides a more detailed vision of the exo-metabolome. The statistical analyses carried out on the resulting metabolic profiles allow us to successfully highlight several metabolic pathways affected by these drugs. Notably, we show that Kidrolase plays a major role in the metabolic pathways of this DLBCL cell line.

The Alternative RelB NF-kB Subunit Exerts a Critical Survival Function upon Metabolic Stress in Diffuse Large B-Cell Lymphoma-Derived Cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults and reveals distinct genetic and metabolic signatures. NF-κB transcription factor family is involved in diverse biological processes enabling tumor development and resistance to anticancer-therapy through activation of its two main pathways, the canonical and the alternative NF-κB pathways, the main actor of the latter being the RelB NF-kB subunit. RelB DNA binding activity is frequently activated in DLBCL patients and cell lines. RelB activation defines a new DLBCL subgroup with dismal outcome upon immunochemotherapy, and RelB confers DLBCL cell resistance to DNA damage. However, whether RelB can impact on DLBCL cell metabolism and survival upon metabolic stress is unknown. Here, we reveal that RelB controls DLBCL oxidative energetic metabolism. Accordingly, RelB inhibition reduce DLBCL mitochondrial ATP production, and sensitizes DLBCL cells to apoptosis induced by Metformin and L-asparaginase (®Kidrolase), two FDA approved antimetabolic drugs targeting mitochondrial metabolism. RelB also confers DLBCL cell resistance to glutamine deprivation, an essential amino acid that feeds the TCA cycle. Taken together, our findings uncover a new role for RelB in the regulation of DLBCL cell metabolism and DLBCL cell survival upon metabolic stress.

A propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex

The molecular targets and mechanisms of propolis ameliorating metabolic syndrome are not fully understood. Here, we report that Brazilian green propolis reduces fasting blood glucose levels in obese mice by disrupting the formation of CREB/CRTC2 transcriptional complex, a key regulator of hepatic gluconeogenesis. Using a mammalian two-hybrid system based on CREB-CRTC2, we identify artepillin C (APC) from propolis as an inhibitor of CREB-CRTC2 interaction. Without apparent toxicity, APC protects mice from high fat diet-induced obesity, decreases fasting glucose levels, enhances insulin sensitivity and reduces lipid levels in the serum and liver by suppressing CREB/CRTC2-mediated both gluconeogenic and SREBP transcriptions. To develop more potential drugs from APC, we designed and found a novel compound, A57 that exhibits higher inhibitory activity on CREB-CRTC2 association and better capability of improving insulin sensitivity in obese animals, as compared with APC. In this work, our results indicate that CREB/CRTC2 is a suitable target for developing anti-metabolic syndrome drugs.

Application of Immune Checkpoint Inhibitors in Solid Organ Transplantation Recipients: A Systematic Review.

Solid organ transplantation (SOT) is a treatment method for end-stage organ diseases and improve their life quality, while using long-term immunosuppressant drugs (ISD) is needed to suppress the function of the immune system. Immune checkpoint inhibitors (ICIs) are a class of anti-tumor drugs that kill tumors by activating the autoimmune system. The primary objective of our systematic review is to investigate the risk factors for organ rejection and the efficacy of ICIs in solid organ transplantation recipients (SOTRs). We searched four databases to find relevant articles up to January 2021. A total of 61 articles involving 106 SOTRs met the screening criteria and were included in our systematic review. The collected data were statistical described, and the risk factors were analyzed by logistic regression. Forty-four patients (41.5%) developed host-versus-graft response (HVGR) after ICIs. mTOR inhibitors (pre-ICIs) (p = 0.069, OR = 0.377, 95% CI 0.132-1.078) and calcineurin inhibitors (post-ICIs) (p = 0.056, OR = 0.375, 95%CI 0.137-1.025) may help reduce the incidence of HVGR. Hormones (pre-ICIs) (p = 0.026, OR = 3.150, 95%CI 1.150-8.628) and anti-metabolites (pre-ICIs) (p = 0.022, OR = 3.214, 95%CI 1.185-8.720) may adversely affect the efficacy of ICIs. Only 35.6% of patients both responded well to ICIs treatment and did not develop HVGR. Our systematic review summarizes the use of ICIs in SOTRs and evaluates the efficacy of ICIs and the risk factors that induce HVGR. Through risk factor analysis, we found that mTOR inhibitors and calcineurin inhibitors may help to reduce the occurrence of HVGR;hormones and anti-metabolic drugs may have adverse effects on the efficacy of ICIs. In addition, there is a contradictory relationship between the occurrence of HVGR and the efficacy of ICIs.

SGLT2 Inhibitors: The “Metabolic Molecule” Or “Disease Modifying Anti Metabolic Drugs- DMAMDs”?

The major health hazard of the modern world, “Metabolic Syndrome” or “Syndrome X”, defined by WHO, as pathologic condition characterised by abdominal obesity, insulin resistance, hypertension and dyslipidemia [1]. The criteria for diagnosis are listed in Figure 1 [2]. It is being accepted almost a decade ago that we are in the phase of epidemic for this Non Communicable Condition. Though it was started in western world, spread of western lifestyle across the globe, truly it has now become the major global issue. Until recently the condition was far more prevalent in urban population than rural but in today’s time, especially in Country like India, the incidence showed trends towards becoming almost equal [3]. Though recognised all over the world, the condition is rather dealt as managing different component(s) of the syndrome rather than taking the syndrome per say as diagnosis. We rather tend to care much of those patients who actually show prominently one or more components of metabolic syndrome, and this approach is leading us to neglect rather major bulk of patients who, in spite qualifying for criteria of diagnosis of metabolic syndrome, where not only patients are in early asymptomatic phase, but also the physicians caring for them do not reinforce the importance of the needed care at this very moment to prevent or delay the progression of the condition. Healthcare all over world, particularly in India has shown enormous growth, in terms of not only infrastructure but also skill development [4]. Today we do have much better level of expertise in all the subspecialty with regards to high end care of all such conditions arise from one or more components of metabolic syndrome like Heart Failure, Chronic liver disease, chronic kidney disease and Diabetes (related complication). In developing country like India, somewhere 3 to 4 decades ago to subject a patient for liver or kidney transplant used to be mere dream of treating consultants but today we are not only doing the transplants smoothly but also survival rate is getting better and better [5]. But its quiet unfortunate that in spite of all these progresses, the actual numbers of such patients needing high end care is steadily on rise, thanks to increase in life expectancy in general and relatively better exposure to needed healthcare [5]. But author do strongly believe that still whatever we are seeing is more at treatment cum cure level but nothing much at prevention level is going on. In decades to come, we have large population at risk, at this very moment, for all such advanced staged chronic metabolic conditions. We are in genuine need of a molecule which can be offered to all such early or intermediate metabolic syndrome patient, expecting the improvement in almost all the aspect on the syndrome. Author do believe, the group of drugs known as “SGLT2 Inhibitors”, an originally used for Hyperglycemia management, has now expanded its preventive effects on various metabolic conditions, showing promising results in all the trials and early real world evidences, is the real nomination for the “Metabolic Molecule” or “Disease modifying anti metabolic drugs- DMAMDs” of today.

Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms

Proliferating cancer cells exhibit metabolic alterations and specific nutritional needs for adapting to their rapid growth. These changes include using aerobic glycolysis, lipid metabolic disorder, and irregular protein degradation. It may be useful to target metabolic abnormalities for cancer chemoprevention. Epidemiological and mechanism-related studies have indicated that many FDA-approved anti-metabolic drugs decrease tumor risk, inhibit tumor growth, or enhance the effect of chemotherapeutic drugs. Drugs targeting nutrient metabolism have fewer side effects with long-term use compared to chemotherapeutic drugs. The characteristics of these drugs make them promising candidates for cancer chemoprevention. Here, we summarize recent discoveries of the chemo-preventive effects of drugs targeting nutrient metabolic pathways and discuss future applications and challenges. Understanding the effects and mechanisms of anti-metabolic drugs in cancer has important implications for exploring strategies for cancer chemoprevention.

The Course of SARS-CoV-2 in a Patient After a Recent Kidney Transplant: A Literature Review on COVID-19 Therapy

BackgroundKidney transplant recipients are at high risk of severe complications and death due to coronavirus disease 2019 (COVID-19).MethodsThe first part of the article describes a case of COVID-19 in our patient after a recent kidney transplant. The second part of the article presents the outcome of literature search from multiple resources from April 2020 until March 2021. s were screened, followed by full-text review with data extraction. Part 2 discusses current treatment options of COVID-19, and part 3 refers to this treatment application in patients after solid organ transplant.ResultsWe have summarized 45 studies from China, France, Italy, Spain, the United Kingdom, and the United States. Mortality rates from published studies were variable. Based on early data from Spain, 42% of patients who developed COVID-19 within 60 days of transplant died. According to results of the European Renal Association COVID-19 Database collaboration group, the 28-day COVID-19–related mortality is 21.3% for kidney transplant recipients, which is still markedly higher than what is observed in other populations. Acute kidney injury was common, and mycophenolate mofetil and mammalian target of rapamycin were discontinued in most patients.ConclusionsEffective therapy has been sought since the outbreak of the pandemic, and at the same time intensive work has been done to produce a vaccine that could effectively protect against the disease. Summing up the efforts of numerous groups of researchers from around the world that have been continued since the beginning of 2020, we may assume the following:(1) we still do not have causal drugs that would reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and allow its complete elimination, but antispike monoclonal antibodies against SARS-CoV-2 seem to be very promising, and (2) the withdrawal of antiproliferative and antimetabolic drugs and the continuation of steroids and calcineurin inhibitors is now a commonly accepted approach in patients after organ transplant.

Progress on genome-scale metabolic models integrated with multi-omics data

The genome-scale metabolic network model (GEM) is a mathematical framework based on gene-protein-reaction associations combined with stoichiometric balance and is capable of facilitating the computation and prediction of multiscale phenotypes by optimizing the objective function of interest. It has been increasingly used as an important tool for understanding cellular metabolism and characterizing cell phenotypes. In cells, metabolism is tightly controlled by intricate regulatory mechanisms at the different system levels and is strictly regulated to ensure the dynamic adaptation of biochemical reaction fluxes for maintaining cell homeostasis to ultimately achieve optimal metabolic fitness. Advances in high-throughput screening and analysis technologies have generated massive amounts of genome sequences, along with transcriptomic, proteomic and metabolomic data, providing quantitative regulatory information to gain insights into cellular metabolism; however, integrating the available omics data into constraint-based metabolic models and quantitatively profiling genotype-phenotype relationships remains an outstanding challenge for computational biology. Here, we describe the recent developments in introducing macromolecular expression into GEMs and generating metabolic expression (ME) models, which increase the complexity and predictive capability of computational frameworks. Various algorithms employ different approaches to combine additional layers of omics data to limit the cone of allowable flux distributions in the metabolic model. In this review, we categorize all methods by five different grouping criteria and evaluate their practical perspectives. The first category of methods utilizes a threshold to distinguish active and inactive states of the corresponding reactions based on the gene expression measurement data. The second uses omics data to build cell- and tissue-specific models of human metabolism by removing unexpressed reactions from the global human metabolic network. The third category of methods involves modifying reaction bounds on the basis of mRNA and protein abundance, in which the width of the “flux cone” is adjusted via the maximum possible flux in the upper bound of the FBA optimization problem dependent on gene and protein expression levels. The imposition of constraints further defines the associated solution space of the model to improve the prediction accuracy. The fourth model incorporates transcriptional regulation networks (TRNs), which describe the phenomenological interactions between different biomolecules in response to genetic and environmental perturbation, into GEMs and avoids the obstacles of information formulation to achieve comprehensive knowledge regarding the metabolic and regulatory events occurring inside the cell. The last category integrates time-series transcriptomics data with flux-based bilevel optimization to comprehend the interplay between metabolism and regulation in time-dependent processes. We compare the advantages and limitations of different categories and explore the application areas of integrated models in analyzing metabolic characteristics, interpreting phenotypic states and the consequences of environmental and genetic perturbations while discovering potential drug targets and screening anti-metabolic drugs for cancer treatment. Finally, we also highlight the future perspectives and challenges for GEM-based reconstruction with omics data integration.

Skin Cancer Treatment by Nanoskin Cellulose: Future Cancer Wound Healing

Cancer cells can be proliferating in a few months and years. It depends on cancer stage. Chemotherapy, immunotherapy and anti-metabolic drugs have been used in order to kill cancer cells and prevent immune system weakly and metastasis. However, such drugs can damage healthy cells too. Natural ways to cancer treatments may help whole body to cancer cells. In this work, it was taking off cancer nodule to skin cancer by surgery and we treat the nodule as wound, using Nanoskin® advance cell therapy (ACT), natural extra cellular matrix which releases nutrients to the skin cancer. Our result shows that the cancer nodule disappears in few weeks in skin, because of natural membrane treatment. In addition, we obtained complete wound healing due anticancer nutrients (beta-glucan) delivery to skin.

Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells

Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.

A review of nutrition and dietary interventions in oncology.

The complex cellular mechanisms and inter-related pathways of cancer proliferation, evasion, and metastasis remain an emerging field of research. Over the last several decades, nutritional research has prominent role in identifying emerging adjuvant therapies in our fight against cancer. Nutritional and dietary interventions are being explored to improve the morbidity and mortality for cancer patients worldwide. In this review, we examine several dietary interventions and their proposed mechanisms against cancer as well as identifying limitations in the currently available literature. This review provides a comprehensive review of the cancer metabolism, dietary interventions used during cancer treatment, anti metabolic drugs, and their impact on nutritional deficiencies along with a critical review of the following diets: caloric restriction, intermittent fasting, ketogenic diet, Mediterranean diet, Japanese diet, and vegan diet.