Targeting the vivid facets of apolipoproteins as a cardiovascular risk factor in rheumatoid arthritis.

Mostly, cardiovascular diseases are blamed for casualties in rheumatoid arthritis (RA) patients. Customarily, dyslipidemia is probably the most prevalent underlying cause of untimely demise in people suffering from RA as it hastens the expansion of atherosclerosis. The engagement of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), etc., is crucial in the progression and proliferation of both RA and abnormal lipid parameters. Thus, lipid abnormalities should be monitored frequently in patients with both primary and advanced RA stages. An advanced lipid profile examination, i.e., direct role of apolipoproteins associated with various lipid molecules is a more dependable approach for better understanding of the disease and selecting suitable therapeutic targets. Therefore, studying their apolipoproteins is more relevant than assessing RA patients' altered lipid profile levels. Among the various apolipoprotein classes, Apo A1 and Apo B are primarily being focused. In addition, it also addresses how calculating Apo B:Apo A1 ratio can aid in analyzing the disease's risk. The marketed therapies available to control lipid abnormalities are associated with many other risk factors. Hence, directly targeting Apo A1 and Apo B would provide a better and safer option.

Beyond the urothelium: Interplay between autonomic nervous system and bladder inflammation in urinary tract infection, bladder pain syndrome with interstitial cystitis and neurogenic lower urinary tract dysfunction in spinal cord injury-ICI-RS 2023.

INTRODUCTION: Inflammation and neuronal hypersensitivity are reactive protective mechanisms after urothelial injury. In lower urinary tract dysfunctions (LUTD), such as urinary tract infection (UTI), bladder pain syndrome with interstitial cystitis (BPS/IC) and neurogenic LUTD after spinal cord injury (SCI), chronic inflammation can develop. It is unclear how the protective reactionary inflammation escalates into chronic disease in some patients. METHODS: During its 2023 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the urothelial and inflammatory changes after UTI, BPS/IC and SCI. Potential factors contributing to the evolution into chronic disease were explored in a think-tank. RESULTS: Five topics were discussed. (1) Visceral fat metabolism participates in the systemic pro-inflammatory effect of noradrenalin in BPS/IC and SCI. Sympathetic nervous system-adipocyte-bladder crosstalk needs further investigation. (2) Sympathetic hyperactivity also potentiates immune depression in SCI and needs to be investigated in BPS/IC. Gabapentin and tumor necrosis factor-α are promising research targets. (3) The exact peripheral neurons involved in the integrative protective unit formed by nervous and immune systems need to be further identified. (4) Neurotransmitter changes in SCI and BPS/IC: Neurotransmitter crosstalk needs to be considered in identifying new therapeutic targets. (5) The change from eubiosis to dysbiosis in SCI can contribute to UTI susceptibility and needs to be unraveled. CONCLUSIONS: The think-tank discussed whether visceral fat metabolism, immune depression through sympathetic hyperactivity, peripheral nerves and neurotransmitter crosstalk, and the change in microbiome could provide explanations in the heterogenic development of chronic inflammation in LUTD. High-priority research questions were identified.

Administration of α-lipoic acid and silymarin attenuates aggression by modulating endocrine, oxidative stress and inflammatory pathways in mice.

Aggression, a highly prevalent behavior among all the psychological disorders having strong association with psychiatric imbalance, neuroendocrine changes and neurological disturbances (including oxidative stress & neuroinflammation) require both pharmacological and non-pharmacological treatments. Focusing the preclinical neuroendocrine determinants of aggression, this interventional study was designed to elucidate the curative effect of antioxidants on aggression in male mice. Adult albino male mice (n = 140) randomly divided into two main treatment groups for α-lipoic acid (ALA) and silymarin with 5 subgroups (n = 10) for each curative study, namely control, disease (aggression-induced), standard (diazepam, 2.5 mg/kg), low dose (100 mg/kg) and high dose (200 mg/kg) treatment groups of selected antioxidants. Resident-intruder paradigm and levodopa (L-dopa 375 mg/kg, p.o.) induced models were used for aggression. Effect of antioxidant treatment (i.e., 21 days bid) on aggression was assessed by evaluating the changes in aggressive behavior, oxidative stress biomarkers superoxide dismutase, catalase, glutathione, nitrite and malondialdehyde (SOD, CAT, GSH, nitrite & MDA), neurotransmitters (dopamine, nor-adrenaline and serotonin), pro-inflammatory cytokines tumor necrosis factor-α and interleukin- 6 (TNF-α & IL-6) along with serum testosterone examination. This study showed potential ameliorative effect on aggressive behavior with both low (100 mg/kg) and high (200 mg/kg) doses of antioxidants (ALA & silymarin). Resident-intruder or L-dopa induced aggression in male mice was more significantly tuned with ALA treatment than silymarin via down regulating both oxidative stress and inflammatory biomarkers. ALA also exhibited notable effects in managing aggression-induced disturbances on plasma testosterone levels. In conclusion, ALA is more effective than silymarin in attenuating aggression in mice.

The curative and mechanistic acumen of curcuminoids formulations against haloperidol induced Parkinson's disease animal model.

Parkinson's disease (PD) is slowly developing neurodegenerative disorder associated with gradual decline in cerebration and laboriousness to perform routine piece of work. PD imposed a social burden on society through higher medical cost and by loss of social productivity in current era. The available treatment options are expensive and associated with serious adverse effect after long term use. Therefore, there is a critical clinical need to develop alternative pharmacotherapies from natural sources to prevent and cure the pathological hall marks of PD with minimal cost. Our study aimed to scrutinize the antiparkinsonian potential of curcuminoids-rich extract and its binary and ternary inclusion complexes. In healthy rats, 1 mg/kg haloperidol daily intraperitoneally, for 3 weeks was used to provoke Parkinsonism like symptoms except control group. Curcuminoids rich extract, binary and ternary inclusion complexes formulations 15-30 mg/kg, L-dopa and carbidopa (100 + 25 mg/kg) were orally administered on each day for 3 weeks. Biochemical, histopathological and RT-qPCR analyses were conducted after neurobehavioral observations. Findings of current study indicated that all curcuminoids formulations markedly mitigated the behavioral abnormalities, recovered the level of antioxidant enzymes, acetylcholinesterase inhibitory activity and neurotransmitters. Histological analysis revealed that curcuminoids supplements stabilized the neuronal loss, pigmentation and Lewy bodies' formation. The mRNA expressions of neuro-inflammatory and specific PD pathological biomarkers were downregulated by treatment with curcuminoids formulations. Therefore, it is suggested that these curcuminoids rich extract, binary and ternary supplements should be considered as promising therapeutic agents in development of modern anti-Parkinson's disease medications.

Molecular Mechanism Operating in Animal Models of Neurogenic Detrusor Overactivity: A Systematic Review Focusing on Bladder Dysfunction of Neurogenic Origin.

Neurogenic detrusor overactivity (NDO) is a severe lower urinary tract disorder, characterized by urinary urgency, retention, and incontinence, as a result of a neurologic lesion that results in damage in neuronal pathways controlling micturition. The purpose of this review is to provide a comprehensive framework of the currently used animal models for the investigation of this disorder, focusing on the molecular mechanisms of NDO. An electronic search was performed with PubMed and Scopus for literature describing animal models of NDO used in the last 10 years. The search retrieved 648 articles, of which reviews and non-original articles were excluded. After careful selection, 51 studies were included for analysis. Spinal cord injury (SCI) was the most frequently used model to study NDO, followed by animal models of neurodegenerative disorders, meningomyelocele, and stroke. Rats were the most commonly used animal, particularly females. Most studies evaluated bladder function through urodynamic methods, with awake cystometry being particularly preferred. Several molecular mechanisms have been identified, including changes in inflammatory processes, regulation of cell survival, and neuronal receptors. In the NDO bladder, inflammatory markers, apoptosis-related factors, and ischemia- and fibrosis-related molecules were found to be upregulated. Purinergic, cholinergic, and adrenergic receptors were downregulated, as most neuronal markers. In neuronal tissue, neurotrophic factors, apoptosis-related factors, and ischemia-associated molecules are increased, as well as markers of microglial and astrocytes at lesion sites. Animal models of NDO have been crucial for understanding the pathophysiology of lower urinary tract (LUT) dysfunction. Despite the heterogeneity of animal models for NDO onset, most studies rely on traumatic SCI models rather than other NDO-driven pathologies, which may result in some issues when translating pre-clinical observations to clinical settings other than SCI.

Spinal Cord Injury and Complications Related to Neuraxial Anaesthesia Procedures: A Systematic Review.

The use of neuraxial procedures, such as spinal and epidural anaesthesia, has been linked to some possible complications. In addition, spinal cord injuries due to anaesthetic practice (Anaes-SCI) are rare events but remain a significant concern for many patients undergoing surgery. This systematic review aimed to identify high-risk patients summarise the causes, consequences, and management/recommendations of SCI due to neuraxial techniques in anaesthesia. A comprehensive search of the literature was conducted in accordance with Cochrane recommendations, and inclusion criteria were applied to identify relevant studies. From the 384 studies initially screened, 31 were critically appraised, and the data were extracted and analysed. The results of this review suggest that the main risk factors reported were extremes of age, obesity, and diabetes. Anaes-SCI was reported as a consequence of hematoma, trauma, abscess, ischemia, and infarction, among others. As a result, mainly motor deficits, sensory loss, and pain were reported. Many authors reported delayed treatments to resolve Anaes-SCI. Despite the potential complications, neuraxial techniques are still one of the best options for opioid-sparing pain prevention and management, reducing patients' morbidity, improving outcomes, reducing the length of hospital stay, and pain chronification, with a consequent economic benefit. The main findings of this review highlight the importance of careful patient management and close monitoring during neuraxial anaesthesia procedures to minimise the risk of spinal cord injury and complications.

Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics.

The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.

Current trends in epigenetic, cellular and molecular pathways in management of rheumatoid arthritis.

Rheumatoid arthritis is a systemic chronic polyarticular autoimmune disorder of joints and joint membrane mainly affecting feet and hands. The pathological manifestation of the disease includes infiltration of immune cells, hyperplasia of the lining of synovium, formation of pannus and bone and cartilage destruction. If left untreated, the appearance of small focal necrosis, adhesion of granulation, and formation of fibrous tissue on the surface of articular cartilage is noted. The disease primarily affects nearly 1% of the population globally, women being more affected than men with a ratio 2:1 and can initiate regardless of any age. The synovial fibroblast in rheumatoid arthritis individuals exhibits an aggressive phenotype which upregulates the manifestation of protooncogenes, adhesive compounds, inflammatory cytokines and matrix-deteriorating enzymes. Apart from the inflammatory effects of cytokines, chemokines are also noted to induce swelling and pain in arthritic individuals by residing in synovial membrane and forming pannus. The current treatment of rheumatoid arthritis includes treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, treatment with biologics such as inhibitors of TNF-α, interleukins, platelet activating factor, etc. which provides significant relief from symptoms and aids in management of the disease. The current review highlights the pathogenesis involved in the onset of rheumatoid arthritis and also covers epigenetic, cellular and molecular parameters associated with it to aid better and advanced therapeutic approaches for management of the debilitating disease.

Unveiling the Pharmacological and Nanotechnological Facets of Daidzein: Present State-of-the-Art and Future Perspectives.

Herbal drugs have been attracting much scientific interest in the last few decades and nowadays, phytoconstituents-based research is in progress to disclose their unidentified medicinal potential. Daidzein (DAI) is the natural phytoestrogen isoflavone derived primarily from leguminous plants, such as the soybean and mung bean, and its IUPAC name is 4',7-dihydroxyisoflavone. This compound has received great attention as a fascinating pharmacophore with remarkable potential for the therapeutic management of several diseases. Certain pharmacokinetic properties of DAI such as less aqueous solubility, low permeability, and poor bioavailability are major obstacles restricting the therapeutic applications. In this review, distinctive physicochemical characteristics and pharmacokinetics of DAI has been elucidated. The pharmacological applications in treatment of several disorders like oxidative stress, cancer, obesity, cardiovascular, neuroprotective, diabetes, ovariectomy, anxiety, and inflammation with their mechanism of action are explained. Furthermore, this review article comprehensively focuses to provide up-to-date information about nanotechnology-based formulations which have been investigated for DAI in preceding years which includes polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carrier, polymer-lipid nanoparticles, nanocomplexes, polymeric micelles, nanoemulsion, nanosuspension, liposomes, and self-microemulsifying drug delivery systems.

Molecular Aspects and Therapeutic Implications of Herbal Compounds Targeting Different Types of Cancer.

Due to genetic changes in DNA (deoxyribonucleic acid) sequences, cancer continues to be the second most prevalent cause of death. The traditional target-directed approach, which is confronted with the importance of target function in healthy cells, is one of the most significant challenges in anticancer research. Another problem with cancer cells is that they experience various mutations, changes in gene duplication, and chromosomal abnormalities, all of which have a direct influence on the potency of anticancer drugs at different developmental stages. All of these factors combine to make cancer medication development difficult, with low clinical licensure success rates when compared to other therapy categories. The current review focuses on the pathophysiology and molecular aspects of common cancer types. Currently, the available chemotherapeutic drugs, also known as combination chemotherapy, are associated with numerous adverse effects, resulting in the search for herbal-based alternatives that attenuate resistance due to cancer therapy and exert chemo-protective actions. To provide new insights, this review updated the list of key compounds that may enhance the efficacy of cancer treatment.

An advanced automation platform coupled with mass spectrometry for investigating in vitro human skin permeation of UV filters and excipients in sunscreen products.

RATIONALE: Systemic absorption of UV-filtering chemicals following topical application of sunscreens may present a safety concern. The Food and Drug Administration (FDA) had recommended an in vitro skin permeation test (IVPT) to evaluate the potential of this safety risk for the evaluation of sunscreens prior to clinical studies. Therefore, a sensitive and robust bioanalytical method(s) were required for IVPT studies of different topical sunscreen products. METHODS: An analytical procedure to quantitate sunscreen UV-filtering components and excipients in IVPT samples including avobenzone, octocrylene, oxybenzone, ecamsule, methylparaben and propylparaben was developed employing a RapidFire 360 robotic sample delivery system coupled with a triple quadrupole mass spectrometer. The analytical procedure was developed and validated according to the requirements of the FDA Bioanalytical Method Validation Guidance for Industry (2018). RESULTS: The analytical method provided a turnaround time of 12 seconds per sample and was determined to be accurate, precise, specific, and linear over the corresponding analytical ranges. The validated method was successfully applied for two IVPT studies for evaluating the skin permeation potential of UV-filtering chemicals and assisting with the selection of the sunscreen products for the clinical study conducted by the FDA. CONCLUSIONS: This work highlights the first analytical procedure that has applied a non-chromatographic-MS/MS automation platform to an in vitro biopharmaceutics study. The analytical platform simultaneously quantitated four UV filters and two excipients in complex media to evaluate their permeation in IVPT studies. The sample throughput and analytical performance of advanced automation platforms indicate their analytical procedure has the potential to significantly advance the efficiency of IVPT studies to evaluate permeation of a wide variety of UV chemical filters and excipients for topical OTC sunscreen products.

Detailed investigation of the composition and transformations of phenolic compounds in fresh and fermented Vaccinium floribundum berry extracts by high-resolution mass spectrometry and bioinformatics.

INTRODUCTION: Blueberries are known for their very high content of biologically active phenolic compounds; nonetheless, differently from the North American and European species of blueberries, Neotropical blueberries have not been extensively studied yet. OBJECTIVES: In the present paper, the phenolic composition of Vaccinium floribundum Kunth, which is endemic to the Andean regions and grows 1,600 to 4,500 meters above sea level, was investigated by ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). Native and fermented berries were compared in terms of phenolic composition as well as antioxidant activity, total phenolic content, and total anthocyanin content. MATERIALS AND METHODS: V. floribundum native and fermented berries were extracted and analyzed by UHPLC-HRMS. The acquired datasets were processed by Compound Discoverer 3.1 using a dedicated data analysis workflow that was specifically set up for phenolic compound identification. RESULTS: In total, 309 compounds were tentatively identified, including anthocyanins, flavonoids, phenolic acids, and proanthocyanidins. The molecular transformations of phenolic compounds during fermentation were comprehensively investigated for the first time, and by a customized data processing workflow, 13 quinones and quinone methides were tentatively identified in the fermented samples. Compared to other species of the genus Vaccinium, a peculiar phenolic profile is observed, with low abundance of highly methylated compounds. CONCLUSION: Andean berries are a rich source of a wide variety of phenolic compounds. Untargeted MS analyses coupled to a dedicated data processing workflow allowed expanding the current knowledge on these berries, improving our understanding of the fate of phenolic compounds after fermentation.

Spinal Cord Injury Causes Marked Tissue Rearrangement in the Urethra-Experimental Study in the Rat.

Traumatic spinal cord injury (SCI) results in the time-dependent development of urinary impairment due to neurogenic detrusor overactivity (NDO) and detrusor-sphincter-dyssynergia (DSD). This is known to be accompanied by massive changes in the bladder wall. It is presently less clear if the urethra wall also undergoes remodelling. To investigate this issue, female rats were submitted to complete spinal transection at the T8/T9 level and left to recover for 1 week and 4 weeks. To confirm the presence of SCI-induced NDO, bladder function was assessed by cystometry under urethane anesthesia before euthanasia. Spinal intact animals were used as controls. Urethras were collected and processed for further analysis. Following thoracic SCI, time-dependent changes in the urethra wall were observed. Histological assessment revealed marked urethral epithelium reorganization in response to SCI, as evidenced by an increase in epithelial thickness. At the muscular layer, SCI resulted in strong atrophy of the smooth muscle present in the urethral sphincter. Innervation was also affected, as evidenced by a pronounced decrease in the expression of markers of general innervation, particularly those present in sensory and sympathetic nerve fibres. The present data show an evident impact of SCI on the urethra, with significant histological rearrangement, accompanied by sensory and sympathetic denervation. It is likely that these changes will affect urethral function and contribute to SCI-induced urinary dysfunction, and they deserve further investigation.

Development of Neurogenic Detrusor Overactivity after Thoracic Spinal Cord Injury Is Accompanied by Time-Dependent Changes in Lumbosacral Expression of Axonal Growth Regulators.

Thoracic spinal cord injury (SCI) results in urinary dysfunction, which majorly affects the quality of life of SCI patients. Abnormal sprouting of lumbosacral bladder afferents plays a crucial role in this condition. Underlying mechanisms may include changes in expression of regulators of axonal growth, including chondroitin sulphate proteoglycans (CSPGs), myelin-associated inhibitors (MAIs) and repulsive guidance molecules, known to be upregulated at the injury site post SCI. Here, we confirmed lumbosacral upregulation of the growth-associated protein GAP43 in SCI animals with bladder dysfunction, indicating the occurrence of axonal sprouting. Neurocan and Phosphacan (CSPGs), as well as Nogo-A (MAI), at the same spinal segments were upregulated 7 days post injury (dpi) but returned to baseline values 28 dpi. In turn, qPCR analysis of the mRNA levels for receptors of those repulsive molecules in dorsal root ganglia (DRG) neurons showed a time-dependent decrease in receptor expression. In vitro assays with DRG neurons from SCI rats demonstrated that exposure to high levels of NGF downregulated the expression of some, but not all, receptors for those regulators of axonal growth. The present results, therefore, show significant molecular changes at the lumbosacral cord and DRGs after thoracic lesion, likely critically involved in neuroplastic events leading to urinary impairment.

Appraisal of the pharmacokinetic profile, histopathology and stability studies of a fast dissolving oral film based on natural polysaccharide.

The present research is designed to evaluate the pharmacokinetic profile, histological evaluation, and stability studies of an orodispersible film (ODF) of tizanidine (TZ) and meloxicam (MX) prepared from a natural polysaccharide, i.e., xanthan gum. In vivo release study of TZ and MX was performed in rabbits and results indicated the better pharmacokinetics parameters and improved the oral bioavailability when compared to the oral aqueous suspension and solution of TZ and MX, respectively. The intermediate stability studies were performed at 30±2°C and 65±5% RH, whereas, the accelerated stability studies were carried out at 40±2°C and 75±5% RH, respectively for the duration of six months and results indicated that the ODF was stable for six months without any substantial difference in essential physico-chemical parameters, mechanical attributes, and morphological constraints. The toxicity profile of ODF was determined through histopathology of vital organs after administering the ODF to the rabbits. Histopathology revealed that the tissues of all vital organs are normal and did not exhibit any abnormalities, lesions, or hemorrhage. Therefore, the ODF prepared from xanthan gum exhibited a non-toxic and stable formulation with a better pharmacokinetics profile of MX and TZ.

The urethra in continence and sensation: Neural aspects of urethral function.

AIMS: Traditionally, the urethra has been considered a mere conduit to guide urine from the bladder to the external side of the body. Building evidence indicates that the urethra may directly influence bladder function via mechanisms restricted to the lower urinary tract (LUT). METHODS: Here, we discuss the tissue arrangement of the urethra and addressed the contribution of new paraneuronal cells to LUT function. We also briefly reviewed two frequent LUT pathologies associated with urethral dysfunction. RESULTS: Continence depends on an intact and functional urethral sphincter, composed of smooth, and striated muscle fibers and regulated by somatic and autonomic fibers. Recent studies suggest the existence of an urethro-vesical reflex that also contributes to normal LUT function. Indeed, the urethral lumen is lined by a specialized epithelium, the urothelium, in the proximal urethra. In this region, recent evidence demonstrates the presence of specific paraneuronal cells, expressing the neurotransmitters acetylcholine and serotonin. These cells are in close proximity of nerve fibers coursing in the lamina propria and are able to release neurotransmitters and rapidly induce detrusor contractions, supporting the existence of an urethro-vesical crosstalk. CONCLUSION: The mechanism underlying the fast communication between the urethra and thebladder are beginning to be understood and should involve the interaction between specificepithelial cells and fibres innervating the urethral wall. It is likely that this reflex should bealtered in pathological conditions, becoming an attractive therapeutic target.

Applications of Adductomics in Chemically Induced Adverse Outcomes and Major Emphasis on DNA Adductomics: A Pathbreaking Tool in Biomedical Research.

Adductomics novel and emerging discipline in the toxicological research emphasizes on adducts formed by reactive chemical agents with biological molecules in living organisms. Development in analytical methods propelled the application and utility of adductomics in interdisciplinary sciences. This review endeavors to add a new dimension where comprehensive insights into diverse applications of adductomics in addressing some of society's pressing challenges are provided. Also focuses on diverse applications of adductomics include: forecasting risk of chronic diseases triggered by reactive agents and predicting carcinogenesis induced by tobacco smoking; assessing chemical agents' toxicity and supplementing genotoxicity studies; designing personalized medication and precision treatment in cancer chemotherapy; appraising environmental quality or extent of pollution using biological systems; crafting tools and techniques for diagnosis of diseases and detecting food contaminants; furnishing exposure profile of the individual to electrophiles; and assisting regulatory agencies in risk assessment of reactive chemical agents. Characterizing adducts that are present in extremely low concentrations is an exigent task and more over absence of dedicated database to identify adducts is further exacerbating the problem of adduct diagnosis. In addition, there is scope of improvement in sample preparation methods and data processing software and algorithms for accurate assessment of adducts.

Free fatty acid receptor 1: a ray of hope in the therapy of type 2 diabetes mellitus.

Free fatty acid receptor 1 (FFAR1) is a G-protein coupled receptor with prominent expression on pancreatic beta cells, bones, intestinal cells as well as the nerve cells. This receptor mediates a multitude of functions in the body including release of incretins, secretion of insulin as well as sensation of pain. Since FFAR1 causes secretion of insulin and regulates glucose metabolism, efforts were made to unfold its structure followed by discovering agonists for the receptor and the utilization of these agonists in the therapy of type 2 diabetes mellitus. Development of such functional FFAR1 agonists is a necessity because the currently available therapy for type 2 diabetes mellitus has numerous drawbacks, of which, the major one is hypoglycemia. Since the most prominent effect of the FFAR1 agonists is on glucose concentration in the body, so the major research is focused on treating type 2 diabetes mellitus, though the agonists could benefit other metabolic disorders and neurological disorders as well. The agonists developed so far had one major limitation, i.e., hepatotoxicity. Although, the only agonist that could reach phase 3 clinical trials was TAK-875 developed by Takeda Pharmaceuticals but it was also withdrawn due to toxic effects on the liver. Thus, there are numerous agonists for the varied binding sites of the receptor but no drug available yet. There does seem to be a ray of hope in the drugs that target FFAR1 but a lot more efforts towards drug discovery would result in the successful management of type 2 diabetes mellitus.

Polyphenols Targeting MAPK Mediated Oxidative Stress and Inflammation in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disorder, predominantly symmetric, which causes joint inflammation, cartilage degeneration and bone erosion, resulting in deformity and the loss of physical function. Although the management of RA has steadily improved, the pathophysiological mechanism is incompletely elucidated, and therapeutic options are still limited. Due to shortcomings in the efficacy or safety profiles of conventional RA therapies, therapeutic alternatives have been considered. Therefore, natural extracts containing polyphenolic compounds can become promising adjuvant agents for RA global management, due to their antioxidant, anti-inflammatory and apoptotic properties. Polyphenols can regulate intracellular signaling pathways in RA and can generate different immune responses through some key factors (i.e., MAPK, interleukins (ILs 1 and 6), tumor necrosis factor (TNF), nuclear factor light k chain promoter of activated receptor (NF-κB), and c-Jun N-terminal kinases (JNK)). The critical function of the Toll like-receptor (TLR)-dependent mitogen-activating protein kinase (MAPK) signaling pathway in mediating the pathogenic characteristics of RA has been briefly discussed. Oxidative stress can trigger a change in transcription factors, which leads to the different expression of some genes involved in the inflammatory process. This review aims to provide a comprehensive perspective on the efficacy of polyphenols in mitigating RA by inhibiting signaling pathways, suggesting future research perspectives in order to validate their use.

Zinc supplementation improves the harvest purity of ß-glucuronidase from CHO cell culture by suppressing apoptosis.

The variability of trace metals in cell culture media is a potential manufacturing concern because it may significantly affect the production and quality of therapeutic proteins. Variability in trace metals in CHO cell culture has been shown to impact critical production metrics such as cell growth, viability, nutrient consumption, and production of recombinant proteins. To better understand the influence of excess supplementation, zinc and copper were initially supplemented with 50-µM concentrations to determine the impact on the production and quality of ß-glucuronidase, a lysosomal enzyme, in a parallel bioreactor system. Ethylenediaminetetraacetic acid (EDTA), a metal chelator, was included as another treatment to induce a depletion of trace metal bioavailability to examine deficiency. Samples were drawn daily to monitor cell growth and viability, nutrient levels, ß-glucuronidase activity, and trace zinc flux. Cell cycle analysis revealed the inhibition of sub-G0/G1 species in zinc supplemented cultures, maintaining higher viability compared to the control, EDTA-, and copper-supplemented cultures. Enzyme activity analysis in the harvests revealed higher specific activity of ß-glucuronidase in reactors supplemented with zinc. A confirmation run was conducted with supplementations of zinc at concentrations of 50, 100, and 150 µM. Further cell cycle analysis and caspase-3 analysis demonstrated the role of zinc as an apoptosis suppressor responsible for the enhanced harvest purity of ß-glucuronidase from zinc-supplemented bioreactors.