Advances in analytical technologies for emerging drug modalities and their separation challenges in LC-MS systems.

The last few years have seen a rise in the identification and development of bio-therapeutics through the use of cutting-edge delivery methods or bio-formulations, which has created bio-analytical difficulties. Every year, new bio-pharmaceutical product innovations come out, but the analytical development of these products is challenging. Quantifying the products and components of conjugated molecular structures is essential for preclinical and clinical research in order to guide therapeutic development, given their intrinsic complexity. Furthermore, a significant amount of information is needed for the measurement of these unique modalities by LC-MS techniques. Numerous LC-MS based methods have been developed, including AEX-HPLC-MS, RP-IP-LCMS, HILIC-MS, LCHRMS, Microflow-LC-MS, ASMS, Hybrid LBA/LC-MS, and more. However, these methods continue to face problems, prompting the development of alternative approaches. Therefore, developing bio-molecules that are this complicated and, low in concentration requires a skilled LC-MS based approach and knowledgeable personnel. This review covers general novel modalities classifications, sample preparation techniques, current status and bio-analytical strategies for analyzing various novel modalities, including gene bio-therapeutics, oligonucleotides, antibody-drug conjugates, monoclonal antibodies and PROTACs. It also covers how these strategies have been used in the past and how they are being used now to address challenges in the development of LC-MS based methods, as well as improvement strategies, current advancements and recent developed methods. We additionally covered on the benefits and drawbacks of different LC-MS based techniques for the examination of bio-pharmaceutical products and the future perspectives.

Comparative analysis of plasma affinity depletion methods: Impact on protein composition and phosphopeptide abundance in human plasma.

Affinity-based protein depletion and TiO2 enrichment methods play a crucial role in detection of low-abundant proteins and phosphopeptides enrichment, respectively. Here, we assessed the effectiveness of HSA/IgG (HU2) and Human 7 (HU7) depletion methods and their impact on phosphopeptides coverage through comparative proteome analysis, utilizing in-solution digestion and nano-LC-Orbitrap mass spectrometry (MS). Our results demonstrated that both HU2 and HU7 affinity depletion significantly decreased high-abundant proteins by 1.5-7.8-fold (p < 0.001). A total of 1491 proteins were identified, with 48 proteins showing significant expression in the depleted groups. Notably, cadherin-13, neutrophil defensin 1, APM1, and desmoplakin variant protein were exclusively detected in the HU2/HU7-depleted groups. Furthermore, study on effect of depletion on phosphopeptides revealed an increase in tandem MS spectral counts with notable decrease (∼50%) in peptide spectrum matching in depleted groups, which was attributed to significant reduction in protein counts. Our post translation modification workflow for phosphoproteomics detected 42 phosphorylated peptides, corresponding to 12 phosphoproteins with unique peptide match ≥2 (high false discovery rates confidence). Among them, 10 phosphorylated proteins are highly expressed in depleted groups. Overall, these findings offer valuable insights in selection of protein depletion methods for comprehensive plasma proteomics analysis.

Investigation of antimicrobial susceptibility patterns, risk factors and their impact on mortality in cancer patients at a tertiary care cancer hospital- A prospective study.

BACKGROUND: Cancer patients are vulnerable to infections due to immunosuppression caused by cancer itself and its treatment. The emergence of antimicrobial-resistant bacteria further complicates the treatment of infections and increases the mortality and hospital stays. This study aimed to investigate the microbial spectrum, antimicrobial resistance patterns, risk factors, and their impact on clinical outcomes in these patients. METHODS: A prospective study was conducted at a tertiary care cancer hospital in Patna, Bihar, India, which included cancer patients aged 18 years and older with positive microbial cultures. RESULTS: This study analysed 440 patients, 53% (234) of whom were females, with an average age of 49.27 (± 14.73) years. A total of 541 isolates were identified, among which 48.01% (242) were multidrug resistant (MDR), 29.76% (150) were extensively drug resistant (XDR), and 19.84% (112) were sensitive. This study revealed that patients who underwent surgery, chemotherapy, were hospitalized, had a history of antibiotic exposure, and had severe neutropenia were more susceptible to MDR and XDR infections. The average hospital stays were 16.90 (± 10.23), 18.30 (± 11.14), and 22.83 (± 13.22) days for patients with sensitive, MDR, and XDR infections, respectively. The study also revealed overall 30-day mortality rate of 31.81% (140), whereas the MDR and XDR group exhibited 38.92% and 50.29% rates of 30-day mortality respectively (P < 0.001). Possible risk factors identified that could lead to mortality, were cancer recurrence, sepsis, chemotherapy, indwelling invasive devices such as foley catheter, Central venous catheter and ryles tube, MASCC score (< 21) and pneumonia. CONCLUSIONS: This study emphasizes the necessity for personalized interventions among cancer patients, such as identifying patients at risk of infection, judicious antibiotic use, infection control measures, and the implementation of antimicrobial stewardship programs to reduce the rate of antimicrobial-resistant infection and associated mortality and hospital length of stay.

The Current Landscape in the Development of Small-molecule Modulators Targeting Sphingosine-1-phosphate Receptors to Treat Neurodegenerative Diseases.

Sphingosine 1-phosphate (S1P) is extensively researched as a lysophospholipid and is crucial in various physiological and pathological processes. It achieves this via signalling through five different subtypes of G protein-coupled receptors (GPCRs), namely S1PR1 to S1PR5. S1PR modulators possess the ability to traverse the blood-brain barrier, potentially leading to direct ac-tions within the Central Nervous System (CNS). S1PR modulators specifically bind to receptors located on the surface of naive and central memory lymphocytes, causing these cells to be trapped or confined within the lymph node. The investigation of the S1P pathway has resulted in the ap-proval of three S1PR modulators, namely fingolimod, siponimod, and ozanimod, as medications for the treatment of patients suffering from Multiple Sclerosis (MS). Additionally, new S1PR modulators, such as ponesimod and etrasimod, are currently being developed and tested in clini-cal trials. Research on the creation of S1P modulators in neurodegenerative illnesses is ongoing as scientists continue to explore novel possibilities for selective S1P modulators. This study provides a concise overview of sphingolipid metabolism, the mechanism by which S1P receptors are af-fected, and the structural characteristics of several small molecule S1P modulators, with a particu-lar focus on their structure-activity connections.

Analytical quality by design approach for the development of high-performance liquid chromatography method for simultaneous analysis of metformin and sitagliptin in the presence of major degradation products.

An analytical quality by design-based high-performance liquid chromatography method for determining metformin (MET) and sitagliptin (SIT) in stress-degraded samples was developed and validated. The analytical target profile and risk assessment-driven critical method variables, for example, pH, % aqueous, and buffer concentration, were studied for their effect on method responses of retention time and resolution using a central composite design. The correlation regression coefficient was more than 0.8, and variables interaction was significant on method responses with curvature effect. The method operable design region afforded an aqueous range of 55%-70% and an ortho-phosphoric acid buffer of 0.1% with a pH of 3.0-4.0 as a robust region for the suitable method performance characteristics. The separation of MET and SIT from their degradants (m/z 85.0509; m/z 193.0694) on the C8 column was achieved using a mobile phase consisting of 0.1% ortho-phosphoric acid and methanol (60:40% v/v; pH 3.0). The optimized method eluted MET and SIT at 4.3 ± 0.2 and 7.1 ± 0.2 min, respectively, with acceptable specificity and resolution. The linearity ranges of 25-250 µg/mL (r2 : 0.9982) and 5-50 µg/mL (r2 : 0.9989) was established for MET and SIT, respectively. The % recovery (98.81%-102.17%), precision (0.55%-1.65%), and robustness study for method variables were acceptable.

SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects.

BACKGROUND: Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades. OBJECTIVE: This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer. METHOD: Articles were analysed using search engines and databases namely Pubmed and Scopus. RESULT: Under cancerous circumstances, the level of Inhibitor of Apoptosis Proteins (IAPs) gets elevated, which suppresses the pathway of programmed cell death, plus supports the proliferation of lung cancer. As it is a major apoptosis regulator, natural drugs that imitate the IAP antagonistic response like SMAC mimetic agents/Diablo have been identified to trigger cell death. SMAC i.e. second mitochondria activators of caspases is a molecule produced by mitochondria, stimulates apoptosis by neutralizing/inhibiting IAP and prevents its potential responsible for the activation of caspases. Various preclinical data have proven that these agents elicit the death of lung tumour cells. Apart from inducing apoptosis, these also sensitize the cancer cells toward other effective anticancer approaches like chemo, radio, or immunotherapies. There are many SMAC mimetic agents such as birinapant, BV-6, LCL161, and JP 1201, which have been identified for diagnosis as well as treatment purposes in lung cancer and are also under clinical investigation. CONCLUSION: SMAC mimetics acts in a restorative way in the prevention of lung cancer.

IFN-λ3 is induced by Leishmania donovani and can inhibit parasite growth in cell line models but not in the mouse model, while it shows a significant association with leishmaniasis in humans.

The intracellular protozoan parasite Leishmania donovani causes debilitating human diseases that involve visceral and dermal manifestations. Type 3 interferons (IFNs), also referred to as lambda IFNs (IFNL, IFN-L, or IFN-λ), are known to play protective roles against intracellular pathogens at the epithelial surfaces. Herein, we show that L. donovani induces IFN-λ3 in human as well as mouse cell line-derived macrophages. Interestingly, IFN-λ3 treatment significantly decreased parasite load in infected cells, mainly by increasing reactive oxygen species production. Microscopic examination showed that IFN-λ3 inhibited uptake but not replication, while the phagocytic ability of the cells was not affected. This was confirmed by experiments that showed that IFN-λ3 could decrease parasite load only when added to the medium at earlier time points, either during or soon after parasite uptake, but had no effect on parasite load when added at 24 h post-infection, suggesting that an early event during parasite uptake was targeted. Furthermore, the parasites could overcome the inhibitory effect of IFN-λ3, which was added at earlier time points, within 2-3 days post-infection. BALB/c mice treated with IFN-λ3 before infection led to a significant increase in expression of IL-4 and ARG1 post-infection in the spleen and liver, respectively, and to different pathological changes, especially in the liver, but not to changes in parasite load. Treatment with IFN-λ3 during infection did not decrease the parasite load in the spleen either. However, IFN-λ3 was significantly increased in the sera of visceral leishmaniasis patients, and the IFNL genetic variant rs12979860 was significantly associated with susceptibility to leishmaniasis.

Cronobacter sakazakii infection implicates multifaceted neuro-immune regulatory pathways of Caenorhabditis elegans.

The neural pathways of Caenorhabditis elegans play a crucial role in regulating host immunity and inflammation during pathogenic infections. To understand the major neuro-immune signaling pathways, this study aimed to identify the key regulatory proteins in the host C. elegans during C. sakazakii infection. We used high-throughput label-free quantitative proteomics and identified 69 differentially expressed proteins. KEGG analysis revealed that C. sakazakii elicited host immune signaling cascades primarily including mTOR signaling, axon regeneration, metabolic pathways (let-363 and acox-1.4), calcium signaling (mlck-1), and longevity regulating pathways (ddl-2), respectively. The abrogation in functional loss of mTOR-associated players deciphered that C. sakazakii infection negatively regulated the lifespan of mutant worms (akt-1, let-363 and dlk-1), including physiological aberrations, such as reduced pharyngeal pumping and egg production. Additionally, the candidate pathway proteins were validated by transcriptional profiling of their corresponding genes. Furthermore, immunoblotting showed the downregulation of mTORC2/SGK-1 during the later hours of pathogen exposure. Overall, our findings profoundly provide an understanding of the specificity of proteome imbalance in affecting neuro-immune regulations during C. sakazakii infection.

Fluoride-Induced Mitochondrial Dysfunction and Approaches for Its Intervention.

Fluoride is present everywhere in nature. The primary way that individuals are exposed to fluoride is by drinking water. It's interesting to note that while low fluoride levels are good for bone and tooth growth, prolonged fluoride exposure is bad for human health. Additionally, preclinical studies link oxidative stress, inflammation, and programmed cell death to fluoride toxicity. Moreover, mitochondria play a crucial role in the production of reactive oxygen species (ROS). On the other hand, little is known about fluoride's impact on mitophagy, biogenesis, and mitochondrial dynamics. These actions control the growth, composition, and organisation of mitochondria, and the purification of mitochondrial DNA helps to inhibit the production of reactive oxygen species and the release of cytochrome c, which enables cells to survive the effects of fluoride poisoning. In this review, we discuss the different pathways involved in mitochondrial toxicity and dysfunction induced by fluoride. For therapeutic approaches, we discussed different phytochemical and pharmacological agents which reduce the toxicity of fluoride via maintained by imbalanced cellular processes, mitochondrial dynamics, and scavenging the ROS.

Older PLHIV are at Higher Cardiovascular Risk with Poor Quality of Life.

BACKGROUND: People with HIV (PLHIV) face increased cardiovascular disease (CVD) risk due to inflammation and immune activation. Aging further amplifies this risk. Limited data exist on CVD risk in older PLHIV in India despite 2.14 million PLHIV with higher CVD risk factors. METHODS: In a cross-sectional study in Bihar, India, 73 PLHIV and 30 control participants were enrolled. Demographics, social factors, clinical information, and CVD risk factors were collected. HbA1c levels and lipid profiles were analyzed, and 10-year CVD risk scores were calculated using the Framingham risk score (FRS) and Qrisk3. Quality of life (QoL) was assessed using WHOQOL- HIV-BREF. RESULTS: Results showed higher LDL levels in non-HIV older participants and higher HDL levels in younger PLHIV participants. BMI differed significantly, with higher BMI in non-HIV older individuals and lower BMI in younger PLHIV individuals. Older PLHIV participants had significantly higher mean FRS and Q-Risk scores compared to older non-PLHIV and younger PLHIV groups. Among older PLHIV participants, six had higher CVD risk per FRS, while none in the other groups were classified as high CVD risk. Psychological, social relations and spirituality domains were highly deteriorated in older PLHIV, scoring 44.48, 42.72, and 41.2, respectively. The physical domain scored 57.6, and the environment scored 52.72 in the WHOQOL-HIV bref. CONCLUSION: In conclusion, older PLHIV in Bihar, India, face higher CVD risk compared to younger PLHIV and non-HIV individuals. FRS and Q-Risk scores effectively assessed CVD risk, identifying higher risk in older PLHIV. Age and BMI were significant predictors of high CVD risk. These findings emphasize CVD risk assessment and tailored management for older PLHIV. The QoL assessment findings indicate moderate deterioration in psychological, social relations, and spirituality domains among older PLHIV individuals. These results suggest greater challenges in psychological well-being, social interactions, and spirituality compared to the overall sample. Further research with larger samples and longitudinal designs is needed to confirm and extend these findings.

Development and Validation of Knowledge Attitudes and Practices Questionnaire (Nu-KAPQ): for the assessment of Knowledge, Attitudes, and Practices Associated with Arsenic.

More than 70 million individuals have been exposed to environmental arsenic toxicity, worldwide. United Nation Children's Fund (UNICEF) policy brief -2018 report to mitigate arsenic in drinking water, emphasizes assessing, and changing the knowledge, attitudes, and practices (KAP) as one of the long-term effective solutions to be implemented as a part of surveillance strategies. This study aims to develop a valid and reliable tool to assess knowledge, attitude, and practices of arsenic and its risk in general health. A cross-sectional survey of N=449 general population was conducted in the outpatient department of Rajendra Memorial Research Institute of Medical Sciences-Indian Council for Medical Research for data collection. The construct validation of the questionnaire was done using Exploratory Factor Analysis, Confirmatory factor analysis. The Item-Content Validity Index(I-CVI) and Scale-Content Validity Index (S-CVI) Kappa scores were used to analyze the content validity of the items. The I-CVI ranges from 0.70 to 1, the and the moderate to high cumulative content validity is S-CVI/Universal Agreement=0.84; S-CVI/Average =0.96. Following the principal component analysis, the cumulative Kaiser-Meyer-Olkin measure of sampling adequacy (KMO) was 0.91 and the three domains in the tool (Kaiser-Meyer-Olkin measure of sampling adequacy for Knowledge (0.917), Attitude (0.825) & Practices (0.80)) were within the acceptable range. The Barret's test for sphericity was (P <0.001) and was highly acceptable. The Confirmatory Factor Analysis model of Nu-KAP has demonstrated excellent model fit where, majority of fit indices has sown good fit (X2/df=1.88, Root Mean Square Error of Approximation = 0.04, Comparative Fit Index=0.98, Goodness of Fit Index = 0.93, and Tucker Lewis Index=0.977). The Cronbach's alpha of 19 item tool was 0.72. The Nu-KAPQ questionnaire demonstrated exceptional validity and reliability while also capturing and integrating all pertinent psychometric analytic domains. Conclusively, this questionnaire can be used to assess psychometric properties associated with arsenic bridging the gap in current research to understand people's perception towards arsenic, since it is a crucial component of arsenic mitigation.

Investigation of the anti-cancer potential of epoxyazadiradione in neuroblastoma: experimental assays and molecular analysis.

Neuroblastoma, the most common childhood solid tumor, originates from primitive sympathetic nervous system cells. Epoxyazadiradione (EAD) is a limonoid derived from Azadirachta indica, belonging to the family Meliaceae. In this study, we isolated the EAD from Azadirachta indica seed and studied the anti-cancer potential against neuroblastoma. Herein, EAD demonstrated significant efficacy against neuroblastoma by suppressing cell proliferation, enhancing the rate of apoptosis and cycle arrest at the SubG0 and G2/M phases. EAD enhanced the pro-apoptotic Caspase 3 and Caspase 9 and inhibited the NF-kß translocation in a dose-dependent manner. In order to identify the specific EAD target, a gel-free quantitative proteomics study on SH-SY5Y cells using Liquid Chromatography with tandem mass spectrometry was done in a dose-dependent manner, followed by detailed bioinformatics analysis to identify effects on protein. Proteomics data identified that Enolase1 and HSP90 were up-regulated in neuroblastoma. EAD inhibited the expression of Enolase1 and HSP90, validated by mRNA expression, immunoblotting, Enolase1 and HSP90 kit and flow-cytometry based bioassay. Molecular docking study, Molecular dynamic simulation, and along with molecular mechanics/Poisson-Boltzmann surface area analysis also suggested that EAD binds at the active site of the proteins and were stable throughout the 100 ns Molecular dynamic simulation study. Overall, this study suggested EAD exhibited anti-cancer activity against neuroblastoma by targeting Enolase1 and HSP90 pathways.Communicated by Ramaswamy H. Sarma.

Loganic acid protects against ulcerative colitis by inhibiting TLR4/NF-κB mediated inflammation and activating the SIRT1/Nrf2 anti-oxidant responses in-vitro and in-vivo.

Ulcerative colitis (UC) is an idiopathic, chronic disorder of the intestines characterized by excessive inflammation and oxidative stress. Loganic acid (LA) is an iridoid glycoside reported to have antioxidant and anti-inflammatory properties. However, the beneficial effects of LA on UC are unexplored yet. Thus, this study aims to explore the potential protective effects of LA and its possible mechanisms. In-vitro models were employed using LPS-stimulated RAW 264.7 macrophage cells, and Caco-2 cells, whereas an in-vivo model of ulcerative colitis was employed using 2.5% DSS in BALB/c mice. Results indicated that LA significantly suppressed the intracellular ROS levels and inhibited the phosphorylation of NF-κB in both RAW 264.7 and Caco-2 cells, contrarily LA activated the Nrf2 pathway in RAW 264.7 cells. In DSS-induced colitis mice, LA significantly alleviated the inflammation and colonic damage by decreasing the pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, and IFN-γ), oxidative stress markers (MDA, and NO), and also expression levels of various inflammatory proteins (TLR4 and NF-кB) which was evidenced by immunoblotting. On the contrary, the release of GSH, SOD, HO-1, and Nrf2 were profoundly increased upon LA treatment.Subsequently, molecular docking studies showed that LA interacts with active site regions of target proteins (TLR4, NF-κB, SIRT1, and Nrf2) through hydrogen bonding and salt bridge interaction. The current findings demonstrated that LA could exhibit a protective effect in DSS-induced ulcerative colitis through its anti-inflammatory and anti-oxidant effects via inactivating the TLR4/NF-κB signaling pathway and activating the SIRT1/Nrf2 pathways.

The neuroprotective effect of ascorbic acid against imidacloprid-induced neurotoxicity and the role of HO-1 in mice.

Imidacloprid (IMI) is not only a neurotoxic agricultural pesticide but also a possible food contaminant. The aims of this study were to (1) explore the relationship between recurrent IMI administration and neuronal toxicity in mice and (2) evaluate the potential neuroprotective effect of ascorbic acid (AA), a substance with significant free radical scavenger and having property to block the inflammatory pathways. Mice were categorized as naïve controls (administered vehicles for 28 days); the IMI-treatment animal group (administered po 45-mg/kg body weight of IMI per day for 28 days); and the IMI + AA treatment animal group (administered the same IMI dose + 200 mg/kg of AA orally for 28 days). On day 28, memory losses were assessed using the Y-maze and novel target identification behavioral tests. Mice were sacrificed 24 h after the final IMI treatments, as well as hippocampus tissues, were utilized to determine histological assessments, oxidative stress biomarkers, and Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression levels. The findings demonstrated that IMI-treated mice had substantial impairment of spatial and non-spatial memory functions, as well as reduced antioxidant enzyme and acetylcholinesterase activity. The AA neuroprotective action was achieved through the suppression of the HO-1 expression as well as the stimulation of Nrf2 expression in hippocampal tissues. In summary, recurrent IMI exposure causes oxidative stress and neurotoxicity in mice, and the administration of AA significantly reduces the IMI toxicity possibly by the activation of the HO-1/Nrf2 pathway.

Monoamine Oxidase: A Potential Link in Papez circuit to Generalized Anxiety Disorders.

Anxiety is a common mental illness that affects a large number of people around the world, and its treatment is often based on the use of pharmacological substances such as benzodiazepines, serotonin, and 5-hydroxytyrosine (MAO) neurotransmitters. MAO neurotransmitters levels are deciding factors in the biological effects. This review summarizes the current understanding of the MAO system and its role in the modulation of anxiety-related brain circuits and behavior. The MAO-A polymorphisms have been implicated in the susceptibility to generalized anxiety disorder (GAD) in several investigations. The 5-HT system is involved in a wide range of physiological and behavioral processes, involving anxiety, aggressiveness, stress reactions, and other elements of emotional intensity. Among these, 5-HT, NA, and DA are the traditional 5-HT neurons that govern a range of biological activities, including sleep, alertness, eating, thermoregulation, pains, emotion, and memory, as anticipated considering their broad projection distribution in distinct brain locations. The DNMTs (DNA methyltransferase) protein family, which increasingly leads a prominent role in epigenetics, is connected with lower transcriptional activity and activates DNA methylation. In this paper, we provide an overview of the current state of the art in the elucidation of the brain's complex functions in the regulation of anxiety.

Serratiopeptidase Attenuates Lipopolysaccharide-Induced Vascular Inflammation by Inhibiting the Expression of Monocyte Chemoattractant Protein-1.

Lipopolysaccharide (LPS) has potent pro-inflammatory properties and acts on many cell types including vascular endothelial cells. The secretion of the cytokines MCP-1 (CCL2), interleukins, and the elevation of oxidative stress by LPS-activated vascular endothelial cells contribute substantially to the pathogenesis of vascular inflammation. However, the mechanism involving LPS-induced MCP-1, interleukins, and oxidative stress together is not well demonstrated. Serratiopeptidase (SRP) has been widely used for its anti-inflammatory effects. In this research study, our intention is to establish a potential drug candidate for vascular inflammation in cardiovascular disorder conditions. We used BALB/c mice because this is the most successful model of vascular inflammation, suggested and validated by previous research findings. Our present investigation examined the involvement of SRP in vascular inflammation caused by lipopolysaccharides (LPSs) in a BALB/c mice model. We analyzed the inflammation and changes in the aorta by H&E staining. SOD, MDA, and GPx levels were determined as per the instructions of the kit protocols. ELISA was used to measure the levels of interleukins, whereas immunohistochemistry was carried out for the evaluation of MCP-1 expression. SRP treatment significantly suppressed vascular inflammation in BALB/c mice. Mechanistic studies demonstrated that SRP significantly inhibited the LPS-induced production of proinflammatory cytokines such as IL-2, IL-1, IL-6, and TNF-α in aortic tissue. Furthermore, it also inhibited LPS-induced oxidative stress in the aortas of mice, whereas the expression and activity of monocyte chemoattractant protein-1 (MCP-1) decreased after SRP treatment. In conclusion, SRP has the ability to reduce LPS-induced vascular inflammation and damage by modulating MCP-1.

Deuterated driven new chemical entities: An optimistic way to improve therapeutic efficacy.

In organic chemistry, the use of deuterium exchange as a tool to study the mechanism of chemical reaction has been well explored. Since two decades, the research focus on deuterated bioactive molecules has been gaining attention for investigating the therapeutic potential of deuterium replacement in a chemical structure. Recently, Food Drug Administration (FDA) approved the first deuterium-labeled drug "deutetrabenazine", and notified the deuterated drugs as new chemical entities (NCEs). Henceforth, the deuterium substitution driven structure activity relationship, preclinical pharmacokinetics, and toxicity studies were much initiated. Deuteration of a bioactive molecule often results in improved therapeutic efficacy due to the altered pharmacokinetic profile. This review provides a conceptual framework on the importance of deuterium atom in chemical structure of a drug, and its biological value in improved physiochemical properties, pharmacokinetics, biological target interaction, diagnosis, and toxicity. In addition, this review concisely updated the recent deuteration methods, chemical stability, challenges in drug development, deuterium-based imaging in diagnosis, and selected synthetic scheme of deuterated molecules.

CD4 + Count: a Variable to Be Considered to Prioritize COVID-19 Vaccination in PLHIV.

The outbreak of the COVID-19 propagates, pressurizing the healthcare system by emphasizing and worsening the inequities. While many vaccines have shown excellent efficacy in protecting the general public from the COVID-19 infection, the efficacy of these vaccines for people living with HIV (PLHIV), especially those having a different range of CD4 + T-cell, has yet to be thoroughly investigated. Few studies have uncovered the escalated infection and death rates due to the COVID-19 infection in individuals with low CD4 + T-cells. Additionally, PLHIV has a low CD4 + count; furthermore, specific CD4 + T cells for coronavirus have a vigorous Th1 role and are related to the protective antibody responses. Follicular helper T cells (TFH) are vulnerable to HIV and virus-specific CD4 & CD8 T-cells which are essential for viral infection clearance and defective immune responses which further contributes to the development of illness. The specific CD8 & CD4 + T-cell reaction to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was identified in almost all COVID-19 recovered individuals, which is related to the size of antibodies of immunoglobulin G. It has previously been demonstrated that PLHIV has decreased responses to certain vaccines and that these responses are reliant on CD4 + T-cell levels. COVID-19 vaccines will likely have a lower response or limited effect, in PLHIV having low CD4 + T-cells.

Epigenetic basis for PARP mutagenesis in glioblastoma: A review.

Several modifications in the glioblastoma genes are caused by epigenetic modifications, which are crucial in appropriate developmental processes such as self-renewal and destiny determination of neural stem cells. Poly (ADP-ribose)polymerase (PARP) is an essential cofactor involved in DNA repair as well as several other cellular functions such as transcription and chromatin shape modification. Inhibiting PARP has evolved for triggering cell damage in cancerous cells when paired with certain other anticancer drugs including temozolomide (TMZ). PARP1 is involved with in base excision repair (BER) pathway, however its functionality differs across types of tumours. Epigenomics as well as chromosomal statistics have contributed to the growth of main subgroups of glioma, which serve as foundation for the categorization of central nervous system (CNS) tumours as well as a unique classification based only on DNA methylation information, which demonstrates extraordinary diagnostic accuracy. Unfortunately, not all patients respond to PARP inhibitors (PARPi), and there is no way to anticipate who will and who will not. In this field, PARPi are one of the innovative medicines currently being explored. As a result, cancer cells that also have a homologous recombination defect become fatal synthetically. As well as preparing the tumour microenvironment for immunotherapy, PARPi may enhance the lethal effects of chemotherapy and radiotherapy. This article analyzes the justification and clinical evidence for PARPi in glioma to offer potential therapeutic approaches. Despite the effectiveness of these targeted drugs, researchers have looked into a number of resistance mechanisms as well as the growing usage of PARPi in clinical practice for the treatment of various malignancies.

The Possible Role of Selected Vitamins and Minerals in the Therapeutic Outcomes of Leishmaniasis.

Leishmaniasis is a protozoal disease declared as an endemic in areas suffering from severe malnutrition and poverty. The factors associated with poverty like low income, ecological factors, and malnutrition cause disruption in immunity and host defense increasing risk of infection. Altered resistance to infection and host susceptibility are associated with low micronutrient levels in undernourished patients. Malnutrition has been recognized as a poor predictive marker for leishmaniasis, in particular the deficiency of trace elements like zinc, iron, and vitamin A, B, C, D which has a prominent function in the regulation of innate and adaptive immunity, cell proliferation, human physiology, etc. Malnourishment can exacerbate host sensitivity and pathophysiologic intensity to infection in variety of ways, whereas infection can enhance underlying poor nutrition or enhance host vulnerability and sandfly's urge to attack specific hosts. The intensity of leishmaniasis can be influenced by body mass and micronutrient availability in the blood. Vitamin D, C, zinc, and iron are proved effective in inhibiting the growth of leishmaniasis in both amastigote or promastigote forms, either directly or by acting as precursor for a pathway which inhibits the parasite growth. This article elucidates a new perception to the crucial role of micronutrients and their probable role in the therapeutic outcomes of leishmaniasis. Since there is requirement of novel drugs to fight drug resistance and relapse of leishmaniasis, this article may pave way to understand the importance of micronutrients and their role in therapeutic outcomes of leishmaniasis.