Cardioprotective potential of compound 3K, a selective PKM2 inhibitor in isoproterenol-induced acute myocardial infarction: A mechanistic study.

Myocardial infarction (MI) or heart attack arises from acute or chronic prolonged ischemic conditions in the myocardium. Although several risk factors are associated with MI pathophysiology, one of the risk factors is an imbalance in the oxygen supply. The current available MI therapies are still inadequate due to the complexity of MI pathophysiology. Pyruvate kinase M2 (PKM2) has been implicated in numerous CVDs pathologies. However, the effect of specific pharmacological intervention targeting PKM2 has not been studied in MI. Therefore, in this study, we explored the effect of compound 3K, a PKM2-specific inhibitor, in isoproterenol-induced acute MI model. In this study, in order to induce MI in rats, isoproterenol (ISO) was administered at a dose of 100 mg/kg over two days at an interval of 24 h. Specific PKM2 inhibitor, compound 3K (2 and 4 mg/kg), was administered in MI rats to investigate its cardioprotective potential. After the last administration of compound 3K, ECG and hemodynamic parameters were recorded using a PV-loop system. Cardiac histology, western blotting, and plasmatic cardiac damage markers were evaluated to elucidate the underlying mechanisms. Treatment of compound 3K significantly reduced ISO-induced alterations in ECG, ventricular functions, cardiac damage, infarct size, and cardiac fibrosis. Compound 3K treatment produced significant increase in PKM1 expression and decrease in PKM2 expression. In addition, HIF-1α, caspase-3, c-Myc, and PTBP1 expression were also reduced after compound 3K treatment. This study demonstrates the cardioprotective potential of compound 3K in MI, and its mechanisms of cardioprotective action.

Outcome of forgotten biliary stents for more than five years-A two-decade experience.

BACKGROUND AND OBJECTIVES: Prolonged biliary stenting may lead to complications such as cholangitis, stentolith and stent migration. There is limited data on forgotten biliary stents for more than five years in literature. The aim of this retrospective study was to analyze the complications and outcomes in patients who forgot to get their biliary stents removed or exchanged for more than five years. METHODS: The study population included patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) and plastic biliary stent placements in a tertiary care center from 1990 to 2022 for benign biliary diseases. Loss to follow-up and subsequent forgotten stent for more than five years were observed in 40 patients who underwent ERCP during this study period. We retrospectively analyzed the indications of stenting, present status of stent, complications and outcomes in the study patients. RESULTS: The mean age of the study patients was 51.5 ± 11.5 years with 27 females. Indications of biliary stent placement were choledocholithiasis (33, 82.5%), bile leak (3, 7.5%), benign biliary stricture (2, 5%) and choledochal cyst (2, 5%). The mean duration of forgotten stent was 5.9 ± 3.6 years. Presenting symptoms were abdominal pain (37, 92.5%), fever (26, 65%) and jaundice (32, 80%). Most commonly placed stent was 7 French double pigtail of 10 cm length. Complications in the study patients were cholangitis (35, 87.5%), internal migration (2, 5%), pancreatitis (1, 2.5%) and portal hypertension (1, 2.5%). The outcomes were stone removal (30, 90.9%), stent removal (31, 77.5%), stent reinsertion (19, 47.5%), broken stent (3, 7.5%) and surgery (2, 5%). CONCLUSIONS: Prolonged duration (> 5 years) of forgotten stent is uncommon and is observed most commonly in patients with choledocholithiasis. The most common complication of long duration of forgotten stents was cholangitis followed by internal migration, pancreatitis and portal hypertension. Stone and stent removal was successful in a majority of patents, while surgery was required in less number of patients.

An insight into crosstalk among multiple signalling pathways contributing to the pathophysiology of PTSD and depressive disorders.

Post-traumatic stress disorder (PTSD) and depressive disorders represent two significant mental health challenges with substantial global prevalence. These are debilitating conditions characterized by persistent, often comorbid, symptoms that severely impact an individual's quality of life. Both PTSD and depressive disorders are often precipitated by exposure to traumatic events or chronic stress. The profound impact of PTSD and depressive disorders on individuals and society necessitates a comprehensive exploration of their shared and distinct pathophysiological features. Although the activation of the stress system is essential for maintaining homeostasis, the ability to recover from it after diminishing the threat stimulus is also equally important. However, little is known about the main reasons for individuals' differential susceptibility to external stressful stimuli. The solution to this question can be found by delving into the interplay of stress with the cognitive and emotional processing of traumatic incidents at the molecular level. Evidence suggests that dysregulation in these signalling cascades may contribute to the persistence and severity of PTSD and depressive symptoms. The treatment strategies available for this disorder are antidepressants, which have shown good efficiency in normalizing symptom severity; however, their efficacy is limited in most individuals. This calls for the exploration and development of innovative medications to address the treatment of PTSD. This review delves into the intricate crosstalk among multiple signalling pathways implicated in the development and manifestation of these mental health conditions. By unravelling the complexities of crosstalk among multiple signalling pathways, this review aims to contribute to the broader knowledge base, providing insights that could inform the development of targeted interventions for individuals grappling with the challenges of PTSD and depressive disorders.

Inhibition of Pyruvate kinase M2 (PKM2) by shikonin attenuates isoproterenol-induced acute myocardial infarction via reduction in inflammation, hypoxia, apoptosis, and fibrosis.

Myocardial infarction (MI) is a major cause of mortality and disability globally. MI results from acute or chronic myocardial ischemia characterized by an imbalance of oxygen demand and supply, leading to irreversible myocardial injury. Despite several significant efforts in the understanding of MI, the therapy of MI is not satisfactory due to its complicated pathophysiology. Recently, therapeutic potential of targeting pyruvate kinase M2 (PKM2) has been postulated in several cardiovascular diseases. PKM2 gene knockout and expression studies implicated the role of PKM2 in MI. However, the effects of pharmacological interventions targeting PKM2 have not been investigated in MI. Therefore, in the present study, effect of PKM2 inhibitor has been investigated in the MI along with elucidation of possible mechanism(s). MI in rats was induced by administrations of isoproterenol (ISO) at a dose of 100 mg/kg s.c. for two consecutives days at 24-h interval. At the same time, shikonin (PKM2 inhibitor) was administered at 2 and 4 mg/kg in ISO-induced MI rats. After the shikonin treatment, the ventricular functions were measured using a PV-loop system. Plasma MI injury markers, cardiac histology, and immunoblotting were performed to elucidate the molecular mechanism. Treatment of shikonin 2 and 4 mg/kg ameliorated cardiac injury, reduced infarct size, biochemical alterations, ventricular dysfunction, and cardiac fibrosis in ISO-induced MI. Expression of PKM2 in the ventricle was reduced while PKM1 expression increased in the shikonin treated group, indicating PKM2 inhibition restores PKM1 expression. In addition, PKM splicing protein (hnRNPA2B1 & PTBP1), HIF-1α, and caspase-3 expression were reduced after shikonin treatment. Our findings suggest that pharmacological inhibition of PKM2 with shikonin could be a potential therapeutic strategy to treat MI.

Engineered polyspecific antibodies: A new frontier in the field of immunotherapeutics.

The 21st-century beginning remarked with the huge success of monospecific MAbs, however, in the last couple of years, polyspecific MAbs (PsAbs) have been an interesting topic and show promise of being biobetter than monospecific MAbs. Polyspecificity, in which a single antibody serves multiple specific target binding, has been hypothesized to contribute to the development of a highly effective antibody repertoire for immune defence. This polyspecific MAb trend represents an explosion that is gripping the whole pharmaceutical industry. This review is concerned with the current development and quality enforcement of PsAbs. All provided literature on monospecific MAbs and polyspecific MAbs (PsAbs) were searched using various electronic databases such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent and books via the keywords Antibody engineering, Polyspecific antibody, Conventional antibody, non-conventional antibody, and Single domain antibody. In the literature, there are more than 100 different formats to construct PsAb by quadroma technology, chemical conjugation and genetic engineering. Till March 2023, nine PsAb have been approved around the world, and around 330 are in advanced developmental stages, showing the dominancy of PsAb in the growing health sector. Recent advancements in protein engineering techniques and the fusion of non-conventional antibodies have made it possible to create complex PsAbs that demonstrate higher stability and enhanced potency. This marks the most significant achievement for cancer immunotherapy, in which PsAbs have immense promise. It is worth mentioning that seven out of the nine PsAbs have been approved as anti-cancer therapy. As PsAbs continue to acquire prominence, they could pave the way for the development of novel immunotherapies for multiple diseases.

Recombinant human endostatin as a potential anti-angiogenic agent: therapeutic perspective and current status.

Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and their affordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.

BTD: A TRPC5 activator ameliorates mechanical allodynia in diabetic peripheral neuropathic rats by modulating TRPC5-CAMKII-ERK pathway.

Mechanical allodynia is a serious complication of painful diabetic neuropathy (PDN) with limited treatment options. The transient receptor potential canonical 5 (TRPC5) channel is a promising target in pain; however, its role in painful diabetic neuropathy has not yet been elucidated. In this study, we have investigated the role of TRPC5 channels using BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl)-propanamide)],a potent TRPC5 activator and HC070, as TRPC5 channel inhibitor in rat model of PDN. In this study, streptozotocin was used to induce diabetes in male Sprague-Dawley rats. The alterations in mechanical and thermal pain thresholds, nerve functional deficits in diabetic animals were assessed by various behavioral and functional parameters.TRPC5 involvement was investigated by treating neuropathic rats with BTD, TRPC5 channel activator (1 and 3 mg/kg, i.p. for 14 days) and HC070, a TRPC5 channel inhibitor (1 and 3 mg/kg). BTD and HC070 effects in pain reduction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the lumbar spinal cord. BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated mechanical allodynia but not thermal hyposensation or nerve functional deficit in diabetic neuropathic rats. BTD treatment down-regulated TRPC5 expression by increasing the activity of protein kinase C. It also subsequently down-regulated the downstream pain markers (CAMKII, ERK) in the spinal cord. Additionally, a decrease in inflammatory cytokines (TNF-α, IL-6) also demonstrated BTD's potent anti-inflammatory properties in reducing mechanical allodynia. On the other hand, HC070 did not exert any beneficial effects on behavioural and nerve functional parameters. The study concludes that BTD ameliorated mechanical allodynia in a rat model of painful diabetic neuropathy not only through modulation of the TRPC5-CAMKII-ERK pathway but also through its anti-inflammatory and anti-apoptotic properties. Overall, BTD is a promising therapeutic molecule in the treatment of mechanical allodynia in painful diabetic neuropathy.

Aetiology and clinical spectrum of gastric outlet obstruction in North West India.

Our study to evaluate the aetiological and clinical spectrum of gastric outlet obstruction (GOO) in North-west India showed malignant cause (54.9%) was more common than benign (45.1%). Common causes of malignancy were gall bladder (37.5%), gastric (31.8%) and pancreatic carcinoma (19.6%); commonest benign causes were opioid abuse (29%), peptic ulcer disease (21.6%), ingestion of corrosives (20.2%) and chronic pancreatitis (12.3%).

Amelioration of Parkinson's disease by pharmacological inhibition and knockdown of redox sensitive TRPC5 channels: Focus on mitochondrial health.

AIMS: Transient receptor potential canonical 5 (TRPC5) channels are redox-sensitive cation-permeable channels involved in temperature and mechanical sensation. Increased expression and over-activation of these channels has been implicated in several central nervous system disorders such as epilepsy, depression, traumatic brain injury, anxiety, Huntington's disease and stroke. TRPC5 channel activation causes increased calcium influx which in turn activates numerous downstream signalling pathways involved in the pathophysiology of neurological disorders. Therefore, we hypothesized that pharmacological blockade and knockdown of TRPC5 channels could attenuate the behavioural deficits and molecular changes seen in CNS disease models such as MPTP/MPP+ induced Parkinson's disease (PD). MATERIALS AND METHODS: In the present study, PD was induced after bilateral intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the Sprague Dawley rats. Additionally, SH-SY5Y neurons were exposed to 1-methyl-4-phenylpyridinium (MPP+) to further determine the role of TRPC5 channels in PD. KEY FINDINGS: We used clemizole hydrochloride, a potent TRPC5 channel blocker, to reverse the behavioural deficits, molecular changes and biochemical parameters in MPTP/MPP+-induced PD. Furthermore, knockdown of TRPC5 expression using siRNA also closely phenocopies these effects. We further observed restoration of tyrosine hydroxylase levels and improved mitochondrial health following clemizole treatment and TRPC5 knockdown. These changes were accompanied by diminished calcium influx, reduced levels of reactive oxygen species and decreased apoptotic signalling in the PD models. SIGNIFICANCE: These findings collectively suggest that increased expression of TRPC5 channels is a potential risk factor for PD and opens a new therapeutic window for the development of pharmacological agents targeting neurodegeneration and PD.

Transient Receptor Potential Canonical 5 (TRPC5) Channels Activator, BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4- benzothiadiazin-3-yl)-propanamide)] Ameliorates Diabetic Cardiac Autonomic Neuropathy in Rats.

BACKGROUND: Diabetic cardiac autonomic neuropathy (DCAN) is a serious diabetic complication with no approved pharmacological agents for its treatment. Parasympathetic system dysfunction characterized by vagal nerve damage is one of the major drivers of DCAN. The TRPC5 or transient receptor potential canonical 5 channel is a promising target in autonomic dysfunction; however, its role in vagal nerve damage and subsequent DCAN has not yet been elucidated. The present study investigated the role of the TRPC5 channel in DCAN using [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl) propanamide)] or BTD, which is a potent TRPC5 activator. OBJECTIVES: The role of the TRPC5 channel and its activator, BTD, was investigated in the treatment of parasympathetic dysfunction associated with DCAN. METHODS: Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin. The alterations in cardiac autonomic parameters in diabetic animals were assessed by heart rate variability, hemodynamic parameters, and baroreflex sensitivity. TRPC5's role in DCAN was investigated by treating diseased rats with BTD (1 and 3 mg/kg, i.p. for 14 days). BTD's beneficial effects in parasympathetic dysfunction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the vagus nerve. RESULTS: BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated heart rate variability, hemodynamic dysfunction, and baroreflex sensitivity in diseased rats. BTD treatment down regulated TRPC5 expression by increasing the activity of protein kinase C in the vagus nerve. It also down-regulated the apoptotic marker CASPASE-3 and also exerted potent anti-inflammatory action on pro-inflammatory cytokines levels in the vagus. CONCLUSION: BTD ameliorated parasympathetic dysfunction associated with DCAN by virtue of its TRPC5 modulatory, anti-inflammatory, and anti-apoptotic properties.

2-Aminoethoxydiphenyl borate ameliorates mitochondrial dysfunctions in MPTP/MPP+ model of Parkinson's disease.

Mitochondrial dysfunction is closely linked with the pathophysiology of several neurodegenerative disorders including Parkinson's disease (PD). Despite several therapeutic advancements related to symptomatic modification of PD pathology, strategies targeting mitochondrial dysfunctions remain largely elusive. Recently, transient receptor potential (TRP) channels have been shown to play a pivotal role in the control of mitochondrial and neuronal functioning in PD. In this study, the effect of 2-aminoethoxydiphenyl borate (2-APB), TRP channel blocker was investigated in the context of mitochondrial dysfunctions in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administered Sprague Dawley rats. MPP+-treated SH-SY5Y cells exhibited reductions in cell viability, generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Co-treatment with 2-APB led to an increase in cell viability, reduction in intracellular and mitochondrial ROS and improvement in mitochondrial membrane potential compared to MPP+-treated SH-SY5Y cells. In addition, intranigral administration of MPTP led to a significant reduction in motor function in the rats. Fourteen days of 2-APB (3 and 10 mg/kg, i.p.) treatment improved behavioural parameters. MPTP-induced decrease in complex I activity and mitochondrial potential were also blocked by 2-APB in the mitochondria isolated from the brain regions i.e. midbrain and striatum. MPTP-induced decrease in tyrosine hydroxylase levels were also restored by 2-APB. Moreover, MPTP-induced reduction in proteins involved in mitochondrial biogenesis, viz. peroxisome proliferator-activated-receptor-gamma coactivator and mitochondrial transcription factor-A were increased after 2-APB treatment in vivo. In summary, 2-APB has a promising neuroprotective role in the MPP+/MPTP models of PD via targeting mitochondrial dysfunctions and biogenesis.

Fused human paraoxonase 1 as a prophylactic agent against organophosphate poisoning.

Organophosphates (OPs) are highly neurotoxic compounds and certain OP-compounds are also exploited as a weapon of mass destruction and chemical warfare in terrorist attacks. Available prophylactic and post-exposure treatments are less effective and also have serious side-effects. Thus, there is a dire need to develop effective and safe prophylactic agent(s) against OP-poisoning. Human Paraoxonase 1 (hPON1) can hydrolyze a wide range of OP molecules and can be developed as an effective and safe prophylactic agent. Thus, there is a dire need in the art to develop variant(s) of rhPON1 that not only possess 'good' OP-hydrolyzing activity but also have improved pharmacokinetic properties. In this report, we describe the characterization of the fused hPON1 (FHP) variant that not only exhibit enhanced in vivo pharmacokinetic properties but also delay / prevent the symptoms of OP-poisoning and prevents OP-induced mortality in rats.

Role of rare-earth oxides, conjugated with [Formula: see text], in the enhancement of power conversion efficiency of dye sensitized solar cells (DSSCs).

Different rare-earth (RE) metal-oxides nano-particles (NPs) viz. Samarium (III) oxide (Sm2O3), Neodymium (III) oxide (Nd2O3), and Gadolinium (III) oxide (Gd2O3) were synthesized using co-precipitation route, and investigated by structural, optical, and morphological studies. Findings and supporting studies were presented to understand the role of RE-metal-oxides NPs as photo-anode material for dye sensitized solar cells (DSSCs) applications. Structural analysis of prepared RE-metaloxides, by X-ray diffraction (XRD), reveals the crystalline nature of the particles ranging from 24 to 37 nm. Morphological study by field emission scanning electron microscopy (FESEM) supports the crystalline nature in the nano range of the prepared RE-metal oxides particles. The observed d values of each sample support the growth of Gd2O3, Nd2O3, and Sm2O3 material. The band-gap of prepared material was estimated from the UV-VIS absorption data and Tauc relation. The observed band gap values are 3.55 eV, 3.31 eV, and 3.52 eV for Gd2O3, Nd2O3, and Sm2O3 respectively. These values are reasonably high compare to the bulk values, indicates the nanostructure formation. Optimized RE-metal oxides NPs employed in the form of TiO2 photo anode for the fabrication of DSSCs. FESEM confirms that the Gd2O3-based photo-anode shows more uniform and decent coverage with more porosity on the TiO2. The EIS measurements of prepared DSSCs also supported the improvement in the photovoltaic output for the modified photo-anode devices as cells with modified photo-anode exhibited less charge recombination at the photo-anode/dye/electrolyte interface with increased electron lifetime leading to improved device performance as compared to the unmodified-based DSSCs. The highest efficiency 5.51% was demonstrated by [Formula: see text]/[Formula: see text] photo-anode-based DSSCs compare to Sm2O3, and Nd2O3 activated photo-anode.

A synbiotic combination of Bifidobacterium longum Bif10 and Bifidobacterium breve Bif11, isomaltooligosaccharides and finger millet arabinoxylan prevents dextran sodium sulphate induced ulcerative colitis in mice.

Decreased bifidobacterial abundance, disrupted gut barrier function, dysregulated immune response and ulceration have been reported in the gut microbiota of IBD patients. Non-digestible carbohydrates with bifidogenic effect enrich the gut microbiota with Bifidobacterium spp. and could help in overcoming inflammatory gut conditions. In this study, the protective effect of Bifidobacterium longum Bif10 and Bifidobacterium breve Bif11; isomaltooligosaccharides (IMOS); Finger millet arabinoxylan (FM-AX) and their Synbiotic mix were evaluated against dextran sodium sulphate (DSS) induced UC in male Balb/c mice for 25 days. All the interventions ameliorated symptoms of colitis such as disease activity index (DAI), histological damage to the colon, gut-bacterial dysbiosis and inflammation. However, the synbiotic mix was more potent in amelioration of some of the parameters such as decreased TNF-α and lipocalin levels; increased anti-inflammatory markers (IL-10 and IL-22), and improved short chain fatty acids (SCFAs) levels in the cecum content. Furthermore, mouse colitis histological scoring (MCHI) also suggested the preventive role of synbiotic mix. All the dietary interventions aid in improving the DAI and immune parameters; restoration or regeneration of the altered selected gut bacteria, enhances the SCFA production, strengthens gut barrier, prevents gut inflammation and decreases the colonic MCHI score in DSS fed mice.

Role of Pyruvate Kinase M2 (PKM2) in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the world's leading cause of death, accounting for 32% of all fatalities. Although therapeutic agents are available for CVDs, however, most of them have significant limitations such as the time-dependency effect, hypotension, and bradycardia. To overcome the limitations of current pharmacological therapies, new molecular targets and pathways need to be identified and investigated to provide better treatment options for CVDs. Recent evidence suggested the involvement of pyruvate kinase M2 (PKM2) and targeting PKM2 by its modulators (inhibitors and activators) has shown promising results in several CVDs. PKM2 regulates gene activation in the context of apoptosis, mitosis, hypoxia, inflammation, and metabolic reprogramming. PKM2 modulators might have a significant impact on the molecular pathways involved in CVD pathogenesis. Therefore, PKM2 modulators can be one of the therapeutic options for CVDs. This review provides an insight into PKM2 involvement in various CVDs along with their therapeutic potential.

Immunomodulatory potential of apolipoproteins and their mimetic peptides in asthma: Current perspective.

Asthma prevailed as a common inflammatory disease affecting mainly the lower respiratory tract, with notable inflammation in the upper airways leading to significant morbidity and mortality. An extensive search for a new therapeutic target is continuously being carried out. Still, the majority have failed in the trials, and eventually, the drugs, including ß2-adrenergic agonists, muscarinic antagonists, and certain corticosteroids, remain the backbone for asthma control. Numerous endogenous factors aid in maintaining the normal homeostasis of the lungs and prevents disease progression. One among them is the apolipoproteins which are different sets of lipoprotein moieties that not only aid in the transport and metabolism of lipids but also impart immunomodulatory roles in various pathologies. Modern research joins the links between the immunomodulatory nature of apolipoproteins in chronic respiratory diseases like asthma and COPD, which can assist in ameliorating the disease progression. Recent studies have elucidated the protective roles of apoA-I and apoE in asthma. This has enabled the utilization of certain apolipoprotein-mimetic peptides to treat these severe pulmonary diseases in the long run. In this review, we have described the prominent and probable mechanistic roles of apolipoproteins like apoA-I, apoB, apoE, apoJ, and apoM in the pathogenesis and treatment of asthma along with the development of apoA-I and apoE-mimetics as a cardinal treatment strategy for eosinophilic as well as corticosteroid resistant neutrophilic asthma.

Apolipoprotein-mimetic Peptides: Current and Future Prospectives.

Apolipoprotein-mimetic peptides, mimicking the biological properties of apolipoproteins, have shown beneficial properties against various diseases (central and peripheral diseases) and have emerged as potential candidates for their treatments. Progress has been made from first-generation to second-generation apolipoprotein-mimetic peptides. Understanding these peptides from the first generation to the second generation is discussed in this review. First, we discussed the structural and therapeutic potentials of first-generation apolipoprotein-mimetic peptides. Further, we discussed the development of second-generation apolipoprotein-mimetic peptides, like dual-domain and bihelical peptides the emergence of second-generation apolipoprotein-mimetic peptides as potential candidates in different preclinical and clinical studies has also been emphasized.

Crosstalk between neurological, cardiovascular, and lifestyle disorders: insulin and lipoproteins in the lead role.

Insulin resistance and impaired lipoprotein metabolism contribute to a plethora of metabolic and cardiovascular disorders. These alterations have been extensively linked with poor lifestyle choices, such as consumption of a high-fat diet, smoking, stress, and a redundant lifestyle. Moreover, these are also known to increase the co-morbidity of diseases like Type 2 diabetes mellitus and atherosclerosis. Under normal physiological conditions, insulin and lipoproteins exert a neuroprotective role in the central nervous system. However, the tripping of balance between the periphery and center may alter the normal functioning of the brain and lead to neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke, depression, and multiple sclerosis. These neurological disorders are further characterized by certain behavioral and molecular changes that show consistent overlap with alteration in insulin and lipoprotein signaling pathways. Therefore, targeting these two mechanisms not only reveals a way to manage the co-morbidities associated with the circle of the metabolic, central nervous system, and cardiovascular disorders but also exclusively work as a disease-modifying therapy for neurological disorders. In this review, we summarize the role of insulin resistance and lipoproteins in the progression of various neurological conditions and discuss the therapeutic options currently in the clinical pipeline targeting these two mechanisms; in addition, challenges faced in designing these therapeutic approaches have also been touched upon briefly.

Neuroprotective Potential of HC070, a Potent TRPC5 Channel Inhibitor in Parkinson's Disease Models: A Behavioral and Mechanistic Study.

Transient receptor potential canonical 5 (TRPC5) channels are predominantly expressed in the striatum and substantia nigra of the brain. These channels are permeable to calcium ions and are activated by oxidative stress. The physiological involvement of TRPC5 channels in temperature and mechanical sensation is well documented; however, evidence for their involvement in the pathophysiology of neurodegenerative disorders like Parkinson's disease (PD) is sparse. Thus, in the present study, the role of TRPC5 channels and their associated downstream signaling was elucidated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+) model of PD. Bilateral intranigral administration of MPTP and 24 h MPP+ exposure were performed to induce PD in the Sprague-Dawley rats and SH-SY5Y cells, respectively. MPTP led to behavioral anomalies and TRPC5 overexpression accompanied by increased calcium influx, apoptosis, oxidative stress, and mitochondrial dysfunctions. In addition, tyrosine hydroxylase (TH) expression was significantly lower in the midbrain and substantia nigra compared to sham animals. Intraperitoneal administration of potent and selective TRPC5 inhibitor, HC070 (0.1 and 0.3 mg/kg) reversed the cognitive and motor deficits seen in MPTP-lesioned rats. It also restored the TH and TRPC5 expression both in the striatum and midbrain. Furthermore, in vitro and in vivo studies suggested improvements in mitochondrial health along with reduced oxidative stress, apoptosis, and calcium-mediated excitotoxicity. Together, these results showed that inhibition of TRPC5 channels plays a crucial part in the reversal of pathology in the MPTP/MPP+ model of Parkinson's disease.

Colon targeted chitosan-melatonin nanotherapy for preclinical Inflammatory Bowel Disease.

Inflammatory Bowel (IBD) is an umbrella term which includes Crohn's Disease (CD) and Ulcerative Colitis (UC). At present, therapies available for management of the UC includes, corticosteroid, immuno-suppressants and antibiotics are used for mild to moderate UC conditions which can cause nephrotoxicity, hepatotoxicity and cardiotoxicity. Hence, a novel therapeutic candidate having potent anti-inflammatory effect is urgently warranted for the management of UC. Melatonin has emerged as a potent anti-inflammatory agent. However, poor solubility limits its therapeutic potential. Therefore, colon targeted Eudragit-S-100 coated chitosan nanoparticles have been demonstrated to improve melatonin therapeutic efficacy. It was found that melatonin loaded chitosan and colon targeted chitosan nanoparticles had promising anti-inflammatory efficacy in terms of NO scavenging activity in an in-vitro LPS challenged macrophages. Also, colon targeted oral chitosan nano-formulation exhibited remarkable protection in an in vivo UC mice model by improving gross pathological parameters, histo-architectural protection, goblet cell depletion, and immune cells infiltration which can be extrapolated to clinical studies.