Dilpreet Kour

@yale.edu

Postdoctoral Associate, Department of Neurology, Yale School of Medicine
Yale University



              

https://researchid.co/dilpreetkour

RESEARCH, TEACHING, or OTHER INTERESTS

Neuroscience, Molecular Biology, Pharmacology

23

Scopus Publications

Scopus Publications

  • Native-state and cell type-specific proteomics using TurboID proximity labeling in mouse models
    Prateek Kumar, Dilpreet Kour, Rashmi Kumari, Wooyoung Eric Jang, Nicholas T. Seyfried, Levi B. Wood, Matthew J. Rowan, and Srikant Rangaraju
    Elsevier

  • Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in primary astrocytes and 5x-FAD mice
    Dilpreet Kour, Parul Khajuria, Kuhu Sharma, Alpa Sharma, Ankita Sharma, Syed Mudassir Ali, Priya Wazir, P. Ramajayan, Sanghapal D. Sawant, Utpal Nandi,et al.
    Frontiers Media SA
    Background and AimAlzheimer’s disease (AD) progresses with Aβ plaque deposition and neuroinflammation. Given the complexity of AD pathology, single-target therapies have frequently failed in clinical trials. We hypothesized that a multitarget approach could yield better therapeutic outcomes. To this end, we identified isobavachalcone (IBC), a natural compound with dual pharmacological activity in reducing Aβ plaques and neuroinflammation.Experimental ProcedurePrimary astrocytes were isolated from 3 to 4 days old C57BL/6J mice pups for in-vitro assays, while in-vivo studies were conducted on 5x-FAD mice. Protein alterations were evaluated using ELISA, western blotting, immunocytochemistry, and immunohistochemistry. Behavioral analyses included the radial arm maze, open field, and rotarod tests. Data from all in vitro and in vivo experiments were analyzed by using one-way ANOVA and post-hoc Bonferroni tests.ResultsIn-vitro analyses in astrocytes demonstrated that IBC at 5 and 10 μM concentrations induce AMPK phosphorylation through CAMKK2, promoting autophagy and inhibiting the NLRP3 inflammasome in primary astrocytes. IBC-treated astrocytes exhibited significant clearance of extracellular amyloid beta. Mechanistic studies highlighted autophagy as a key factor in reducing both NLRP3 inflammasome activity and Aβ levels. Two months of treatment of 5x-FAD mice with IBC at 25 and 50 mg/kg significantly improved cognitive functions, as evidenced by enhanced memory and motor performance in behavioral tests. Subsequent brain tissue analysis revealed that IBC upregulated autophagic proteins to reduce the brain’s amyloid beta levels, resulting in decreased expression of neuroinflammation markers.ConclusionIBC effectively ameliorates AD pathology through autophagy-mediated clearance of Aβ and suppressing neuroinflammation in 5x-FAD mice.

  • ADME/PK Insights of Crocetin: A Molecule Having an Unusual Chemical Structure with Druglike Features
    Diksha Manhas, Sumit Dhiman, Harpreet Kour, Dilpreet Kour, Kuhu Sharma, Priya Wazir, Bhavna Vij, Ajay Kumar, Sanghapal D. Sawant, Zabeer Ahmed,et al.
    American Chemical Society (ACS)

  • EIDD-1931 Treatment Tweaks CYP3A4 and CYP2C8 in Arthritic Rats to Expedite Drug Interaction: Implication in Oral Therapy of Molnupiravir
    Mahir Bhardwaj, Dilpreet Kour, Garima Rai, Srija Bhattacharya, Diksha Manhas, Bhavna Vij, Ajay Kumar, Debaraj Mukherjee, Zabeer Ahmed, Sumit G. Gandhi,et al.
    American Chemical Society (ACS)

  • Site-selective synthesis and pharmacological elucidation of novel semi-synthetic analogues of koenimbine as a potential anti-inflammatory agent
    Nusrit Iqbal Andrabi, Aminur R. Sarkar, Syed Assim Haq, Diljeet kumar, Dilpreet Kour, Diksha Saroch, Sanket Kumar Shukla, Ajay Kumar, Asha Bhagat, Asif Ali,et al.
    Elsevier BV

  • Gentiacaulein inhibits glucose transport to induce PRKAA1-mediated autophagy to clear amyloid beta and associated inflammation in primary astrocytes
    Ankita Sharma, Sukhleen Kaur, Abubakar Wani, Dilpreet Kour, Mehboob Ali, Syed Mudassir Ali, Lakhvinder Singh, Abhishek Gour, Utpal Nandi, Manish Datt,et al.
    Informa UK Limited
    ABSTRACT Being present in substantial numbers, astrocytes play an indispensable role in maintaining homeostasis in the brain. However, their positive or negative involvement in pathological conditions in the brain has not been explored much. In recent years, an emerging thought of targeting astrocytes for the resolution of neurodegenerative diseases has gained momentum. In this study, we have attempted to explore the likelihood of targeting astrocytes by using a natural compound, gentiacaulein (GENT), for clearance of amyloid-β (Aβ) through autophagy and amelioration of neuroinflammation associated with Aβ. We found that GENT treatment of astrocytes hampered the transport of glucose across the cell membrane, which resulted in a reduction in ATP production. With increased treatment time, AMP: ATP ratio was increased significantly, which caused the induction of PRKAA1-mediated autophagy. We further show that increased autophagy considerably enhanced the clearance of amyloid-β by astrocytes. GENT reduced the Aβ mediated inflammation by inhibiting the nuclear translocation of NF-κB and decreased the release of inflammatory cytokines TNF-α and IL-6. The role of PRKAA1 in GENT-induced autophagy and anti-inflammatory activity was confirmed when its knockdown reversed these effects. Our data suggest that targeting astrocytes can be a good strategy to prevent/treat Alzheimer’s disease.

  • Ellagic Acid Exerts Dual Action to Curb the Pathophysiological Manifestations of Sickle Cell Disease and Attenuate the Hydroxyurea-Induced Myelosuppression in Berkeley Mice
    Abhishek Gour, Dilpreet Kour, Ramajayan Pandian, Mahir Bhardwaj, Sanghapal D. Sawant, Ajay Kumar, and Utpal Nandi
    American Chemical Society (ACS)
    The use of adjuvant therapy is an attractive approach to manage sickle cell disease (SCD) symptomatically. The present study aimed to investigate the potential of ellagic acid as an adjuvant therapy with hydroxyurea (HU), a key drug for SCD with myelosuppressive toxic effects. A panel of experiments was performed using SCD patient's blood (ex vivo) and transgenic mice model of SCD (in vivo). Ellagic acid exhibited the following beneficial pharmacological actions: (a) potent anti-sickling, polymerization inhibitory, and inherent non-hemolytic activity; (b) pronounced action to abrogate HU-induced neutropenia and to improve key hematological parameters during SCD (RBC, Hb, platelet levels); (c) considerable action to foster vascular tone (L-proline); (d) marked attenuating effect against oxidative stress (nitrotyrosine, hypoxanthine, MDA, GSH); (e) substantial inhibitory role against inflammation (analgesic activity and regulation of hemin, TNF-α, IL-1β, NF-κB/IκBα); (f) remarkable outcome of declining vaso-occlusive crisis (P-selectin, ERK1/2); (g) notable shielding deed against elevated biochemical marker for organ toxicity (creatinine); (h) noticeably prevented histopathological alterations of the spleen. Additionally, the pharmacokinetic study results of HU in the presence and absence of ellagic acid using a mouse model demonstrate that ellagic acid could be safely co-administered with HU. Overall findings suggest that ellagic acid is a promising candidate for adjuvant therapy in SCD based on its own significant ability against SCD and potentiating capability of HU action via targeting improvement at the various stages of pathophysiological complications during SCD and minimizing HU-induced toxicological manifestations.

  • Molecular mechanism for the involvement of CYP2E1/NF-κB axis in bedaquiline-induced hepatotoxicity
    Pankul Kotwal, Parul Khajuria, Sumit Dhiman, Dilpreet Kour, Shakti Kumar Dhiman, Ajay Kumar, and Utpal Nandi
    Elsevier BV

  • Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice
    Dilpreet Kour, Mehboob Ali, Parul Khajuria, Kuhu Sharma, Palash Ghosh, Sukhleen Kaur, Surbhi Mahajan, P. Ramajayan, Sonali S. Bharate, Subhash Bhardwaj,et al.
    Frontiers Media SA
    Sickle cell disease (SCD) is accompanied by several complications, which emanate from the sickling of erythrocytes due to a point mutation in the β-globin chain of hemoglobin. Sickled erythrocytes are unable to move smoothly through small blood capillaries and therefore, cause vaso occlusion and severe pain. Apart from pain, continuous lysis of fragile sickled erythrocytes leads to the release of heme, which is a strong activator of the NLRP3 inflammasome, thus producing chronic inflammation in sickle cell disease. In this study, we identified flurbiprofen among other COX-2 inhibitors to be a potent inhibitor of heme-induced NLRP3 inflammasome. We found that apart from being a nociceptive agent, flurbiprofen exerts a strong anti-inflammatory effect by suppressing NF-κB signaling, which was evidenced by reduced levels of TNF-α and IL-6 in wild-type and sickle cell disease Berkeley mice models. Our data further demonstrated the protective effect of flurbiprofen on liver, lungs, and spleen in Berkeley mice. The current sickle cell disease pain management regime relies mainly on opiate drugs, which is accompanied by several side effects without modifying the sickle cell disease-related pathology. Considering the potent role of flurbiprofen in inhibiting NLRP3 inflammasome and other inflammatory cytokines in sickle cell disease, our data suggests that it can be explored further for better sickle cell disease pain management along with the possibility of disease modification.

  • In-vitro anti-sickling potential of baicalin and naringenin isolated from Oroxylum indicum and Citrus aurantium on human sickle red blood cells
    Bashir Ahmad Lone, Nitika Sharma, Dilpreet Kour, Anil Bhushan, Dixhiya Rani, Ajay Kumar, Prashant Kumar Gupta, and Prasoon Gupta
    Informa UK Limited
    Abstract Sickle cell disease (SCD) is a rare inherited disorder in which red blood cells (RBCs) under oxidative stress have altered sickle shape resulting in clinical complications. In this study, a library of pure natural products were screened to see their effectiveness in preventing sickling induced in blood samples of SCA patients, ex-vivo. The results indicated that baicalin (1) and naringenin (2), reduced sickling by 46.03 and 37.48 percent, respectively, compared to positive control, 4-hydroxybenzoic acid (4-HBA), which inhibited RBC sickling by 56.87 percent. As a result of this screening, two compounds, baicalin (1) and naringenin (2), have been identified as potent sickling inhibitors. Study has clearly shown promising role of flavonoids for the management of SCD crisis for that not effective therapy is available. These phytochemicals or plant extracts can be explored further as an alternative anti-sickling remedy, owing to their high efficacy in the management of SCD crisis. Graphical Abstract

  • Ayurveda-based phytochemical composition attenuates lung inflammation and precipitates pharmacokinetic interaction with favipiravir: an in vivo investigation using disease-state of acute lung injury
    Abhishek Gour, Ashish Dogra, Mahendra K. Verma, Mahir Bhardwaj, Dilpreet Kour, Ashiya Jamwal, Bapi Gorain, Mukesh Kumar, Bhavna Vij, Ajay Kumar,et al.
    Informa UK Limited
    Abstract Acute respiratory distress syndrome (ARDS) is a critical form of acute lung injury (ALI). Here, we investigated the effect of a defined combination of ten pure phytochemicals in equal proportions of weight (NPM) from plants, recommended by Ayurveda for any protective action against lipopolysaccharide (LPS)-induced ALI. Results indicate that NPM markedly improved protein and neutrophil contents, myeloperoxidase and hydroxyproline levels, oxidative stress markers (glutathione and malonaldehyde), inflammatory cytokines, and genes (IL-6, TNF-α, TGF-β, and NF-κB/IκBα) in BALF/lung tissue. The histopathological examination of the lung revealed the shielding effect of NPM against ALI. NPM exhibited a protective effect on the lung by reducing oxidative stress and inhibiting inflammation. A substantial drop in favipiravir’s oral exposure was observed in ALI-state compared to normal-state, but oral exposure upon NPM treatment in ALI-state followed similar behaviour of favipiravir alike normal-state without NPM treatment. Overall, results offer potential insight into Ayurvedic recommendations for immunity boosting during ALI situations. Graphical abstract

  • Ameliorating effect of rutin against diclofenac-induced cardiac injury in rats with underlying function of FABP3, MYL3, and ANP
    Ashish Dogra, Dilpreet Kour, Abhishek Gour, Mahir Bhardwaj, Swarnendu Bag, Shakti Kumar Dhiman, Ajay Kumar, Gurdarshan Singh, and Utpal Nandi
    Informa UK Limited
    Abstract Diclofenac is a widely prescribed anti-inflammatory drug having cardiovascular complications as one of the main liabilities that restrict its therapeutic use. We aimed to investigate for any role of rutin against diclofenac-induced cardiac injury with underlying mechanisms as there is no such precedent to date. The effect of rutin (10 and 20 mg/kg) was evaluated upon concomitant oral administration for fifteen days with diclofenac (10 mg/kg). Rutin significantly attenuated diclofenac-induced alterations in the serum cardiac markers (LDH, CK-MB, and SGOT), serum cytokine levels (TNF-α and IL-6), and oxidative stress markers (MDA and GSH) in the cardiac tissue. Histopathological examination and Scanning Electron Microscopy (SEM) findings displayed a marked effect of rutin to prevent diclofenac-mediated cardiac injury. Altered protein expression of myocardial injury markers (cTnT, FABP3, and ANP) and apoptotic markers (Bcl-2 and Caspase-3) in the cardiac tissue upon diclofenac treatment was considerably shielded by rutin treatment. MYL3 was unaffected due to diclofenac or rutin treatment. Rutin also significantly improved diclofenac-induced gastrointestinal and hepatic alterations based on the observed ameliorative effects in key mediators, oxidative stress markers, histopathology examination, and SEM findings. Overall results suggest that rutin can protect the diclofenac-induced cardiac injury by lowering oxidative stress, inhibiting inflammation, and reducing apoptosis. Further research work directs toward the development of phytotherapeutics for cardioprotection.

  • Glabridin Plays Dual Action to Augment the Efficacy and Attenuate the Hepatotoxicity of Methotrexate in Arthritic Rats
    Ashish Dogra, Dilpreet Kour, Mahir Bhardwaj, Sumit Dhiman, Amit Kumar, Bhavna Vij, Ajay Kumar, and Utpal Nandi
    American Chemical Society (ACS)
    Glabridin is chemically an isoflavane class of natural phenols and is found mainly in the roots of Glycyrrhiza glabra. It has several beneficial pharmacological actions for the management of inflammatory disorders as well as can counteract drug-induced toxic effects. On the other hand, methotrexate (MTX) is the first-line disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis. However, its treatment is associated with major side effects like hepatotoxicity. In the quest to explore a suitable combination therapy that can improve the efficacy and reduce the hepatotoxicity of MTX, we hypothesized that glabridin might serve the purpose for which there is no literature precedent to date. We explored the antiarthritic efficacy of MTX in the presence or the absence of glabridin using Mycobacterium-induced arthritic model in rats. The results of reduction in paw swelling, inhibition of serum cytokines (TNF-α, IL-6, and IL-1β), and improvement in the bone joints from radiological and histopathological findings suggest that glabridin can substantially augment the antiarthritic efficacy of MTX. Further, results of concomitant glabridin treatment with MTX in the experimental time frame demonstrate that glabridin could considerably prevent the MTX-induced hepatic alteration in serum biochemical markers (SGPT and SGOT) and oxidative stress markers (malondialdehyde (MDA) and glutathione reduced (GSH)). Moreover, glabridin showed a marked effect in impeding the regulation of NF-κB/IκBα and Nrf2/Keap1 pathways in the hepatic tissues. The results of simultaneous administration of glabridin with MTX in the rat model indicate that glabridin had no pronounced effect of causing severe alteration in the pharmacokinetic behavior of MTX. In summary, glabridin can significantly potentiate the antiarthritic efficacy of MTX and can also minimize its hepatotoxicity via the inhibition of inflammation and oxidative stress. Further research should be performed to develop glabridin as a phytotherapeutics for the improved efficacy and better tolerability of MTX at the reduced dose level of MTX.

  • Epicatechin exerts dual action to shield sickling and hydroxyurea-induced myelosuppression: Implication in sickle cell anemia management
    Abhishek Gour, Dilpreet Kour, Ashish Dogra, Diksha Manhas, Priya Wazir, Sanjeev Kumar Digra, Ajay Kumar, and Utpal Nandi
    Elsevier BV

  • Investigating the Potential Use of Andrographolide as a Coadjuvant in Sickle Cell Anemia Therapy
    Abhishek Gour, Pankul Kotwal, Ashish Dogra, Dilpreet Kour, Sumit Dhiman, Amit Kumar, Sanjeev Kumar Digra, Ajay Kumar, Gurdarshan Singh, and Utpal Nandi
    American Chemical Society (ACS)
    Andrographolide is one of the main active principles of Andrographolide paniculata and has been extensively explored for its therapeutic use. Current studies focus on phytotherapeutics-based adjuvant therapy to symptomatically treat sickle cell anemia (SCA) as there is no specific drug/gene therapy available to date. The present study aimed to explore the potential of andrographolide as an adjuvant therapy for SCA in the presence or absence of hydroxyurea (HU), a key drug for SCA treatment. A panel of ex vivo and in vivo experimentations was performed to explore the antisickling activity of andrographolide, followed by evaluating pharmacokinetic and pharmacodynamic (PK/PD) activities in the presence of HU. Andrographolide showed significant antisickling activity using blood from SCA patients (ex vivo) and did not show any deleterious effect to cause hemolysis using rat blood (ex vivo). It displayed a substantial decrease in HU-induced decline in splenic lymphocyte proliferation and cytokine level (TNF-α and IFN-γ) using rat splenocytes (ex vivo). Concomitant oral administration of andrographolide with HU in rats for 15 days exhibited a noticeable improvement in the RBC count and hemoglobin levels comparable to the efficacy of l-glutamine (in vivo). Simultaneous administration of andrographolide with HU caused no marked effect on any pharmacokinetic parameters of HU except the highest plasma concentration of HU and its corresponding time point, which significantly dropped and delayed, respectively (in vivo). No considerable effect of andrographolide was observed on urease and horseradish peroxidase activity (in vitro). Overall, results suggest that andrographolide has several beneficial actions to be an adjuvant therapy to symptomatically manage SCA, but it should be avoided during the prescribed therapy of HU.

  • Tetramethoxystilbene Inhibits NLRP3 Inflammasome Assembly via Blocking the Oligomerization of Apoptosis-Associated Speck-like Protein Containing Caspase Recruitment Domain: In Vitro and in Vivo Evaluation
    Mohd Abdullaha, Mehboob Ali, Dilpreet Kour, Ramesh Mudududdla, Parul Khajuria, Ajay Kumar, and Sandip B. Bharate
    American Chemical Society (ACS)
    Nucleotide-binding domain leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome complex regulates the caspase-1 activity and subsequent processing of interleukin-1β (IL-1β). Various inflammatory diseases involve the activation of inflammasome complexes; thus, the intervention in complex formation via small molecules offers a new therapeutic opportunity. The structure-guided design and synthesis of a series of methoxystilbenes and methoxy-2-phenylnaphthalenes identified new inhibitors of NLRP3 inflammasome complex. The tetramethoxystilbene 4o and trimethoxy 2-phenylnaphthalene 1t inhibit the release of a mature form of IL-1β in J774A.1 cells with IC50 values of 1.39 and 2.07 μM, respectively. Mechanistic investigation revealed that tetramethoxystilbene 4o blocks the oligomerization of apoptosis-associated speck-like protein (ASC), which is the vital step in the formation of NLRP3 inflammasome assembly, thus preventing the activation of caspase-1 and the IL-1β release. Treatment of LPS+ATP challenged mice with 20 mg/kg of 4o significantly suppressed the levels of IL-1β. The data presented herein warrant further investigation of methoxystilbenes in disease-specific models of inflammatory diseases.

  • IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy
    Mehboob Ali, Mehak Gupta, Abubakar Wani, Ankita Sharma, Mohd Abdullaha, Dilpreet Kour, Sushil Choudhary, Sandip B. Bharate, Gurdarshan Singh, and Ajay Kumar
    Frontiers Media SA
    Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.

  • Effect of Concomitant Hydroxyurea Therapy with Rutin and Gallic Acid: Integration of Pharmacokinetic and Pharmacodynamic Approaches
    Abhishek Gour, Ashish Dogra, Dilpreet Kour, Gurdarshan Singh, Ajay Kumar, and Utpal Nandi
    American Chemical Society (ACS)
    Hydroxyurea (HU) is the first-ever approved drug by USFDA for sickle cell anemia (SCA). However, its treatment is associated with severe side effects like myelosuppression. Current studies are focused on the supplementation therapy for symptomatic management of SCA. In the present study, we aimed to explore rutin’s and gallic acid’s potential individually, for concomitant therapy with HU using pharmacokinetic and pharmacodynamic approaches since there is no such precedent till date. In vivo pharmacokinetic studies of HU in rats showed that rutin could be safely co-administered with HU, while gallic acid significantly raised the plasma concentration of HU. Both the phytochemicals did not have any marked inhibitory effect on urease but have considerable effects on horseradish peroxidase enzyme. The experimental phytoconstituents displayed a very low propensity to cause in vitro hemolysis. Gallic acid markedly enhanced the HU-induced decrease in lymphocyte proliferation. A substantial improvement by rutin or gallic acid was observed in HU-induced reduction of the main hematological parameters in rats. Combined treatment of HU with rutin and gallic acid reduced serum levels of both IL-6 and IL-17A. Overall, both rutin and gallic acid are found to have promising phytotherapy potential with HU. Further exploration needs to be done on both candidates for use as phytotherapeutics for SCA.



  • Iodine-NH<inf>4</inf>OAc mediated regioselective synthesis of 2-aroyl-3-arylimidazo[1,2-: A] pyridines from 1,3-diaryl-prop-2-en-1-ones
    Dilpreet Kour, Annah Gupta, Kamal K. Kapoor, Vivek K. Gupta, Rajnikant Rajnikant, Deepika Singh, and Parthasarathi Das
    Royal Society of Chemistry (RSC)
    An efficient, metal-free regioselective synthesis of 2-aroyl-3-arylimidazo[1,2-a]pyridines from 1,3-diaryl-prop-2-en-1-ones has been developed by their reaction with 2-aminopyridine in the presence of I2/NH4OAc.