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Browsing by Author "Jain, Manju"

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Atypical leishmaniasis: A global perspective with emphasis on the Indian subcontinent
(Public Library of Science, 2018) Thakur L.; Singh K.K.; Shanker V.; Negi A.; Jain, Aklank; Matlashewski G.; Jain, Manju
Background: Among the neglected tropical diseases, leishmaniasis continues to be prevalent in many tropical and subtropical countries despite international, national, and local efforts towards its control and elimination over the last decade. This warrants a critical evaluation of such factors as under-reporting, asymptomatic infections, post kala azar dermal leishmaniasis (PKDL) cases, and drug resistance. In this review, we highlight lesser-understood atypical presentations of the disease involving atypical parasite strains against a background of classical leishmaniasis with a focus on the Indian subcontinent. Methods and findings: A literature review based on endemic areas, the nature of disease manifestation, and underlying causative parasite was performed with data collected from WHO reports for each country. Searches on PubMed included the term 'leishmaniasis' and ' eishmaniasis epidemiology' alone and in combination with each of the endemic countries, Leishmania species, cutaneous, visceral, endemic, non-endemic, typical, classical, atypical, and unusual with no date limit and published in English up to September 2017. Our findings portray a scenario with a wider distribution of the disease in new endemic foci, with new discoveries of parasite-driven atypical disease manifestations in different regions of the world. Unlike the classical picture, some Leishmania species are associated with more than one disease presentation, e.g., the L. donovani complex, generally associated with the visceral form, is now also associated with a cutaneous disease presentation, while L. tropica species complex, known to cause cutaneous disease, can cause viscerotropic disease. This phenomenon points towards the discovery of novel parasite variants as etiologic agents of atypical disease manifestations and represents an excellent opportunity to identify and study genes that control disease virulence and tropism. Conclusions: The increased recognition of atypical leishmaniasis as an outcome of parasite variants has major implications for leishmaniasis control and elimination. Identifying molecular correlates of parasite isolates from distinct regions associated with different disease phenotypes is required to understand the current epidemiology of leishmaniasis in regions with atypical disease.-2018 Thakur et al. http://creativecommons.org/licenses/by/4.0/.
The emerging role of long non-coding RNA in gallbladder cancer pathogenesis
(Elsevier B.V., 2017) Khandelwal, Akanksha; Malhotra, Akshay; Jain, Manju; Vasquez, Karen M.; Jain, Aklank; Khandelwal, A.; Malhotra, A.; Jain, M.; Vasquez, K.M.; Jain, A.
Gallbladder cancer (GBC) is the most common and aggressive form of biliary tract carcinoma with an alarmingly low 5-year survival rate. Despite its high mortality rate, the underlying mechanisms of GBC pathogenesis are not completely understood. Recently, from a growing volume of literature, long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression and appear to play vital roles in many human cancers. To date, a number of lncRNAs have been implicated in GBC, but their potential roles in GBC have not been systematically examined. Thus, in this review, we critically discuss the emerging roles of lncRNAs in GBC, and the pathways involved. Specifically, we note that some lncRNAs show greater expression in T1 and T2 tumor stages compared to T3 and T4 tumor stages and that their dysregulation leads to alterations in cell cycle progression and can cause an increase in GBC cell proliferation or apoptosis. In addition, some lncRNAs control the epithelial-mesenchymal transition process, while others take part in the regulation of ERK/MAPK and Ras cancer-associated signaling pathways. We also present their potential utility in diagnosis, prognosis, and/or treatment of GBC. The overall goal of this review is to stimulate interest in the role of lncRNAs in GBC, which may open new avenues in the determination of GBC pathogenesis and may lead to the development of new preventive and therapeutic strategies for GBC. ? 2016 Elsevier B.V. and Soci?t? Fran?aise de Biochimie et Biologie Mol?culaire (SFBBM)
An Insight into Immunopathology of Leishmaniasis
(Springer Nature, 2023-01-31T00:00:00) Chauhan, Yogesh; Nikita, Rajkumari; Madaan, Priyanka; Jain, Manju
Leishmaniasis is a disease complex with clinical manifestations ranging from systemic visceral leishmaniasis (VL) to cutaneous leishmaniasis (CL) with skinrestricted lesions to mucocutaneous leishmaniasis (MCL) that extends to mucous membranes. These classical disease outcomes are understood as an outcome of the infecting parasite species/subspecies along with the immune correlates that define host immune status. Further each of the visceral, cutaneous and/or mucocutaneous disease forms exhibits heterogenous gradation of parasite load, extent of parasite dissemination and collateral host immunopathological damage that may result in asymptomatic, mild, moderate or severe disease phenotype. A complex network of crosstalk between immune cells, viz. neutrophils, macrophages and heterogenous T cells, with varied effector immune molecules defines the disease protective versus progressive response. Unlike a clear Th1 versus Th2 immune response in VL and CL murine models, the immune correlates in classical VL and CL human subjects exhibit a mixed response with considerable heterogeneity. A net balance of the inflammatory versus antiinflammatory immune response induced by the complement of antigen pool presented by discrete parasite species along with the immune regulation mediated by T regulatory cells drives the immunopathological outcome. Such immune heterogeneity extends to a newer disease phenomenon of atypical leishmaniasis wherein the parasite species classically known to cause VL is reported to cause cutaneous disease and vice versa. The biology of such atypical leishmaniasis cases is beginning to be explored in terms of the host immune changes apart from the differences in the parasite determinants. The chapter seeks to highlight the host immune heterogeneity that is associated with different disease outcomes in a classical setting along with atypical clinical manifestations. � The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.
An Insight Into Systemic Immune Response in Leishmania donovani Mediated Atypical Cutaneous Leishmaniasis in the New Endemic State of Himachal Pradesh, India
(Frontiers Media S.A., 2022-01-04T00:00:00) Thakur, Lovlesh; Madaan, Priyanka; Jain, Aklank; Shankar, Vinay; Negi, Ajeet; Chauhan, Shashi Bhushan; Sundar, Shyam; Singh, Om Prakash; Jain, Manju
Leishmaniasis continues to afflict known and newer endemic sites despite global efforts towards its control and elimination. In this regard, the emergence of newer endemic sites with unusual disease formats is recognized wherein Leishmania donovani complex classically known to cause visceral disease is demonstrated to cause cutaneous manifestation. In this context, atypical cutaneous leishmaniasis (CL) cases caused by L. donovani genetic variants from the newer endemic state of Himachal Pradesh (HP) in India are beginning to be understood in terms of parasite determinants. The atypical CL manifestation further needs to be explored to define host immune correlates with a possible role in driving the unusual disease progression. In the given study, we performed comprehensive systemic-immune profiling of the atypical CL patients from the study area in HP, India, in comparison with the classical visceral leishmaniasis (VL) patients from the northeast region of India. The systemic immune response was studied using ELISA-based assessment of Th1, Th2, Th17, Treg, and Th22 specific plasma cytokine expression pattern and parasite-specific total serum IgG/IgG subclasses. The specified immune correlates are known to exhibit heterogeneous association with the different infecting parasite species, infection load, and co-lateral host immunopathology in classical CL and VL. In the atypical CL patient group, altered expression of IL-10 emerged as the key finding that could potentially fine-tune the Th1/Th17/Th22 effector cytokine axis towards a localized cutaneous manifestation. A reduced expression of IL-10 along with a high IFN-?/IL-10 ratio as a readout of effective parasite killing defined atypical cutaneous outcome. In contrast, high circulatory IL-10 levels and a depressed IFN-?/IL-10 ratio were seen in classical VL patients in line with an ineffective parasite-killing cytokine response. Overall,�the study highlights new knowledge on host immune correlates in terms of cytokine expression pattern and IgG subclasses that underline atypical disease manifestation such that L. donovani, a generally visceralizing parasite species cause skin localized cutaneous lesions. Copyright � 2022 Thakur, Madaan, Jain, Shankar, Negi, Chauhan, Sundar, Singh and Jain.
An intraspecies Leishmania donovani hybrid from the Indian subcontinent is associated with an atypical phenotype of cutaneous disease
(Elsevier Inc., 2022-01-22T00:00:00) Lypaczewski, Patrick; Thakur, Lovlesh; Jain, Aklank; Kumari, Sandhya; Paulini, Kayla; Matlashewski, Greg; Jain, Manju
Leishmaniasis is a neglected tropical disease endemic in over 90 countries. The disease has two main pathologies; cutaneous leishmaniasis (CL) that generally self-heals, and visceral leishmaniasis (VL) that is fatal if untreated. The majority of VL cases, concentrated on the Indian subcontinent (ISC) and East Africa, are caused by Leishmania donovani. However, recent foci of CL on the ISC have been attributed as an atypical phenotype of L. donovani including a recent outbreak in Himachal Pradesh, India. Whole genome sequencing and phylogenetic analysis was undertaken to investigate the origins and genetic factors leading to this pathology atypical of L. donovani. Here we demonstrate the isolate from Himachal Pradesh is derived from a genetic hybridization between two independent L. donovani parents from the �Yeti� ISC1 divergent clade of parasites, identified in the Nepalese highlands. This reveals that intraspecies L. donovani hybrids can give rise to a novel strain associated with CL. � 2022 The Author(s)
Leishmania donovani persistence and circulation causing cutaneous leishmaniasis in unusual-foci of Nepal
(Nature Research, 2023-07-29T00:00:00) Rai, Tinmaya; Shrestha, Srijan; Prajapati, Sabita; Bastola, Anup; Parajuli, Niraj; Ghimire, Pragya Gautam; Bhandari, Parmananda; Pandey, Kishor; Jain, Manju; Matlashewski, Greg; Bras-Goncalves, Rachel; Manandhar, Krishna Das
Cutaneous leishmaniasis cases have increased dramatically in recent years in Nepal. The study offers molecular identification of the Leishmania species using 40 patient�s aspiration biopsy samples, targeting markers kinetoplast minicircle DNA (kDNA) and internal transcribed spacer-1 (ITS1). Among molecularly diagnosed 22 cutaneous leishmaniasis cases, L. donovani complex was identified in 13 instances and L. major in 9 cases. The ITS1 PCR was positive in 12 of the positive nested- kDNA PCR cases (12/22), confirming L. donovani complex in seven of the cases and L. major in five of the cases. In addition, the study conclude that concurrent occurrence of atypical cutaneous infections caused by L. donovani parasite in 59.1% of cases and typical cutaneous infections caused by L. major parasite in 40.9% of cases. A Phylogentic analaysis showed that the detected L. donovani species present null genetic distances from seven references of L. donovani, but slight differences between ITS1 sequences and not grouped into a significant monophyletic cluster. � 2023, The Author(s).
Micrornas and long noncoding rnas as novel therapeutic targets in estrogen receptor-positive breast and ovarian cancers
(MDPI, 2021-04-15T00:00:00) Barwal, Tushar Singh; Sharma, Uttam; Bazala, Sonali; Singh, Ipsa; Jain, Manju; Prakash, Hridayesh; Shekhar, Shashank; Sandberg, Elise N.; Bishayee, Anupam; Jain, Aklank
Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies often have detrimental side-effects, along with acquired resistance, with increased cancer recurrence. Thus, there is an urgent need to identify novel AIs with fewer side effects and improved therapeutic efficacies. In this regard, we and others have recently suggested noncoding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), as potential molecular targets for utilization in modulating cancer hallmarks and overcoming drug resistance in several cancers, including ER-positive breast and ovarian cancer. Herein, we describe the disruptive functions of several miRNAs and lncRNAs seen in dysregulated cancer metabolism, with a focus on the gene encoding for aromatase (CYP19A1 gene) and estrogen synthesis as a novel therapeutic approach for treating ER-positive breast and ovarian cancers. Furthermore, we discuss the oncogenic and tumor-suppressive roles of several miRNAs (oncogenic miRNAs: MIR125b, MIR155, MIR221/222, MIR128, MIR2052HG, and MIR224; tumor-suppressive miRNAs: Lethal-7f, MIR27B, MIR378, and MIR98) and an oncogenic lncRNA (MIR2052HG) in aromatase-dependent cancers via transcriptional regulation of the CYP19A1 gene. Additionally, we discuss the potential effects of dysregulated miRNAs and lncRNAs on the regulation of critical oncogenic molecules, such as signal transducer, and activator of transcription 3, ?-catenin, and integrins. The overall goal of this review is to stimulate further research in this area and to facilitate the development of ncRNA-based approaches for more efficacious treatments of ER-positive breast and ovarian cancer patients, with a slight emphasis on associated treatment� delivery mechanisms. � 2021 by the authors. Licensee MDPI, Basel, Switzerland.
miR-590�5p: A double-edged sword in the oncogenesis process
(Elsevier Ltd, 2022-06-12T00:00:00) Barwal, Tushar Singh; Singh, Neha; Sharma, Uttam; Bazala, Sonali; Rani, Medha; Behera, Alisha; Kumawat, Ram Kumar; Kumar, Pawan; Uttam, Vivek; Khandelwal, Akanksha; Barwal, Jyoti; Jain, Manju; Jain, Aklank
Accumulating evidence suggests the critical role of miR-590�5p in various aspects of cellular homeostasis, including cancer. Furthermore, we and others have recently demonstrated that miRNA-590�5p acts as an oncogene in some cancers while it acts as a tumor-suppressor in others. However, the role of miR-590�5p in oncogenesis is more complex, like a double-edged sword. Thus, this systematic review introduces the concept, mechanism, and biological function of miR-590�5p to resolve this apparent paradox. We have also described the involvement of miR-590�5p in crucial cancer-hallmarks processes like proliferation, invasion, metastasis, and chemo radioresistance. Finally, we have presented the possible genes/pathways targets of miR-590�5p through bioinformatics analysis. This review may help in designing better biomarkers and therapeutic targets for cancers. � 2022
A Pleiotropic Role of Long Non-Coding RNAs in the Modulation of Wnt/?-Catenin and PI3K/Akt/mTOR Signaling Pathways in Esophageal Squamous Cell Carcinoma: Implication in Chemotherapeutic Drug Response
(MDPI, 2022-03-28T00:00:00) Sharma, Uttam; Murmu, Masang; Barwal, Tushar Singh; Tuli, Hardeep Singh; Jain, Manju; Prakash, Hridayesh; Kaceli, Tea; Jain, Aklank; Bishayee, Anupam
Despite the availability of modern techniques for the treatment of esophageal squamous cell carcinoma (ESCC), tumor recurrence and metastasis are significant challenges in clinical management. Thus, ESCC possesses a poor prognosis and low five-year overall survival rate. Notably, the origin and recurrence of the cancer phenotype are under the control of complex cancer-related signaling pathways. In this review, we provide comprehensive knowledge about long non-coding RNAs (lncRNAs) related to Wnt/?-catenin and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in ESCC and its implications in hindering the efficacy of chemotherapeutic drugs. We observed that a pool of lncRNAs, such as HERES, TUG1, and UCA1, associated with ESCC, directly or indirectly targets various molecules of the Wnt/?-catenin pathway and facilitates the manifestation of multiple cancer phenotypes, including proliferation, metastasis, relapse, and resistance to anticancer treatment. Additionally, several lncRNAs, such as HCP5 and PTCSC1, modulate PI3K/Akt/mTOR pathways during the ESCC pathogenesis. Furthermore, a few lncRNAs, such as AFAP1-AS1 and LINC01014, block the efficiency of chemotherapeutic drugs, including cisplatin, 5-fluorouracil, paclitaxel, and gefitinib, used for ESCC treatment. Therefore, this review may help in designing a better therapeutic strategy for ESCC patients. � 2022 by the authors. Licensee MDPI, Basel, Switzerland.
The regulatory roles of long non-coding RNAs in the development of chemoresistance in breast cancer
(Impact Journals LLC, 2017) Malhotra, Akshay; Jain, Manju; Prakash, Hridayesh; Vasquez, Karen M.; Jain, Aklank; Malhotra, A.; Jain, M.; Prakash, H.; Vasquez, K.M.; Jain, A.
Chemoresistance is one of the major hurdles in the treatment of breast cancer, which limits the effect of both targeted and conventional therapies in clinical settings. Therefore, understanding the mechanisms underpinning resistance is paramount for developing strategies to circumvent resistance in breast cancer patients. Several published reports have indicated that lncRNAs play a dynamic role in the regulation of both intrinsic and acquired chemoresistance through a variety of mechanisms that endow cells with a drug-resistant phenotype. Although a number of lncRNAs have been implicated in chemoresistance of breast cancer, their mechanistic roles have not been systematically reviewed. Thus, here we present a detailed review on the latest research findings and discoveries on the mechanisms of acquisition of chemoresistance in breast cancer related to lncRNAs, and how lncRNAs take part in various cancer signalling pathways involved in breast cancer cells. Knowledge obtained from this review could assist in the development of new strategies to avoid or reverse drug resistance in breast cancer chemotherapy. ? 2017 Malhotra et al.
Role of sphingosine-1-phosphate in mast cell functions and asthma and its regulation by non-coding RNA
(Frontiers Media S.A., 2017) Saluja, Rohit; Kumar, Ashok; Jain, Manju; Goel, Sudhir K.; Jain, Aklank
Sphingolipid metabolites are emerging as important signaling molecules in allergic diseases specifically asthma. One of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), is involved in cell differentiation, proliferation, survival, migration, and angiogenesis. In the allergic diseases, alteration of S1P levels influences the differentiation and responsiveness of mast cells (MCs). S1P is synthesized by two sphingosine kinases (SphKs), sphingosine kinase 1, and sphingosine kinase 2. Engagement of IgE to the FceRI receptor induces the activation of both the SphKs and generates S1P. Furthermore, SphKs are also essential to FceRI-mediated MC activation. Activated MCs export S1P into the extracellular space and causes inflammatory response and tissue remodeling. S1P signaling has dual role in allergic responses. Activation of SphKs and secretion of S1P are required for MC activation; however, S1P signaling plays a vital role in the recovery from anaphylaxis. Several non-coding RNAs have been shown to play a crucial role in controlling the MC-associated inflammatory and allergic responses. Thus, S1P signaling pathway and its regulation by non-coding RNA could be explored as an exciting potential therapeutic target for asthma and other MC-associated diseases. ? 2017 Saluja, Kumar, Jain, Goel and Jain.
STAT signaling as a target for intervention: from cancer inflammation and angiogenesis to non-coding RNAs modulation
(Springer Science and Business Media B.V., 2022-04-26T00:00:00) Tuli, Hardeep Singh; Sak, Katrin; Iqubal, Ashif; Garg, Vivek Kumar; Varol, Mehmet; Sharma, Uttam; Chauhan, Abhishek; Yerer, Mukerrem Betul; Dhama, Kuldeep; Jain, Manju; Jain, Aklank
As a landmark, scientific investigation in cytokine signaling and interferon-related anti-viral activity, signal transducer and activator of transcription (STAT) family of proteins was first discovered in the 1990s. Today, we know that the STAT family consists of several transcription factors which regulate various molecular and cellular processes, including proliferation, angiogenesis, and differentiation in human carcinoma. STAT family members play an active role in transducing signals from cell membrane to nucleus through intracellular signaling and thus activating gene transcription. Additionally, they are also associated with the development and progression of human cancer by facilitating inflammation, cell survival, and resistance to therapeutic responses. Accumulating evidence suggests that not all STAT proteins are associated with the progression of human malignancy; however, STAT3/5 are constitutively activated in various cancers, including multiple myeloma, lymphoma, breast cancer, prostate hepatocellular carcinoma, and non-small cell lung cancer. The present review highlights how STAT-associated events are implicated in cancer inflammation, angiogenesis and non-coding RNA (ncRNA) modulation to highlight potential intervention into carcinogenesis-related cellular processes. � 2022, The Author(s), under exclusive licence to Springer Nature B.V.
Understanding Immune-etiology of Psoriasis: An autoimmune disease
(Central University of Punjab, 2018) Kumari, Anjna; Jain, Manju
Psoriasis is a chronic inflammatory autoimmune disease. Disease etiology is understood in terms of altered crosstalk between skin keratinocytes and immune cell infiltrates, specifically T cells leading to the development of characteristic psoriatic skin lesions. T cell alterations in skin lesions as well as in the peripheral blood of psoriatic patients have been shown to be associated with the disease condition. With a major research focus on keratinocyte abnormalities, more studies are required to understand the immune-etiology of disease. There are fewer reports with inconsistence findings on T cell changes in psoriatic patients. Towards this end, we performed a study using blood samples from psoriasis patients and healthy controls to access alterations in peripheral blood mononuclear cell and T cell count along with phenotyping of blood cells in terms of CD4+ Th and CD8+ Tc cells and expression pattern of T cell-associated cytokines in plasma samples. Furthermore, TREC analysis was done to understand possible origin of T cell alterations associated with psoriasis.
Yin and yang of immunological memory in controlling infections: Overriding self defence mechanisms
(Taylor and Francis Ltd., 2021-04-19T00:00:00) Roy, Roshan Kumar; Yadav, Rakhi; Jain, Aklank; Tripathi, Vishwas; Jain, Manju; Singh, Sandhya; Prakash, Hridayesh
Immunological memory is critical for host immunity and decisive for individual to respond exponentially to previously encountered infection. Both T and B cell memory are known to orchestrate immunological memory with their central and effector memory arms contributing in prolonged immunity/defence mechanisms of host. While central memory helps in maintaining prolonged immunity for a particular infection, effector memory helps in keeping local/seasonal infection in control. In addition to this, generation of long-lived plasma cells is pivotal for generating neutralizing antibodies which can enhance recall and B cell memory to control re-infection. In view of this, scaling up memory response is one of the major objectives for the expected outcome of vaccination. In this line, this review deals with the significance of memory cells, molecular pathways of their development, maintenance, epigenetic regulation and negative regulation in various infections. We have also highlighted the significance of both T and B cell memory responses in the vaccination approaches against range of infections which is not fully explored so far. Highlights Pathogens induce IL-10R, PD-1, T-reg; and downregulate IL7R and IL15R for hijacking memory response IL-7, 15, Tcf-1 (Wnt5/7A), and CD28 signaling is decisive for TCM/TEM and TRM recall. Bach2 expression suppress Bim and Puma and promotes memory B cell activities VCAM1, IFN-?, and GM-CSF pathways are critical for local activation of memory cells Multi-epitope vaccines/adjuvants are potent for inducing specific memory response. � 2021 Taylor & Francis Group, LLC.

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