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Article ; Online: HSP90, a Common Therapeutic Target for Suppressing Skin Injury Caused by Exposure to Chemically Diverse Classes of Blistering Agents.

Srivastava, Ritesh Kumar / Muzaffar, Suhail / Khan, Jasim / Crossman, David K / Agarwal, Anupam / Athar, Mohammad

The Journal of pharmacology and experimental therapeutics

2024 Volume 388, Issue 2, Page(s) 546–559

Abstract: Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates, namely phenylarsine oxide ( ... ...

Abstract	Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates, namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES), respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of vesicants. Murine skin exposure to these chemicals causes tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells, and apoptosis of epidermal and dermal cells. RNA sequencing analysis identified ∼346 inflammatory genes that were commonly altered by both PAO and CEES, along with the identification of cytokine signaling activation as the top canonical pathway. Activation of several proinflammatory genes and pathways is associated with phosphorylation-dependent activation of heat shock protein 90
MeSH term(s)	Humans ; Animals ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Chemical Warfare Agents/toxicity ; Irritants ; Skin ; Mustard Gas/toxicity ; Arsenicals/metabolism ; Arsenicals/pharmacology
Chemical Substances	2-chloroethyl ethyl sulfide (693-07-2) ; NLR Family, Pyrin Domain-Containing 3 Protein ; Chemical Warfare Agents ; Irritants ; Mustard Gas (T8KEC9FH9P) ; Arsenicals
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.123.001795
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Article ; Online: Enhanced Transdermal Delivery of N-Acetylcysteine and 4-Phenylbutyric Acid for Potential Use as Antidotes to Lewisite.

Dandekar, Amruta A / Vora, Deepal / Yeh, Jihee Stephanie / Srivastava, Ritesh Kumar / Athar, Mohammad / Banga, Ajay K

AAPS PharmSciTech

2023 Volume 24, Issue 3, Page(s) 71

Abstract: Lewisite is a highly toxic chemical warfare agent that leads to cutaneous and systemic damage. N-acetylcysteine (NAC) and 4-phenylbutryic acid (4-PBA) are two novel antidotes developed to treat toxicity caused by lewisite and similar arsenicals. Our in ... ...

Abstract	Lewisite is a highly toxic chemical warfare agent that leads to cutaneous and systemic damage. N-acetylcysteine (NAC) and 4-phenylbutryic acid (4-PBA) are two novel antidotes developed to treat toxicity caused by lewisite and similar arsenicals. Our in vivo studies demonstrated safety and effectiveness of these agents against skin injury caused by surrogate lewisite (Phenylarsine oxide) proving their potential for the treatment of lewisite injury. We further focused on exploring various enhancement strategies for an enhanced delivery of these agents via skin. NAC did not permeate passively from propylene glycol (PG). Iontophoresis as a physical enhancement technique and chemical enhancers were investigated for transdermal delivery of NAC. Application of cathodal and anodal iontophoresis with the current density of 0.2 mA/cm
MeSH term(s)	Skin Absorption ; Acetylcysteine/metabolism ; Antidotes ; Oleic Acid/metabolism ; Dimethyl Sulfoxide/metabolism ; Administration, Cutaneous ; Skin/metabolism ; Arsenicals/metabolism ; Sodium Dodecyl Sulfate/metabolism
Chemical Substances	4-phenylbutylamine ; oleyl alcohol (172F2WN8DV) ; Acetylcysteine (WYQ7N0BPYC) ; Antidotes ; 4-phenylbutyric acid (7WY7YBI87E) ; lewisite (0N54LGU5WS) ; Oleic Acid (2UMI9U37CP) ; Dimethyl Sulfoxide (YOW8V9698H) ; Arsenicals ; Sodium Dodecyl Sulfate (368GB5141J)
Language	English
Publishing date	2023-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2052070-0
ISSN	1530-9932 ; 1530-9932
ISSN (online)	1530-9932
ISSN	1530-9932
DOI	10.1208/s12249-023-02527-6
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Article ; Online: Unlocking the enigma of phenotypic drug tolerance: Mechanisms and emerging therapeutic strategies.

Mishra, Alok K / Thakare, Ritesh P / Santani, Bela G / Yabaji, Shivraj M / Dixit, Shivendra K / Srivastava, Kishore K

Biochimie

2023 Volume 220, Page(s) 67–83

Abstract: In the ongoing battle against antimicrobial resistance, phenotypic drug tolerance poses a formidable challenge. This adaptive ability of microorganisms to withstand drug pressure without genetic alterations further complicating global healthcare ... ...

Abstract	In the ongoing battle against antimicrobial resistance, phenotypic drug tolerance poses a formidable challenge. This adaptive ability of microorganisms to withstand drug pressure without genetic alterations further complicating global healthcare challenges. Microbial populations employ an array of persistence mechanisms, including dormancy, biofilm formation, adaptation to intracellular environments, and the adoption of L-forms, to develop drug tolerance. Moreover, molecular mechanisms like toxin-antitoxin modules, oxidative stress responses, energy metabolism, and (p)ppGpp signaling contribute to this phenomenon. Understanding these persistence mechanisms is crucial for predicting drug efficacy, developing strategies for chronic bacterial infections, and exploring innovative therapies for refractory infections. In this comprehensive review, we dissect the intricacies of drug tolerance and persister formation, explore their role in acquired drug resistance, and highlight emerging therapeutic approaches to combat phenotypic drug tolerance. Furthermore, we outline the future landscape of interventions for persistent bacterial infections.
Language	English
Publishing date	2023-12-31
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	120345-9
ISSN	1638-6183 ; 0300-9084
ISSN (online)	1638-6183
ISSN	0300-9084
DOI	10.1016/j.biochi.2023.12.009
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Article ; Online: Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells.

Moore, Kyle H / Boitet, Laurence M / Chandrashekar, Darshan S / Traylor, Amie M / Esman, Stephanie K / Erman, Elise N / Srivastava, Ritesh K / Khan, Jasim / Athar, Mohammad / Agarwal, Anupam / George, James F

The Journal of pharmacology and experimental therapeutics

2024 Volume 388, Issue 2, Page(s) 605–612

Abstract: Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated ... ...

Abstract	Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. We used a nontargeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here we identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and peroxisome proliferator-activated receptor (PPAR)-
MeSH term(s)	Mice ; Humans ; Animals ; Endothelial Cells/metabolism ; Kidney/metabolism ; Acute Kidney Injury/chemically induced ; Acute Kidney Injury/genetics ; Acute Kidney Injury/metabolism ; Epithelial Cells/metabolism ; Fatty Acids/metabolism ; Arsenicals/adverse effects ; Arsenicals/metabolism
Chemical Substances	Fatty Acids ; Arsenicals
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.123.001742
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Article ; Online: Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury.

Kshirsagar, Sharvari / Dandekar, Amruta / Srivastava, Ritesh K / Khan, Jasim / Muzaffar, Suhail / Athar, Mohammad / Banga, Ajay K

International journal of pharmaceutics

2023 Volume 647, Page(s) 123547

Abstract: Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister ...

Abstract	Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.
MeSH term(s)	Humans ; Antidotes ; Acetylcysteine ; Administration, Cutaneous ; Skin ; Drug Delivery Systems ; Needles
Chemical Substances	Antidotes ; lewisite (0N54LGU5WS) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2023-10-25
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2023.123547
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Zs.A 1409: Show issues

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Article ; Online: Development and Evaluation of a Topical Foam Formulation for Decontamination of Warfare Agents.

Vora, Deepal / Dandekar, Amruta A / Srivastava, Ritesh Kumar / Athar, Mohammad / Banga, Ajay K

Molecular pharmaceutics

2022 Volume 19, Issue 12, Page(s) 4644–4653

Abstract: Lewisite is a highly toxic and potent chemical warfare vesicating agent capable of causing pain, inflammation, and blistering. Therapeutic strategies that safely and effectively attenuate this damage are important. Early and thorough decontamination of ... ...

Abstract	Lewisite is a highly toxic and potent chemical warfare vesicating agent capable of causing pain, inflammation, and blistering. Therapeutic strategies that safely and effectively attenuate this damage are important. Early and thorough decontamination of these agents from skin is required to prevent their percutaneous absorption. In our studies, we used phenylarsine oxide (PAO), a surrogate for arsenicals, to simulate lewisite exposure. Various parameters such as determination of extraction solvents, skin extraction efficiency, donor volume, and donor concentration were optimized for decontamination of PAO. We aimed to develop a novel, easy to apply foam formulation that can decontaminate arsenicals. We screened various foaming agents, vehicles, and chemical enhancers for the development of foam. Lead formulation foam F30 was further characterized for foam density, foam expansion, foam liquid stability, foam volume stability, and foam gas fraction. The amount of PAO delivered into human skin in 30 min of exposure was 228.57 ± 28.44 μg/sq·cm. The amount of PAO remaining in human skin after decontamination with blank foam F30 was 50.09 ± 9.71, demonstrating an overall percentage decontamination efficiency of over 75%. Furthermore, the decontamination efficacy of F30 was also tested in the porcine skin model and results indicated an even higher decontamination efficacy. These studies demonstrated that the developed foam formulation can be used for effective decontamination of chemical warfare agents.
MeSH term(s)	Swine ; Animals ; Humans ; Decontamination/methods ; Arsenicals/pharmacology ; Chemical Warfare Agents/toxicity ; Skin
Chemical Substances	lewisite (0N54LGU5WS) ; oxophenylarsine (0HUR2WY345) ; Arsenicals ; Chemical Warfare Agents
Language	English
Publishing date	2022-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.2c00636
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Article ; Online: Combined inhibition of BET bromodomain and mTORC1/2 provides therapeutic advantage for rhabdomyosarcoma by switching cell death mechanism.

Srivastava, Ritesh K / Guroji, Purushotham / Jin, Lin / Mukhtar, M Shahid / Athar, Mohammad

Molecular carcinogenesis

2022 Volume 61, Issue 8, Page(s) 737–751

Abstract: Aberrant activation of multiple complex signaling pathways underlies the pathogenesis of rhabdomyosarcoma (RMS), which remains a cause of mortality in approximately 30% of children with RMS. Bromodomain and extraterminal (BET) domain chromatin remodeling ...

Abstract	Aberrant activation of multiple complex signaling pathways underlies the pathogenesis of rhabdomyosarcoma (RMS), which remains a cause of mortality in approximately 30% of children with RMS. Bromodomain and extraterminal (BET) domain chromatin remodeling regulates several of these pathways. Here, we targeted bromodomain 4 (BRD4) in combination with another molecular metabolic tumor driver, the Akt/mTOR signaling pathway, to provide a highly effective treatment for this neoplasm. We demonstrated that a nexus of these two molecular pathways underlies RMS pathogenesis. Our data show that the combined inhibition of the BET bromodomain and mTORC1/2 signaling abrogates aggressive RMS growth. Thus, the bromodomain inhibitor RVX-208 significantly augmented the therapeutic effects of the dual mTORC1/2 inhibitors, OSI-027 and PP242, both in vitro and in a human xenograft murine model. Drug-treated residual tumors showed a decrease in the activation of underlying signaling mechanisms characterized by a reduction in the expression of p-AKT, p-mTOR, p-p70S6K, cyclin D1, and proliferation. Our ChIP-seq data demonstrated that RVX-208 effectively blocked BRD4 occupancy on its target promoters. ChIP-qPCR assays further confirmed that RVX-208 treatment resulted in a significant decrease in H3K27ac and H4K8ac signals at their target loci. While single RVX-208 treatment induces apoptosis and a single mTORC1/2 inhibitor induces macropinocytosis, their combined treatment led to necroptosis-mediated cell death. These data suggest that combined treatment with drugs targeting BRD4 and mTORC1/2 may be an effective therapeutic intervention for drug-resistant RMS.
MeSH term(s)	Animals ; Apoptosis ; Cell Cycle Proteins ; Cell Line, Tumor ; Cell Proliferation ; Child ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Mice ; Nuclear Proteins/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rhabdomyosarcoma/drug therapy ; Rhabdomyosarcoma/genetics ; Rhabdomyosarcoma/pathology ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	BRD4 protein, human ; Cell Cycle Proteins ; Nuclear Proteins ; Transcription Factors ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.23414
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Article: Topical delivery of nordihydroguaretic acid for attenuating cutaneous damage caused by arsenicals.

Kale, Madhura / Srivastava, Ritesh K / Athar, Mohammad / Banga, Ajay K

Journal of drug delivery science and technology

2020 Volume 58

Abstract: This study evaluated the topical delivery of nordihydroguaretic acid (NDGA), a molecule that can potentially alleviate cutaneous damage caused by exposure to arsenic warfare chemicals. N-acetylcysteine (NAC 0.2% w/v) was added as an antioxidant, ... ...

Abstract	This study evaluated the topical delivery of nordihydroguaretic acid (NDGA), a molecule that can potentially alleviate cutaneous damage caused by exposure to arsenic warfare chemicals. N-acetylcysteine (NAC 0.2% w/v) was added as an antioxidant, preventing the oxidation of NDGA to toxic quinones. A 24 h study was performed to arrive at a minimum concentration of NDGA needed to deliver maximum drug. A solution of 3% w/v delivered the maximum amount of drug at the end of 24 h (37.45 ± 4.32 μg). Short duration studies were carried out to determine the time needed to saturate skin with NDGA. There was no significant difference in the skin concentrations for 24 h and 8 h (14.89 ± 2.36 μg), due to skin saturation. However, there was significant difference in the amount of drug delivered to the epidermis (12.29 ± 1.87 μg) and dermis (2.54 ± 0.56 μg) at the end of 8 h. Solution of NDGA was applied on UV treated skin to assess changes in drug delivery. In vivo studies revealed that 3% NDGA was non-toxic for topical administration.
Language	English
Publishing date	2020-05-12
Publishing country	France
Document type	Journal Article
ZDB-ID	2141013-6
ISSN	1773-2247
ISSN	1773-2247
DOI	10.1016/j.jddst.2020.101773
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Article ; Online: Food and fruit waste valorisation for pectin recovery: Recent process technologies and future prospects.

Sarangi, Prakash Kumar / Mishra, Snehasish / Mohanty, Pratikhya / Singh, Puneet K / Srivastava, Rajesh K / Pattnaik, Ritesh / Adhya, Tapan K / Das, Trupti / Lenka, Basundhara / Gupta, Vijai Kumar / Sharma, Minaxi / Sahoo, Uttam Kumar

International journal of biological macromolecules

2023 Volume 235, Page(s) 123929

Abstract: Pectin possesses a dual property of resistance and flexibility and thus has diverse commercial value which has generated research interest on this versatile biopolymer. Formulated products using pectin could be useful in food, pharma, foam, plasticiser ... ...

Abstract	Pectin possesses a dual property of resistance and flexibility and thus has diverse commercial value which has generated research interest on this versatile biopolymer. Formulated products using pectin could be useful in food, pharma, foam, plasticiser and paper substitute industries. Pectin is structurally tailor-made for greater bioactivity and diverse applications. Sustainable biorefinery leaves greener footprints while producing high-value bioproducts like pectin. The essential oils and polyphenols obtained as byproducts from a pectin-based biorefinery are useful in cosmetics, toiletries and fragrance industries. Pectin can be extracted from organic sources following eco-friendly strategies, and the extraction techniques, structural alterations and the applications are continually being upgraded and standardized. Pectin has great applications in diverse areas, and its green synthesis is a welcome development. In future, growing industrial application of pectin is anticipated as research orients on biopolymers, biotechnologies and renewable source-based processes. As the world is gradually adopting greener strategies in sync with the global sustainable development goal, active involvement of policy makers and public participation are prime. Governance and policy framing are essential in the transition of the world economy towards circularity since green circular bioeconomy is ill-understood among the public in general and within the administrative circles in particular. Concerted efforts by researchers, investors, innovators, and policy and decision makers to integrate biorefinery technologies as loops within loop of biological structures and bioprocesses is suggested. The review focusses on generation of the different nature of food wastes including fruits and vegetables with cauterization of their components. It discusses the innovative extraction and biotransformation approaches for these waste conversions into value-added products at cost-effective and eco-friendly way. This article compiles numerous effective and efficient and green way pectin extraction techniques with their advantages with varying success in an integrated manner.
MeSH term(s)	Fruit/chemistry ; Pectins/analysis ; Biotechnology ; Vegetables
Chemical Substances	Pectins (89NA02M4RX)
Language	English
Publishing date	2023-03-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2023.123929
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Article ; Online: Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa.

Jin, Lin / Chen, Yunjia / Muzaffar, Suhail / Li, Chao / Mier-Aguilar, Carlos A / Khan, Jasim / Kashyap, Mahendra P / Liu, Shanrun / Srivastava, Ritesh / Deshane, Jessy S / Townes, Tim M / Elewski, Boni E / Elmets, Craig A / Crossman, David K / Raman, Chander / Athar, Mohammad

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 49, Page(s) e2315096120

Abstract: Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to ... ...

Abstract	Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by
MeSH term(s)	Humans ; Hidradenitis Suppurativa/genetics ; Skin/metabolism ; Epigenomics ; Epigenesis, Genetic ; Stem Cells/metabolism ; Chromatin/metabolism
Chemical Substances	Chromatin
Language	English
Publishing date	2023-11-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2315096120
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