Publications by authors named "Sachin Kumar Singh"

107 Publications

Combination therapy of vanillic acid and oxaliplatin co-loaded in polysaccharide based functionalized polymeric micelles could offer effective treatment for colon cancer: A hypothesis.

Med Hypotheses 2021 Sep 14;156:110679. Epub 2021 Sep 14.

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India. Electronic address:

Colon cancer is characterised by the persistent change in bowel habits due to the formation of polyps (cancerous) in the inner lining of the colon. Clinically, there are several anticancer drugs available to treat colon cancer. Oxaliplatin (third generation platinum drug) is widely prescribed anticancer drug due to its broad range anticancer properties and low toxicities over cisplatin and carboplatin. Currently, use of oxaliplatin as adjuvant chemotherapy represents a standard care for the treatment of advanced colon cancer. Despite this, its rapid degradation in systemic circulations upon administration, lack of tumor specificity, and low bioavailability limits its anticancer potential. On the other hand, vanillic acid (VA) has shown anticancer potential in colon cancer by targeting mTOR/Ras pathway, HIF-1α inhibition, NF-ĸB, and Nrf2 that regulate cell growth, cell survival, proliferation and adaptation to cancer microenvironment. Normal oral delivery of these two drugs offers non-specific drug release in gastrointestinal tract that leads to unwanted toxicity and very less amount of drug become available for colonic site. Therefore, loading of these two drugs in polysaccharide based functionalized polymeric micelles (FPMs) can offer selective targeting at colonic site and could offer better therapeutic efficacy at much lesser doses of drugs. Therefore, a new hypothesis has been proposed that the combination of vanillic acid with oxaliplatin co-loaded in FPMs could provide colon targeting ability with enhanced potency and safety profile by targeting multiple pathways than current adjuvant chemotherapies available in the market for the treatment of colon cancer.
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http://dx.doi.org/10.1016/j.mehy.2021.110679DOI Listing
September 2021

Advanced drug delivery approaches in managing TGF-β-mediated remodeling in lung diseases.

Nanomedicine (Lond) 2021 Sep 22. Epub 2021 Sep 22.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW, 2007, Australia.

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http://dx.doi.org/10.2217/nnm-2021-0254DOI Listing
September 2021

High Performance Air Breathing Flexible Lithium-Air Battery.

Small 2021 Sep 16:e2102072. Epub 2021 Sep 16.

Department of Mechanical and Industrial Engineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.

Lithium-oxygen (Li-O ) batteries possess the highest theoretical energy density (3500 Wh kg ), which makes them attractive candidates for modern electronics and transportation applications. In this work, an inexpensive, flexible, and wearable Li-O battery based on the bifunctional redox mediator of InBr , MoS cathode catalyst, and Fomblin-based oxygen permeable membrane that enable long-cycle-life operation of the battery in pure oxygen, dry air, and ambient air is designed, fabricated, and tested. The battery operates in ambient air with an open system air-breathing architecture and exhibits excellent cycling up to 240 at the high current density of 1 A g with a relative humidity of 75%. The electrochemical performance of the battery including deep-discharge capacity, and rate capability remains almost identical after 1000 cycle in a bending fatigue test. This finding opens a new direction for utilizing high performance Li-O batteries for applications in the field of flexible and wearable electronics.
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http://dx.doi.org/10.1002/smll.202102072DOI Listing
September 2021

A global comparison of implementation and effectiveness of materiovigilance program: overview of regulations.

Environ Sci Pollut Res Int 2021 Sep 13. Epub 2021 Sep 13.

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India.

Medical devices, being life-saving tools, are considered to be a boon for healthcare system. However, in addition to their therapeutic effects, there are several ill consequences that are caused by these devices. An effective cohort vigilant system was needed to manage such adverse effects. This had led to the introduction of materiovigilance. Materiovigilance is the study and follow-up of occurrences that arise as a result from the usage of the medical equipment. It not only manages adverse events (AE) but also creates harmonization among countries. Keeping these objectives in focus, the principles, perspectives, and practices with regard to materiovigilance that are followed in the USA, Europe, China, Japan, Australia, Canada, and India are being compared. Such a comparison is essential, which will help us to understand the gaps in the current regulatory systems in the above-mentioned countries and furthermore will provide a comprehensive picture to the regulatory authorities to amend any existing laws if required. These amendments may ensure optimal patient safety by providing them a benign experience from the use of medical devices.
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http://dx.doi.org/10.1007/s11356-021-16345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436859PMC
September 2021

Proteomic study of apheresis platelets made HLA class I deficient for transfusion of refractory patients.

Proteomics Clin Appl 2021 Sep 12:e2100022. Epub 2021 Sep 12.

Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.

Purpose: Refractoriness can occur after repeated platelet (PLT) transfusions because of alloimmunization to HLA class I antigens on transfused PLTs and generation of anti-HLA antibodies that bind to the foreign PLTs and initiate their destruction. Such refractoriness can be overcome by provision of HLA-matched PLTs from HLA typed donors. However, since the procedure is both expensive and time-consuming, an alternative approach is to deplete PLTs of HLA class I molecules by a brief treatment with citric acid, on ice. This is shown to be feasible without damaging PLT function. We used label free quantitative mass spectrometry (MS)-based proteomics to investigate the effect of acid treatment on apheresis PLTs for combatting immunologic PLT refractoriness.

Experimental Design: Proteomic analyses are undertaken using PLTs from seven apheresis concentrates, which were split in two with or without acid treatment.

Results: In total 1717 proteins in apheresis PLTs were quantified using proteomics. Data are available via ProteomeXchange with identifier PXD027893 . Of these, the amount of 80 proteins changed significantly after acid treatment, but overall there were not any major differences in proteomes between samples with and without acid treatment.

Conclusions And Clinical Relevance: In general, the changes of PLT proteins after treatment with citric acid were quite small and functionally safe. Hence, this result taken together with our previously published data indicates that acid treated PLTs can be used for treatment of patients with PLT refractoriness and opens up for a clinical trial.
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http://dx.doi.org/10.1002/prca.202100022DOI Listing
September 2021

Development of mushroom polysaccharide and probiotics based solid self-nanoemulsifying drug delivery system loaded with curcumin and quercetin to improve their dissolution rate and permeability: State of the art.

Int J Biol Macromol 2021 Aug 28;189:744-757. Epub 2021 Aug 28.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia.

The role of mushroom polysaccharides and probiotics as pharmaceutical excipients for development of nanocarriers has never been explored. In the present study an attempt has been made to explore Ganoderma lucidum extract powder (GLEP) containing polysaccharides and probiotics to convert liquid self nanoemulsifying drug delivery system (SNEDDS) into solid free flowing powder. Two lipophilic drugs, curcumin and quercetin were used in this study due to their dissolution rate limited oral bioavailability and poor permeability. These were loaded into liquid SNEDDS by dissolving them into isotropic mixture of Labrafill M1944CS, Capmul MCM, Tween-80 and Transcutol P. The liquid SNEDDS were solidified using probiotics and mushroom polysaccharides as carriers and Aerosil-200 as coating agent. The solidification was carried out using spray drying process. The process and formulation variables for spray drying process of liquid SNEDDS were optimized using Box Behnken Design to attain required powder properties. The release of both drugs from the optimized spray dried (SD) formulation was found to be more than 90%, whereas, it was less than 20% for unprocessed drugs. The results of DSC, PXRD and SEM, showed that the developed L-SNEDDS preconcentrate was successfully loaded onto the porous surface of probiotics, mushroom polysaccharides and Aerosil-200.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.08.170DOI Listing
August 2021

Combination therapy of curcumin and fecal microbiota transplant: Potential treatment of polycystic ovarian syndrome.

Med Hypotheses 2021 Sep 15;154:110644. Epub 2021 Jul 15.

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.

Polycystic ovarian syndrome (PCOS) is a combination of various symptoms like anovulation, hirsutism, chronic amenorrhea, infertility, obesity and polycystic ovaries. It affects over 7 million women worldwide. The current strategy to treat this disorder is based on the use of drugs that provide symptomatic relief. Most of these, however, exhibit numerous side effects and are not able to ameliorate all the signs and symptoms of PCOS. As dysbiosis is considered as one of the prime underlying causes of PCOS, restoration of eubiosis was considered as a plausible way to treat it. Bacteriotherpeutics like probiotics, synbiotics and even fecal microbiota transplant (FMT) have shown considerable effectiveness in PCOS. Of these baceteriotherapeutic options, FMT is considered to be the most holistic as it encompasses the bacteriome, virome, fungome, archaeome and even parasitome while both probiotics as well as synbiotics mainly comprise bacteria. Repeated FMT, however, is not a pragmatic option because of its inconvenience, lack of standardization, involved risk and scepticism amongst patients and physicians. If the eubiosis ushered by FMT is sustained for a long time, the repeated administrations of FMT can be avoided and maintenance therapy with any agent that can maintain the eubiotic condition can be adopted. Role of curcumin on gut microbiota is widely known. It is largely attributed to the ability of certain microbes to consume polyphenols as substrates and its positive effect on bacterial consumption of nutrients such as sugars. Based on various mechanisms and studies, a new hypothesis is being proposed wherein FMT and curcumin combination is predicted to be an effective and sustained treatment of PCOS with much lower rates of remission.
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http://dx.doi.org/10.1016/j.mehy.2021.110644DOI Listing
September 2021

Emerging cases of mucormycosis under COVID-19 pandemic in India: Misuse of antibiotics.

Drug Dev Res 2021 Jul 29. Epub 2021 Jul 29.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, New South Wales, Australia.

COVID-19's second wave had a significant impact on India, on May 7, 2021, the largest daily recorded case count was a little more than 4 million, and it has since fallen. Although the number of new cases reported has dropped, during the third week of May 2021, India accounted for about 45% of new cases identified globally and around 34% of deaths. As India maintains its present level of stability, a new urgent threat has emerged in the form of coronavirus-associated mucormycosis. Mucormycosis, an acute and deadly fungal infection caused by Mucorales-related fungal species, is a fungal emergency with a particularly aggressive propensity for contiguous spread, associated with a poor prognosis if not properly and immediately identified, and treated. Mucormycosis, sometimes referred to as the "black fungus," has increased more rapidly in India during the second wave of COVID-19 than during the first wave, with at least 14,872 cases as of May 28, 2021. Uncontrolled diabetic mellitus (DM) and other immunosuppressive diseases such as neutropenia and corticosteroid treatment have traditionally been identified as risk factors for mucormycosis. Therefore, the use of glucocorticoids or high doses of glucocorticoids in mild COVID-19 cases (without hypoxemia) should be avoided. In addition, drugs that target the immune pathway, such as tocilizumab, are not recommended without clear benefits.
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http://dx.doi.org/10.1002/ddr.21862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426670PMC
July 2021

Bracing NK cell based therapy to relegate pulmonary inflammation in COVID-19.

Heliyon 2021 Jul 21;7(7):e07635. Epub 2021 Jul 21.

Department of Biotechnology, School of Engineering &Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India.

The contagiosity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has startled mankind and has brought our lives to a standstill. The treatment focused mainly on repurposed immunomodulatory and antiviral agents along with the availability of a few vaccines for prophylaxis to vanquish COVID-19. This seemingly mandates a deeper understanding of the disease pathogenesis. This necessitates a plausible extrapolation of cell-based therapy to COVID-19 and is regarded equivalently significant. Recently, correlative pieces of clinical evidence reported a robust decline in lymphocyte count in severe COVID-19 patients that suggest dysregulated immune responses as a key element contributing to the pathophysiological alterations. The large granular lymphocytes also known as natural killer (NK) cells play a heterogeneous role in biological functioning wherein their frontline action defends the body against a wide array of infections and tumors. They prominently play a critical role in viral clearance and executing immuno-modulatory activities. Accumulated clinical evidence demonstrate a decrease in the number of NK cells in circulation with or without phenotypical exhaustion. These plausibly contribute to the progression of pulmonary inflammation in COVID-19 pneumonia and result in acute lung injury. In this review, we have outlined the present understanding of the immunological response of NK cells in COVID-19 infection. We have also discussed the possible use of these powerful biological cells as a therapeutic agent in view of preventing immunological harms of SARS-CoV-2 and the current challenges in advocating NK cell therapy for the same.
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http://dx.doi.org/10.1016/j.heliyon.2021.e07635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294777PMC
July 2021

Demethyleneberberine: A possible treatment for Huntington's disease.

Med Hypotheses 2021 Aug 29;153:110639. Epub 2021 Jun 29.

Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt. Electronic address:

Huntington disease (HD) is a type of neurodegenerative disease that is characterized by presence of multiple repeats (more than 36) of cytosine-adenine-guanine (CAG) trinucleotides and mutated huntingtin (mHtt). This can further lead to oxidative stress, enhancement in level of ROS/RNS, mitochondrial dysfunction and neuroinflammations. Many clinical and preclinical trials have been conducted so far for the effective treatment of HD however, none of the drugs has shown complete relief. The regeneration of neurons is a very complicated process and associated with multiple pathological pathways. Hence, finding a unique solution using single drug that could act on multiple pathological pathways is really cumbersome. In the proposed hypothesis the use of demethyleneberberine (DMB) as a potential anti-HD agent has been explained. It is a metabolite of berberine and reported to act on multiple mechanistic pathways that are responsible for HD. Present article highlights new mechanistic insights through which DMB inhibits ROS/RNS, oxidative stress, mitochondrial dysfunctions and neuroinflammation such as NFκB, TNF-α, IL-6 and IL-8, cytokinin. Further its action on cellular apoptosis and neuronal cell death are also reported.
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http://dx.doi.org/10.1016/j.mehy.2021.110639DOI Listing
August 2021

Revolutionizing polymer-based nanoparticle-linked vaccines for targeting respiratory viruses: A perspective.

Life Sci 2021 Sep 24;280:119744. Epub 2021 Jun 24.

University of Alberta, Faculty of Pharmacy and Pharmaceutical Sciences, Edmonton, AB T6G 2N8, Canada; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia. Electronic address:

Viral respiratory tract infections have significantly impacted global health as well as socio-economic growth. Respiratory viruses such as the influenza virus, respiratory syncytial virus (RSV), and the recent SARS-CoV-2 infection (COVID-19) typically infect the upper respiratory tract by entry through the respiratory mucosa before reaching the lower respiratory tract, resulting in respiratory disease. Generally, vaccination is the primary method in preventing virus pathogenicity and it has been shown to remarkably reduce the burden of various infectious diseases. Nevertheless, the efficacy of conventional vaccines may be hindered by certain limitations, prompting the need to develop novel vaccine delivery vehicles to immunize against various strains of respiratory viruses and to mitigate the risk of a pandemic. In this review, we provide an insight into how polymer-based nanoparticles can be integrated with the development of vaccines to effectively enhance immune responses for combating viral respiratory tract infections.
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http://dx.doi.org/10.1016/j.lfs.2021.119744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223024PMC
September 2021

Recent updates on animal models for understanding the etiopathogenesis of polycystic ovarian syndrome.

Life Sci 2021 Sep 23;280:119753. Epub 2021 Jun 23.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Australia.

Polycystic ovarian syndrome (PCOS) is the primary cause of female infertility affecting several women worldwide. Changes in hormonal functions such as hyperandrogenism are considered a significant factor in developing PCOS in women. In addition, many molecular pathways are involved in the pathogenesis of PCOS in women. To have better insights about PCOS, it is data from clinical studies carried on women suffering from PCOS should be collected. However, this approach has several implications, including ethical considerations, cost involved and availability of subject. Moreover, during the early drug development process, it is always advisable to use non-human models mimicking human physiology as they are less expensive, readily available, have a shorter gestation period and less risk involved. Many animal models have been reported that resemble the PCOS pathways in human subjects. However, the models developed on rats and mice are more preferred over other rodent/non-rodent models due to their closer resemblance with human PCOS development mechanism. The most extensively reported PCOS models for rats and mice include those induced by using testosterone, letrozole and estradiol valerate. As the pathophysiology of PCOS is complex, none of the explored models completely surrogates the PCOS related conditions occurring in women. Hence, there is a need to develop an animal model that can resemble the pathophysiology of PCOS in women. The review focuses on various animal models explored to understand the pathophysiology of PCOS. The article also highlights some environmental and food-related models that have been used to induce PCOS.
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http://dx.doi.org/10.1016/j.lfs.2021.119753DOI Listing
September 2021

2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)-Inducible Poly-ADP-Ribose Polymerase (TIPARP/PARP7) Catalytic Mutant Mice (TiparpH532A) Exhibit Increased Sensitivity to TCDD-Induced Hepatotoxicity and Lethality.

Toxicol Sci 2021 Aug;183(1):154-169

Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8 Ontario, Canada.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-adenosine diphosphate (ADP)-ribose polymerase (TIPARP/PARP7), an aryl hydrocarbon receptor (AHR) target gene and mono-ADP-ribosyltransferase, acts as part of a negative feedback loop to repress AHR signaling. This process is prevented by a single H532A mutation in TIPARP that destroys its catalytic activity. We hypothesized that the loss of TIPARP catalytic activity would increase sensitivity to TCDD-induced toxicity in vivo. To test this, we created a catalytically deficient mouse line (TiparpH532A) by introducing a single H532A mutation in TIPARP. Treatment of mouse embryonic fibroblasts or hepatocytes isolated from TiparpH532A mice confirmed the increased TCDD-induced expression of the AHR target genes Cyp1a1, Cyp1b1, and Tiparp. TiparpH532A mice given a single injection of 10 µg/kg TCDD, a nonlethal dose in Tiparp+/+ mice, did not survive beyond day 10. All Tiparp+/+ mice survived the 30-day treatment. TCDD-treated TiparpH532A mice displayed increased expression of AHR target genes, increased steatohepatitis and hepatotoxicity. Hepatic RNA-sequencing revealed 7-fold more differentially expressed genes in TiparpH532A mice than in Tiparp+/+ mice (4542 vs 647 genes) 6 days after TCDD treatment. Differentially expressed genes included genes involved in xenobiotic metabolism, lipid homeostasis and inflammation. Taken together, these data further support TIPARP as a critical negative regulator of AHR activity and show that loss of its catalytic activity is sufficient to increase sensitivity to TCDD-induced steatohepatitis and lethality. Since TIPARP inhibition has recently emerged as a potential anticancer therapy, the impact on AHR signaling, TCDD and polycyclic aromatic hydrocarbon toxicity will need to be carefully considered under conditions of therapeutic TIPARP inhibition.
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http://dx.doi.org/10.1093/toxsci/kfab075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404992PMC
August 2021

Middle East Respiratory Syndrome (MERS) Virus-Pathophysiological Axis and the Current Treatment Strategies.

AAPS PharmSciTech 2021 Jun 8;22(5):173. Epub 2021 Jun 8.

Department of Life Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.

Middle East respiratory syndrome (MERS) is a lethal respiratory disease with its first case reported back in 2012 (Jeddah, Saudi Arabia). It is a novel, single-stranded, positive-sense RNA beta coronavirus (MERS-CoV) that was isolated from a patient who died from a severe respiratory illness. Later, it was found that this patient was infected with MERS. MERS is endemic to countries in the Middle East regions, such as Saudi Arabia, Jordan, Qatar, Oman, Kuwait and the United Arab Emirates. It has been reported that the MERS virus originated from bats and dromedary camels, the natural hosts of MERS-CoV. The transmission of the virus to humans has been thought to be either direct or indirect. Few camel-to-human transmissions were reported earlier. However, the mode of transmission of how the virus affects humans remains unanswered. Moreover, outbreaks in either family-based or hospital-based settings were observed with high mortality rates, especially in individuals who did not receive proper management or those with underlying comorbidities, such as diabetes and renal failure. Since then, there have been numerous reports hypothesising complications in fatal cases of MERS. Over the years, various diagnostic methods, treatment strategies and preventive measures have been strategised in containing the MERS infection. Evidence from multiple sources implicated that no treatment options and vaccines have been developed in specific, for the direct management of MERS-CoV infection. Nevertheless, there are supportive measures outlined in response to symptom-related management. Health authorities should stress more on infection and prevention control measures, to ensure that MERS remains as a low-level threat to public health.
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http://dx.doi.org/10.1208/s12249-021-02062-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186825PMC
June 2021

Acellular Scaffolds as Innovative Biomaterial Platforms for the Management of Diabetic Wounds.

Tissue Eng Regen Med 2021 Oct 28;18(5):713-734. Epub 2021 May 28.

Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.

Diabetic wound (DW) is one of the leading complications of patients having a long history of uncontrolled diabetes. Moreover, it also imposes an economic burden on people suffering from wounds to manage the treatment. The major impending factors in the treatment of DW are infection, prolonged inflammation and decreased oxygen levels. Since these non-healing wounds are associated with an extended recovery period, the existing therapies provide treatment for a limited period only. The areas covered in this review are general sequential events of wound healing along with DW's pathophysiology, the origin of DW and success, as well as limitations of existing therapies. This systematic review's significant aspect is to highlight the fabrication, characterization and applications of various acellular scaffolds used to heal DW. In addition to that, cellular scaffolds are also described to a limited extent.
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http://dx.doi.org/10.1007/s13770-021-00344-1DOI Listing
October 2021

Exploring role of polysaccharides present in Ganoderma lucidium extract powder and probiotics as solid carriers in development of liquisolid formulation loaded with quercetin: A novel study.

Int J Biol Macromol 2021 Jul 17;183:1630-1639. Epub 2021 May 17.

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.

Ganoderma lucidium extract powder (GLEP) contains various polysaccharides which are well known for their antioxidant and anti-inflammatory actions. Probiotics (PB) are well-established for providing a plethora of health benefits. Hence, use of mushroom polysaccharides and probiotics as carriers to solidify liquisolid formulation is anticipated to function as functional excipients i.e. as adsorbent that may provide therapeutic benefits. Quercetin (QUR) has been used as model lipophilic drug in this study. QUR loaded liquisolid compacts (LSCs) were formulated using Tween 80 as solvent. These were further solidified using a combination of PB and GLEP as carriers. Aerosil-200 (A-200) was used as coating agent. The formulation exhibited very good flow characteristics. Dissolution rate of raw QUR was found to be less than 10% in 60 min while in case of QUR loaded LSCs, more than 90% drug release was observed within 5 min. Absence of crystalline peaks of QUR in the DSC and PXRD reports of LSCs and their porous appearance in SEM micrographs indicate that QUR was successfully incorporated in the LSCs. The developed formulation was found to be stable on storage under accelerated stability conditions.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.05.064DOI Listing
July 2021

Advances in nanotechnology-based drug delivery in targeting PI3K signaling in respiratory diseases.

Nanomedicine (Lond) 2021 07 17;16(16):1351-1355. Epub 2021 May 17.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia.

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http://dx.doi.org/10.2217/nnm-2021-0087DOI Listing
July 2021

A novel nano therapeutic using convalescent plasma derived exosomal (CP) for COVID-19: A combined hyperactive immune modulation and diagnostics.

Chem Biol Interact 2021 Aug 13;344:109497. Epub 2021 May 13.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia.

Extracellular vesicles like exosomes are important therapeutic tactics for treating COVID -19. By utilizing convalescent plasma derived exosomes (CP) from COVID-19 recovered persistence could accelerate the treatment strategies in the current state of affairs. Adequate literature has shown that administering the exosome to the in vivo system could be beneficial and could target the pathogens in an effective and precise manner. In this hypothesis we highlight the CP instead of convalescent plasma (CP), perhaps to dispense of exosomes are gratified and it's more effectively acquired immune response conferral through antibodies. COVID-19 convalescent plasma has billions of exosomes and it has aptitudes to carry molecular constituents like proteins, lipids, RNA and DNA, etc. Moreover, exosomes are capable of recognizing antigens with adequate sensitivity and specificity. Many of these derivatives could trigger an immune modulation into the cells and act as an epigenetic inheritor response to target pathogens through RNAs. COIVID-19 resistance activated plasma-derived exosomes are either responsible for the effects of plasma beyond the contained immune antibodies or could be inhibitory. The proposed hypothesis suggests that preselecting the plasma-derived antibodies and RNAs merged exosomes would be an optimized therapeutic tactic for COVID-19 patients. We suggest that, the CP has a multi-potential effect for treatment efficacy by acting as immunotherapeutic, drug carrier, and diagnostic target with noncoding genetic materials as a biomarker.
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http://dx.doi.org/10.1016/j.cbi.2021.109497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116126PMC
August 2021

Sweet pepper and its principle constituent capsiate: functional properties and health benefits.

Crit Rev Food Sci Nutr 2021 May 6:1-25. Epub 2021 May 6.

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India.

Capsiate is a non-pungent analogue of capsaicin. It belongs to the family of capsinoids which are esters of vanillyl alcohol with fatty acids while capsaicin belongs to the family of capsaicinoids that are amides of vanillylamine with a variety of branched-chain fatty acids. While capsaicin is extensively reported for plethora of pharmacological actions, capsiate remains much less explored. Extracted from various species of Capsicum plant, the molecule has also been chemically synthesized via a number of synthetic and enzymatic routes. Based on its action on transient receptor potential vanilloid subfamily member 1 receptors, recent research has focused on its potential roles in treatment of obesity, metabolic disorders, cancer, cardiovascular disorders and gastro-intestinal disorders. Its toxicity profile has been reported to be much safe. The molecule, however, faces the challenge of low aqueous solubility and stability. It has been commercialized for its use as a weight loss supplement. However, the therapeutic potential of the compound which is much beyond boosting metabolism remains unexplored hitherto. This comprehensive review summarizes the studies demonstrating the therapeutic potential of capsiate in various pathological conditions. Discussed also are potential future directions for formulation strategies to develop efficient, safe and cost-effective dosage forms of capsiate to explore its role in various disease conditions. The databases investigated include Cochrane library, Medline, Embase, Pubmed and in-house databases. The search terms were "capsiate," "capsinoids," "thermogenesis," and their combinations. The articles were screened for relevance by going through their abstract. All the articles pertaining to physicochemical, physiological, pharmacological and therapeutic effects of capsiate have been included in the manuscript.
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http://dx.doi.org/10.1080/10408398.2021.1913989DOI Listing
May 2021

Advanced drug delivery systems targeting NF-κB in respiratory diseases.

Future Med Chem 2021 Jul 5;13(13):1087-1090. Epub 2021 May 5.

Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, T6G 2N8, Canada.

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http://dx.doi.org/10.4155/fmc-2021-0013DOI Listing
July 2021

Harnessing amphiphilic polymeric micelles for diagnostic and therapeutic applications: Breakthroughs and bottlenecks.

J Control Release 2021 06 19;334:64-95. Epub 2021 Apr 19.

Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India; Centre of Excellence in Nanoscience & Technology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.

Amphiphilic block copolymers are widely utilized in the design of formulations owing to their unique physicochemical properties, flexible structures and functional chemistry. Amphiphilic polymeric micelles (APMs) formed from such copolymers have gained attention of the drug delivery scientists in past few decades for enhancing the bioavailability of lipophilic drugs, molecular targeting, sustained release, stimuli-responsive properties, enhanced therapeutic efficacy and reducing drug associated toxicity. Their properties including ease of surface modification, high surface area, small size, and enhanced permeation as well as retention (EPR) effect are mainly responsible for their utilization in the diagnosis and therapy of various diseases. However, some of the challenges associated with their use are premature drug release, low drug loading capacity, scale-up issues and their poor stability that need to be addressed for their wider clinical utility and commercialization. This review describes comprehensively their physicochemical properties, various methods of preparation, limitations followed by approaches employed for the development of optimized APMs, the impact of each preparation technique on the physicochemical properties of the resulting APMs as well as various biomedical applications of APMs. Based on the current scenario of their use in treatment and diagnosis of diseases, the directions in which future studies need to be carried out to explore their full potential are also discussed.
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http://dx.doi.org/10.1016/j.jconrel.2021.04.014DOI Listing
June 2021

The FBXW7-NOTCH interactome: A ubiquitin proteasomal system-induced crosstalk modulating oncogenic transformation in human tissues.

Cancer Rep (Hoboken) 2021 Aug 6;4(4):e1369. Epub 2021 Apr 6.

Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, 201310, India.

Background: Ubiquitin ligases or E3 ligases are well programmed to regulate molecular interactions that operate at a post-translational level. Skp, Cullin, F-box containing complex (or SCF complex) is a multidomain E3 ligase known to mediate the degradation of a wide range of proteins through the proteasomal pathway. The three-dimensional domain architecture of SCF family proteins suggests that it operates through a novel and adaptable "super-enzymatic" process that might respond to targeted therapeutic modalities in cancer.

Recent Findings: Several F-box containing proteins have been characterized either as tumor suppressors (FBXW8, FBXL3, FBXW8, FBXL3, FBXO1, FBXO4, and FBXO18) or as oncogenes (FBXO5, FBXO9, and SKP2). Besides, F-box members like βTrcP1 and βTrcP2, the ones with context-dependent functionality, have also been studied and reported. FBXW7 is a well-studied F-box protein and is a tumor suppressor. FBXW7 regulates the activity of a range of substrates, such as c-Myc, cyclin E, mTOR, c-Jun, NOTCH, myeloid cell leukemia sequence-1 (MCL1), AURKA, NOTCH through the well-known ubiquitin-proteasome system (UPS)-mediated degradation pathway. NOTCH signaling is a primitive pathway that plays a crucial role in maintaining normal tissue homeostasis. FBXW7 regulates NOTCH protein activity by controlling its half-life, thereby maintaining optimum protein levels in tissue. However, aberrations in the FBXW7 or NOTCH expression levels can lead to poor prognosis and detrimental outcomes in patients. Therefore, the FBXW7-NOTCH axis has been a subject of intense study and research over the years, especially around the interactome's role in driving cancer development and progression. Several studies have reported the effect of FBXW7 and NOTCH mutations on normal tissue behavior. The current review attempts to critically analyze these mutations prognostic value in a wide range of tumors. Furthermore, the review summarizes the recent findings pertaining to the FBXW7 and NOTCH interactome and its involvement in phosphorylation-related events, cell cycle, proliferation, apoptosis, and metastasis.

Conclusion: The review concludes by positioning FBXW7 as an effective diagnostic marker in tumors and by listing out recent advancements made in cancer therapeutics in identifying protocols targeting the FBXW7-NOTCH aberrations in tumors.
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http://dx.doi.org/10.1002/cnr2.1369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388169PMC
August 2021

Biomedical applications of electrospun nanofibers in the management of diabetic wounds.

Drug Deliv Transl Res 2021 Mar 21. Epub 2021 Mar 21.

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India.

Diabetes mellitus (DM) is a complex disease that affects almost all the body's vital organs. Around 415 million people have been diagnosed with DM worldwide, and most of them are due to type 2 DM. The incidence of DM is estimated to increase by 642 million individuals by 2040. DM is considered to have many complications among which diabetic wound (DW) is one of the most distressing complication. DW affects 15% of people with diabetes and is triggered by the loss of glycaemic control, peripheral neuropathy, vascular diseases, and immunosuppression. For timely treatment, early detection, debridement, offloading, and controlling infection are crucial. Even though several treatments are available, the understanding of overlying diabetes-related wound healing mechanisms as therapeutic options has increased dramatically over the past decades. Conventional dressings are cost-effective; however, they are not productive enough to promote the overall process of DW healing. Thanks to tissue engineering developments, one of the promising current trends in innovative wound dressings such as hydrocolloids, hydrogels, scaffolds, films, and nanofibers which merges traditional healing agents and modern products/practices. Nanofibers prepared by electrospinning with enormous porosity, excellent absorption of moisture, the better exchange rate of oxygen, and antibacterial activities have increased interest. The application of these nanofibers can be extended by starting with a careful selection of polymers, loading with active therapeutic moieties such as peptides, proteins, active pharmaceutical ingredients (API), and stem cells, etc. to make them as potential dosage forms in the management of DWs. This review explains the potential applications of electrospun nanofibers in DW healing. A schematic view of role of nanofibers in diabetic wounds.
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http://dx.doi.org/10.1007/s13346-021-00941-6DOI Listing
March 2021

Applications and practice of advanced drug delivery systems for targeting Toll-like receptors in pulmonary diseases.

Nanomedicine (Lond) 2021 04 18;16(10):783-786. Epub 2021 Mar 18.

University of Alberta, Faculty of Pharmacy & Pharmaceutical Sciences, Edmonton, AB T6G 2N8, Canada.

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http://dx.doi.org/10.2217/nnm-2021-0056DOI Listing
April 2021

Rutin-loaded liquid crystalline nanoparticles attenuate oxidative stress in bronchial epithelial cells: a PCR validation.

Future Med Chem 2021 03 4;13(6):543-549. Epub 2021 Feb 4.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia.

In the present study, the inhibitory potential of rutin-loaded liquid crystalline nanoparticles (LCNs) on oxidative stress was determined in human bronchial epithelial cells (BEAS-2B) by analysing the expression levels of different antioxidant (NADPH quinine oxidoreductase-1 (); γ-glutamyl cysteine synthetase catalytic subunit ()) and pro-oxidant (NADPH oxidase ; ) genes. Our findings revealed that the rutin-loaded LCNs inhibited the genes, namely  and , which caused oxidative stress. In addition, these nanoparticles demonstrated an upregulation in the expression of the antioxidant genes  and in a dose-dependent manner. The study indicates the promising potential of rutin-loaded LCNs as an effective treatment strategy in patients with high oxidant loads in various respiratory diseases.
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http://dx.doi.org/10.4155/fmc-2020-0297DOI Listing
March 2021

Evidence of Coronavirus (CoV) Pathogenesis and Emerging Pathogen SARS-CoV-2 in the Nervous System: A Review on Neurological Impairments and Manifestations.

J Mol Neurosci 2021 Jan 19. Epub 2021 Jan 19.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI), University of Newcastle, New Lambton Heights, Newcastle, NSW, 2305, Australia.

The coronavirus disease 2019 (COVID-19) pandemic is an issue of global significance that has taken the lives of many across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for its pathogenesis. The pulmonary manifestations of COVID-19 have been well described in the literature. Initially, it was thought to be limited to the respiratory system; however, we now recognize that COVID-19 also affects several other organs, including the nervous system. Two similar human coronaviruses (CoV) that cause severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) are also known to cause disease in the nervous system. The neurological manifestations of SARS-CoV-2 infection are growing rapidly, as evidenced by several reports. There are several mechanisms responsible for such manifestations in the nervous system. For instance, post-infectious immune-mediated processes, direct virus infection of the central nervous system (CNS), and virus-induced hyperinflammatory and hypercoagulable states are commonly involved. Guillain-Barré syndrome (GBS) and its variants, dysfunction of taste and smell, and muscle injury are numerous examples of COVID-19 PNS (peripheral nervous system) disease. Likewise, hemorrhagic and ischemic stroke, encephalitis, meningitis, encephalopathy acute disseminated encephalomyelitis, endothelialitis, and venous sinus thrombosis are some instances of COVID-19 CNS disease. Due to multifactorial and complicated pathogenic mechanisms, COVID-19 poses a large-scale threat to the whole nervous system. A complete understanding of SARS-CoV-2 neurological impairments is still lacking, but our knowledge base is rapidly expanding. Therefore, we anticipate that this comprehensive review will provide valuable insights and facilitate the work of neuroscientists in unfolding different neurological dimensions of COVID-19 and other CoV associated abnormalities.
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http://dx.doi.org/10.1007/s12031-020-01767-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814864PMC
January 2021

Induction of Caspase-Mediated Apoptosis in HepG2 Liver Carcinoma Cells Using Mutagen-Antioxidant Conjugated Self-Assembled Novel Carbazole Nanoparticles and In Silico Modeling Studies.

ACS Omega 2021 Jan 21;6(1):265-277. Epub 2020 Dec 21.

Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4041, South Africa.

In this study, novel self-assembled carbazole-thiooctanoic acid nanoparticles (CTNs) were synthesized from amino carbazole (a mutagen) and thiooctanoic acid (an antioxidant). The nanoparticles were characterized using hyperspectral techniques. Then, the antiproliferative potential of CTNs was determined in HepG2 liver carcinoma cells. This study employed a solvent-antisolvent interaction method to synthesize a spherical CTN of size less than 50 nm. Moreover, CT was subsequently capped to gold nanoparticles (AuNPs) in the additional comparative studies. The CT derivative was synthesized from carbazole and lipoic acid by the amide bond formation reaction using a coupling agent. Furthermore, it was characterized using infrared (IR), H nuclear magnetic resonance, dynamic light scattering (DLS), and transmission electron microscopy techniques. The CT-capped gold nanoparticles (CTAuNPs) were prepared from CT, chloroauric acid, and NaBH. The CTAuNPs were characterized using ultraviolet-visible, high-resolution TEM, DLS, and Fourier transform IR techniques. The cytotoxicity and apoptosis-inducing ability of both nanoparticles were determined in HepG2 cells. The results demonstrate that CTNs exhibit antiproliferative activity in the cancerous HepG2 cells. Moreover, molecular docking and molecular dynamics studies were conducted to explore the therapeutic potential of CT against human EGFR suppressor protein to gain more insights into the binding mode of the CT, which may show a significant role in anticancer therapy.
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http://dx.doi.org/10.1021/acsomega.0c04461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807466PMC
January 2021

Overview of in situ gelling injectable hydrogels for diabetic wounds.

Drug Dev Res 2021 Jun 12;82(4):503-522. Epub 2021 Jan 12.

Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.

Diabetes mellitus (DM) is an endocrine disorder that causes increased blood glucose than usual due to insulin impairment. In DM, several complications arise in which diabetic wound (DW) is the most devastating complication. About 25% of patients with DM expected to develop DWs in their lifetime and undergo limb amputations. Even though several treatments such as surgery, debridement, wound dressings, advanced therapies were available, the overall conclusion has been that with very few exceptions, patients still suffer from limitations like pain, frequent dress changing, high rates of failure, and cost involvement. Further, the treatments involving the delivery of therapeutic agents in treating DWs have limited success due to abnormal levels of proteases in the DW environment. In this backdrop, in situ gelling injectable hydrogels have gained special attention due to their easy encapsulation of therapeutic medications and prolonged release, filling the wound defect areas, ease of handling, and minimally invasive surgical procedures. Though the in situ gelling injectable hydrogels are developed a couple of decades ago, their use for treating DW has not yet been explored thoroughly. Thus, in this review, we have covered the sequential events of DW healing, pathophysiology, current treatments, and its limitations, along with a particular emphasis on the mechanism of action of these in situ gelling injectable hydrogels treating DWs.
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http://dx.doi.org/10.1002/ddr.21788DOI Listing
June 2021

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities.

Life Sci 2021 Feb 2;267:118973. Epub 2021 Jan 2.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI), University of Newcastle, New Lambton Heights, Newcastle, NSW 2305, Australia; School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh 173229, India. Electronic address:

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.
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http://dx.doi.org/10.1016/j.lfs.2020.118973DOI Listing
February 2021
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