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Fulltext Polyphenols as Prebiotics in the Management of High-Fat Diet-Induced Obesity: A Systematic Review of Animal Studies

Moorthy M, Sundralingam U, Palanisamy UD

Foods, 2021 Feb 02;10(2).
PMID: 33540692 DOI: 10.3390/foods10020299

Obesity is a disease growing at an alarming rate and numerous preclinical studies have proven the role of polyphenols in managing this disease. This systematic review explores the prebiotic effect of polyphenols in the management of obesity among animals fed on a high-fat diet. A literature search was carried out in PubMed, Scopus, CINAHL, Web of Science, and Embase databases following the PRISMA guidelines. Forty-four studies reported a significant reduction in obesity-related parameters. Most notably, 83% of the studies showed a decrease in either body weight/visceral adiposity/plasma triacylglyceride. Furthermore, 42 studies reported a significant improvement in gut microbiota (GM), significantly affecting the genera Akkermansia, Bacteroides, Blautia, Roseburia, Bifidobacteria, Lactobacillus, Alistipes, and Desulfovibrio. Polyphenols' anti-obesity, anti-hyperglycaemic, and anti-inflammatory properties were associated with their ability to modulate GM. This review supports the notion of polyphenols as effective prebiotics in ameliorating HFD-induced metabolic derangements in animal models.
Fulltext Efficacy of Emu Oil Transfersomes for Local Transdermal Delivery of 4-OH Tamoxifen in the Treatment of Breast Cancer

Sundralingam U, Chakravarthi S, Radhakrishnan AK, Muniyandy S, Palanisamy UD

Pharmaceutics, 2020 Aug 25;12(9).
PMID: 32854385 DOI: 10.3390/pharmaceutics12090807

Oral tamoxifen used in the prevention and treatment of ductal carcinoma in situ (DCIS) (estrogen-positive) patients has limited acceptance, due to its adverse side effects. The efficacy of tamoxifen is related to its major metabolite, 4-hydroxytamoxifen. Local transdermal therapy of 4-hydroxytamoxifen to the breast might avert the toxicity of oral tamoxifen, while maintaining efficacy. We aim to study the skin irritancy, as well as to evaluate the efficacy of the developed transfersome formulations, with/without emu oil, using a syngeneic mouse model of breast cancer. We also quantified tamoxifen/4-hydroxytamoxifen concentrations in blood plasma and performed histopathology. The skin irritancy test showed that the pure emu oil and transfersome formulations with or without the emu oil did not cause skin irritancy in the animals studied. A sensitive and specific LC-MS/MS method for the quantification of tamoxifen and 4-hydroxytamoxifen was developed and validated. Studies on tumor volume and necrosis (histopathology) using the breast cancer mouse model showed that the 4-OHT transfersomal formulations, with and without emu oil, showed comparable efficacy with that of orally administered tamoxifen. However, the transfersomal formulations, with and without emu oil, resulted in significantly lower (10.24 ± 0.07 and 32.45 ± 0.48 ng/mL, respectively) plasma concentrations of 4-hydroxytamoxifen, compared to the oral tamoxifen (TAMX) group (634.42 ± 7.54 ng/mL). This study demonstrated the potential use of emu oil in a local transdermal formulation for the treatment of breast cancer and its reduced adverse effects.
Review: Patient-controlled transdermal 4-hydroxytamoxifen (4-OHT) vs. oral tamoxifen: A systematic review and meta analysis

Sundralingam U, Khan TM, Elendran S, Muniyandy S, Palanisamy UD

Pak J Pharm Sci, 2019 May;32(3):1121-1128.
PMID: 31278729

There has been a number of studies looking into an alternative mode of therapy for the treament of breast cancer via 4-hydroxytamoxifen (4-OHT) transdermal administration.This systematic review aims to compare the safety and efficacy of a transdermal 4-OHT local therapy and oral tamoxifen (oral-T) on the treatment of ductal carcinoma in situ breast cancer. Through a systematic search of health science databases, eligible trials were located and the end points assessed were Ki-67 labeling index, concentration of 4-OHT in breast adipose tissue (ng/g) and plasma (ng/ml). Revman 5.3 version was used to perfom the meta-analysis. Three trials were identified (n=103), while only two were included for meta analysis. The mean difference between the two studies included were 0.40 and -10.58. Overall the I2 value was 89.0%, (Tau2 =53.86) and the differences between the two trials were statistically significant p=0.002. The meta analysis of the randomized controlled trials showed that the use of local transdermal therapy of 4-OHT gel is more safer than oral-T. However, due to the limited number of studies, the potential use of 4-OHT topical transdermal therapy for the treatment of breast cancer could not be concluded for healthcare professionals.
Ratite oils for local transdermal therapy of 4-OH tamoxifen: development, characterization, and ex vivo evaluation

Sundralingam U, Muniyandy S, Radhakrishnan AK, Palanisamy UD

J Liposome Res, 2021 Sep;31(3):217-229.
PMID: 32648792 DOI: 10.1080/08982104.2020.1777155

The anti-inflammatory property of ratite oils as well as its ability to act as a penetration enhancer makes it an ideal agent to be used in transdermal formulations. The present study aims to develop an effective transfersomal delivery of 4-hydroxytamoxifen (4-OHT), an anti-cancer drug, using ratite oil as a carrier agent for the treatment of breast cancer (BC). The 4-OHT transfersomes were prepared with and without ratite oils using soy phosphatidylcholine and three different edge activators (EAs) in five different molar ratios using the rotary evaporation-ultrasonication method. Optimal transfersome formulations were selected using physical-chemical characterization and ex vivo studies. Results from physical-chemical characterization of the developed formulations found sodium taurocholate to be the most suitable EA, which recorded highest entrapment efficiency of 95.1 ± 2.70% with 85:15, (w/w) and lowest vesicle size of 82.3 ± 0.02 nm with 75:25, (w/w) molar ratios. TEM and DSC studies showed that the vesicles were readily identified and present in a nearly perfect spherical shape. In addition, formulations with emu oil had better stability than formulations with ostrich oil. Physical stability studies at 4 °C showed that ratite oil transfersomes were stable up to 4 weeks, while transfersomes without ratite oils were stable for 8 weeks. Ex vivo permeability studies using porcine skin concluded that 4-OHT transfersomal formulations with (85:15, w/w) without emu oil have the potential to be used in transdermal delivery approach to enhance permeation of 4-OHT, which may be beneficial in the treatment of BC.
Fulltext Enhancing the Bioavailability of the Ellagitannin, Geraniin: Formulation, Characterization, and in vivo Evaluation

Elendran S, Shiva Kumar V, Sundralingam U, Tow WK, Palanisamy UD

Int J Pharm, 2024 Jul 20;660:124333.
PMID: 38866080 DOI: 10.1016/j.ijpharm.2024.124333

Geraniin (GE), an ellagitannin (ET) renowned for its promising health advantages, faces challenges in its practical applications due to its limited bioavailability. This innovative and novel formulation of GE and soy-phosphatidylcholine (GE-PL) complex has the potential to increase oral bioavailability, exhibiting high entrapment efficiency of 100.2 ± 0.8 %, and complexation efficiency of 94.6 ± 1.1 %. The small particle size (1.04 ± 0.11 μm), low polydispersity index (0.26 ± 0.02), and adequate zeta potential (-26.1 ± 0.12 mV), indicate its uniformity and stability. Moreover, the formulation also demonstrates improved lipophilicity, reduced aqueous and buffer solubilities, and better partition coefficient. It has been validated by various analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. Oral bioavailability and pharmacokinetics of free GE and GE-PL complex investigated in rabbits demonstrated enhanced plasma concentration of ellagic acid (EA) compared to free GE. Significantly, GE, whether in its free form or as part of the GE-PL complex, was not found in the circulatory system. However, EA levels were observed at 0.5 h after administration, displaying two distinct peaks at 2 ± 0.03 h (T1max) and 24 ± 0.06 h (T2max). These peaks corresponded to peak plasma concentrations (C1max and C2max) of 588.82 ng/mL and 711.13 ng/mL respectively, signifying substantial 11-fold and 5-fold enhancements when compared to free GE. Additionally, it showed an increased area under the curve (AUC), the elimination half-life (t1/2, el) and the elimination rate constant (Kel). The formulation of the GE-PL complex prolonged the presence of EA in the bloodstream and improved its absorption, ultimately leading to a higher oral bioavailability. In summary, the study highlights the significance of the GE-PL complex in overcoming the bioavailability limitations of GE, paving the way for enhanced therapeutic outcomes and potential applications in drug delivery and healthcare.
Fulltext Cytotoxic Labdane Diterpenes, Norlabdane Diterpenes and Bis-Labdanic Diterpenes from the Zingiberaceae: A Systematic Review

Voon KJ, Sivasothy Y, Sundralingam U, Lalmahomed A, Goh AP

Pharmaceuticals (Basel), 2022 Dec 05;15(12).
PMID: 36558968 DOI: 10.3390/ph15121517

Over the years, labdane diterpenes, norlabdane diterpenes, and bis-labdanic diterpenes with cytotoxic activities have been identified across various families in the plant kingdom including the Zingiberaceae. The present review discusses the distribution of these labdane-type diterpenes within the Zingiberaceae; their extraction, isolation, and characterization from the respective Zingiberaceae species; the structural similarities and differences within each group and between the different groups of the labdane-type diterpenes; and their cytotoxic activities against breast, cervical, liver, colorectal, pancreatic, lung and prostate cancer cell lines. The review will also provide insight into how the cytotoxic activities of the labdane-type diterpenes are influenced by their structural features.
Improving oral bioavailability of medicinal herbal compounds through lipid-based formulations - A Scoping Review

Tan OJ, Loo HL, Thiagarajah G, Palanisamy UD, Sundralingam U

Phytomedicine, 2021 Sep;90:153651.
PMID: 34340903 DOI: 10.1016/j.phymed.2021.153651

BACKGROUND: Although numerous medicinal herbal compounds demonstrate promising therapeutic potential, their clinical application is often limited by their poor oral bioavailability. To circumvent this barrier, various lipid-based herbal formulations have been developed and trialled with promising experimental results.
PURPOSE: This scoping review aims to describe the effect of lipid-based formulations on the oral bioavailability of herbal compounds.
METHODS: A systematic search was conducted across three electronic databases (Medline, Embase and Cochrane Library) between January 2010 and January 2021 to identify relevant studies. The articles were rigorously screened for eligibility. Data from eligible studies were then extracted and collated for synthesis and descriptive analysis using Covidence.
RESULTS: A total of 109 studies were included in the present review: 105 animal studies and four clinical trials. Among the formulations investigated, 50% were emulsions, 34% lipid particulate systems, 12% vesicular systems, and 4% were other types of lipid-based formulations. Within the emulsion system classification, self-emulsifying drug delivery systems were observed to produce the best improvements in oral bioavailability, followed by mixed micellar formulations. The introduction of composite lipid-based formulations and the use of uncommon surfactants such as sodium oleate in emulsion preparation was shown to consistently enhance the bioavailability of herbal compounds with poor oral absorption. Interestingly, the lipid-based formulations of magnesium lithospermate B and Pulsatilla chinensis produced an absolute bioavailability greater than 100% indicating the possibility of prolonged systemic circulation. With respect to chemical conjugation, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was the most frequently used and significantly improved the bioavailability of its phytoconstituents.
CONCLUSION: Our findings suggest that there is no distinct lipid-based formulation superior to the other. Bioavailability improvements were largely dependent on the nature of the phytoconstituents. This scoping review, however, provided a detailed summary of the most up-to-date evidence on phytoconstituents formulated into lipid preparations and their oral bioavailability. We conclude that a systematic review and meta-analysis between bioavailability improvements of individual phytoconstituents (such as kaempferol, morin and myricetin) in various lipid-based formulations will provide a more detailed association. Such a review will be highly beneficial for both researchers and herbal manufacturers.
Exploring the Role of Herbal Compounds in Skin Aging: A Systematic Review of Topical Approaches

Goh AP, Goh SM, Tow WK, Toh KM, Palanisamy UD, Sundralingam U

Phytother Res, 2025 Jan;39(1):315-363.
PMID: 39541733 DOI: 10.1002/ptr.8375

Recently, dermatology has increasingly focused on understanding skin aging and exploring novel therapeutic approaches. Despite progress in cosmetic and pharmaceutical research, a significant gap remains in comprehensively understanding the effects and mechanisms of herbal extracts on skin aging. While many studies have examined the bioactivities of herbal compounds in preclinical models, comprehensive human trials have been scarce over the past decade. This review aims to address this gap by synthesizing human trials from the past decade, focusing on the therapeutic effects of herbal extracts on skin aging. The objective is to unravel the mechanisms contributing to skin aging and assess the therapeutic potential of herbal compounds. Following the PRISMA 2020 guideline, a systematic review was performed across OvidMEDLINE, Cochrane Central Register of Controlled Trials, and Embase via Ovid. A meticulous search strategy identified relevant clinical trials. The review highlights the essential role of herbal compounds in skin aging, particularly their antioxidant activity in suppressing the aging process. Analysis of 51 clinical trials offers valuable insights into their diverse effects on skin aging parameters. Herbal compounds are promising alternatives to synthetic products for treating skin aging. Their demonstrated efficacy in mitigating wrinkles, enhancing elasticity, maintaining hydration, and controlling pigmentation underscores their potential in developing antiaging therapeutics. However, further studies are needed to identify specific compounds responsible for these effects and understand their mechanisms. Future directions include conducting large-scale trials, exploring synergies with other ingredients, and optimizing delivery systems for sustainable, effective antiaging therapies.