Therapeutic uses of post-partum tissue-derived mesenchymal stromal cell secretome.

Human post-partum tissue mesenchymal stromal cells (hPPT-MSCs) are widely used in research to investigate their differentiation capabilities and therapeutic effects as potential agents in cell-based therapy. This is ascribed to the advantages offered by the use of MSCs isolated from hPPT over other MSC sources. A paradigm shift in related research is evident that focuses on the secretome of the human MSCs (hMSCs), as therapeutic effects of hMSCs are attributed more so to their secreted growth factors, cytokines and chemokines and to the extracellular vesicles (EVs), all of which are components of the hMSC secretome. Positive therapeutic effects of the hPPT-MSC secretome have been demonstrated in diseases related to skin, kidney, heart, nervous system, cartilage and bones, that have aided fast recovery by replacing damaged, non-functional tissues, via differentiating and regenerating cells. Although certain limitations such as short half -life of the secretome components and irregular secreting patterns exist in secretome therapy, these issues are successfully addressed with the use of cutting-edge technologies such as genome editing and recombinant cytokine treatment. If the current limitations can be successfully overcome, the hPPT-MSC secretome including its EVs may be developed into a cost-effective therapeutic agent amenable to be used against a wide range of diseases/disorders.

Mature leaf concentrate of Sri Lankan wild type Carica papaya Linn. modulates nonfunctional and functional immune responses of rats.

BACKGROUND: The leaf concentrate of Carica papaya is a traditionally acclaimed immunomodulatory remedy against numerous diseases; nonetheless comprehensive scientific validation of this claim is limited. The present study thus investigated the immunomodulatory potential of Carica papaya mature leaf concentrate (MLCC) of the Sri Lankan wild type cultivar using nonfunctional and functional immunological assays. METHODS: Wistar rats (N = 6/ group) were orally gavaged with 3 doses (0.18, 0.36 and 0.72 ml/100g body weight) of the MLCC once daily for 3 consecutive days. Selected nonfunctional (enumeration of immune cells and cytokine levels) and functional (cell proliferation and phagocytic activity) immunological parameters, and acute toxic effects were determined using standard methods. Effect of the MLCC (31.25, 62.5, 125, 250, 500 and 1000 µg/ml) on ex vivo proliferation of bone marrow cells (BMC) and splenocytes (SC), and in vitro phagocytic activity of peritoneal macrophages (PMs), and their corresponding cytokine responses were evaluated. The phytochemical profile of the MLCC was established using liquid chromatography-mass spectrometry (LS-MS) and Gas chromatography-mass spectrometry (GC-MS). RESULTS: Counts of rat platelets, total leukocytes, lymphocyte and monocyte sub populations, and BMCs were significantly augmented by oral gavage of the MLCC (p < 0.05). The highest MLCC dose tested herein significantly reduced pro inflammatory cytokines, Interleukin 6 (IL-6) and Tumor Necrosis Factor α (TNF α) levels of rats (p < 0.05). The in vivo phagocytic index of rat PMs significantly increased by oral gavage of all three doses of the MLCC (p < 0.05). In vitro phagocytic activity of rat PMs were enhanced by the MLCC and triggered a Th1 biased cytokine response. The MLCC at low concentrations elicited ex vivo proliferation of BMC (31.25 µg/ml) and SC (31.25 and 62.5 µg/ml) respectively. Conversely, high concentrations (500 and 1000 µg/ml) exhibited cytotoxicity of both BMC and SC with significant modulation of cytokines. Chemical profile of the MLCC revealed the presence of several immunomodulatory compounds. The oral gavage of the MLCC was found to be safe in terms of both hepatic and renal toxicities. CONCLUSION: The present study established that the mature leaf concentrate (MLCC) of Carica papaya Sri Lankan wild type cultivar is orally active, safe and effectively modulates nonfunctional and functional immunological parameters of rats that unequivocally corroborate the traditional medical claims.

Heavy metal-induced toxicity in the Indian green frog: Biochemical and histopathological alterations.

Heavy metal contamination may have adverse effects on wetland biota, particularly on amphibians. Severe immunotoxic effects elicited in Euphlyctis hexadactylus (Indian green frog) because of metal exposure (Cd, Cr, Cu, Pb, and Zn) in the Bellanwila-Attidiya Sanctuary, a polluted urban wetland in Sri Lanka, provided the rationale for the present study. We evaluated the biochemical and histopathological effects of this metal contamination with a reference E. hexadactylus population and a laboratory exposure group that was subjected to 28 d of exposure to a mixture of Cd, Cr, Cu, Pb, and Zn (5 ppm in each mixture). A histopathological scoring for the semiquantification of tissue damage was established. Results of the biochemical and histopathological markers were remarkably consistent between the 2 exposure scenarios, providing validation for the heavy metal exposure hypothesis. Damage to liver, kidney, lung, and skin of metal-exposed E. hexadactylus quantified multiple impairments absent in the reference frogs. Liver injuries complemented significantly elevated aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transferase (γ-GT), and alkaline phosphatases in frog liver homogenate, indicating hepatocellular leakage and loss of functional and structural integrity of the hepatocyte membrane in both field- and laboratory-exposed frogs. Significant elevation of Kupffer cell hypertrophy, pigmentation, inflammatory cell infiltrates and hepatic inflammation, extramedullary hematopoiesis, karyocytomegaly of hepatocytes (p < 0.05) of the liver, and degeneration of epithelia and necrosis of the lung, manifested as impairments in both metal exposure scenarios. Significantly reduced serum total protein and albumin and significantly elevated urea and creatinine in metal-exposed frogs were indicative of hepatic and renal dysfunction, respectively. The present study affirms histopathology-related biochemical alterations as potential biomarkers for heavy metal toxicity in amphibians. Environ Toxicol Chem 2017;36:2855-2867. © 2017 SETAC.

Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells.

Stem cell therapy has revolutionized modern clinical therapy with the potential of stem cells to differentiate into many different cell types which may help to replace different cell lines of an organism. Innumerous trials are carried out to merge new scientific knowledge and techniques with traditional herbal extracts that may result in less toxic, affordable, and highly available natural alternative therapeutics. Currently, mesenchyamal stromal cell (MSC) lines are treated with individual and mixtures of crude herbal extracts, as well as with purified compounds from herbal extracts, to investigate the mechanisms and effects of these on stem cell growth and differentiation. Human MSCs (hMSCs) possess multilineage, i.e., osteogenic, neurogenic, adipogenic, chondrogenic, and myogenic, differentiation abilities. The proliferative and differentiation properties of hMSCs treated with herbal extracts have shown promise in diseases such as osteoporosis, neurodegenerative disorders, and other tissue degenerative disorders. Well characterized herbal extracts that result in increased rates of tissue regeneration may be used in both stem cell therapy and tissue engineering for replacement therapy, where the use of scaffolds and vesicles with enhanced attaching and proliferative properties could be highly advantageous in the latter. Although the clinical application of herbal extracts is still in progress due to the variability and complexity of bioactive constituents, standardized herbal preparations will strengthen their application in the clinical context. We have critically reviewed the proliferative and differentiation effects of individual herbal extracts on hMSCs mainly derived from bone marrow and elaborated on the plausible underlying mechanisms of action. To be fruitfully used in reparative and regenerative therapy, future directions in this area of study should (i) make use of hMSCs derived from different non-traditional sources, including medical waste material (umbilical cord, Wharton's jelly, and placenta), (ii) take account of the vast numbers of herbal extracts used in traditional medicine globally, and (iii) investigate the mechanisms and pathways of their effects on hMSCs.

A shifting paradigm in the aetiology of oral and pharyngeal cancer in Sri Lanka: a case-control study providing serologic evidence for the role of oncogenic HPV types 16 and 18.

BACKGROUND: Oral and pharyngeal cancer (OPC) of multifactorial aetiology is a major health problem globally. Ranking first in all cancers, OPC poses a significant impact on the Sri Lankan male population. As Human Papillomavirus (HPV) high risk (HR) types are found to be significant risk factors for OPC globally, the current study was undertaken to examine the association between HR-HPV16 and 18 types with OPC in Sri Lanka. MATERIALS AND METHODS: Serum samples of 78 OPC patients and 51 non-cancer controls were assayed for the presence of anti-HPV16 and anti-HPV18 IgG antibodies using in-house established Enzyme Linked Immunosorbent Assays (ELISAs). The association between OPC and its risk factors i.e. HPV, smoking, alcohol, betel quid, poor dentition, was established using Chi-square test. Logistic regression was used to calculate odds ratios (OR), adjusted for the influence of other risk factors. RESULTS: This prototype study in Sri Lanka showed a significant risk of 15 fold in developing OPC due to HPV16/18 seropositivity after removing variability due to other factors. Oncogenic HPV18 showed a higher rate of seropositivity being detected in 32% of OPC patients, and also in 2% of non-cancer control subjects. HR-HPV16 was detected in 23% of OPC patients and in 5.88% of controls. Moreover, seven OPC patients were detected with both anti-HPV16 and anti-HPV18 antibodies. According to the logistic regression models HPV18 seropositivity was associated with a 28 fold risk in developing OPC while that of HPV16 was associated with a 6 fold increase in risk for the development of OPC. A 5 fold risk of developing OPC was also pronounced among smokers while alcohol, betel and poor dentition was not significantly associated with OPC. Statistically significant differences with regard to age, gender, smoking, alcohol, betel use, poor dentition and site specificity of the tumour was not observed between HPV seropositive and seronegative OPC patients. CONCLUSIONS: Both in-house developed ELISAs detected significant proportions of HPV seropositives within the OPC study population suggestive of HPV as a strong risk factor for oral and pharyngeal carcinogenesis in Sri Lanka.