Cannabinoids Drugs and Oral Health-From Recreational Side-Effects to Medicinal Purposes: A Systematic Review.

BACKGROUND: marijuana, the common name for cannabis sativa preparations, is one of the most consumed drug all over the world, both at therapeutical and recreational levels. With the legalization of medical uses of cannabis in many countries, and even its recreational use in most of these, the prevalence of marijuana use has markedly risen over the last decade. At the same time, there is also a higher prevalence in the health concerns related to cannabis use and abuse. Thus, it is mandatory for oral healthcare operators to know and deal with the consequences and effects of cannabis use on oral cavity health. This review will briefly summarize the components of cannabis and the endocannabinoid system, as well as the cellular and molecular mechanisms of biological cannabis action in human cells and biologic activities on tissues. We will also look into oropharyngeal tissue expression of cannabinoid receptors, together with a putative association of cannabis to several oral diseases. Therefore, this review will elaborate the basic biology and physiology of cannabinoids in human oral tissues with the aim of providing a better comprehension of the effects of its use and abuse on oral health, in order to include cannabinoid usage into dental patient health records as well as good medicinal practice. METHODS: the paper selection was performed by PubMed/Medline and EMBASE electronic databases, and reported according to the PRISMA guidelines. The scientific products were included for qualitative analysis. RESULTS: the paper search screened a total of 276 papers. After the initial screening and the eligibility assessment, a total of 32 articles were considered for the qualitative analysis. CONCLUSIONS: today, cannabis consumption has been correlated to a higher risk of gingival and periodontal disease, oral infection and cancer of the oral cavity, while the physico-chemical activity has not been completely clarified. Further investigations are necessary to evaluate a therapeutic efficacy of this class of drugs for the promising treatment of several different diseases of the salivary glands and oral diseases.

Combination of Mycobacterium indicus pranii and Heat-Induced Promastigotes Cures Drug-Resistant Leishmania Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells.

The major issues in available therapeutic modalities against leishmaniasis are cost, toxicity, and the emergence of drug resistance. The aim of this work was to develop a successful therapeutic adjuvant against drug-resistant Leishmania donovani infection by means of combining Mycobacterium indicus pranii with heat-induced promastigotes (HIP). One-month postinfected BALB/c mice were administered subcutaneously with M. indicus pranii (108 cells) and HIP (100 µg) for 5 days. Spleens were harvested for flow cytometric and reverse transcriptase PCR analysis. The antileishmanial effect of the combination strategy was associated with induction of a disease-resolving Th1 and Th17 response with simultaneous downregulation of CD4+ CD25+ Foxp3+ (nTreg) cells and CD4+ CD25- Foxp3- (Tr1) cells in the spleen. The significant expansion of CD4+ TCM (CD4+ CD44hi CD11ahi CD62Lhi) cells was a further interesting outcome of this therapeutic strategy in the context of long-term protection of hosts against secondary infection. Toll-like receptor 2 (TLR2) was also found instrumental in this antiparasitic therapy. Induced interleukin-6 (IL-6) production from expanded CD11c+ CD8α+ (cDC1) and CD11c+ CD11b+ (cDC2) dendritic cells (DCs) but not from the CD11b+ Ly6c+ inflammatory monocytes (iMOs), was found critical in the protective expansion of Th17 as evidenced by an in vivo IL-6 neutralization assay. It also promoted the hematopoietic conversion toward DC progenitors (pre-DCs) from common dendritic cell progenitors (CDPs), the immediate precursors, in bone marrow. This novel combinational strategy demonstrated that expansion of Th17 by IL-6 released from CD11c+ classical DCs is crucial, together with the conventional Th1 response, to control drug-resistant infection.

Anti-Arthritic and Anti-Cancer Activities of Polyphenols: A Review of the Most Recent In Vitro Assays.

Polyphenols have gained widespread attention as they are effective in the prevention and management of various diseases, including cancer diseases (CD) and rheumatoid arthritis (RA). They are natural organic substances present in fruits, vegetables, and spices. Polyphenols interact with various kinds of receptors and membranes. They modulate different signal cascades and interact with the enzymes responsible for CD and RA. These interactions involve cellular machinery, from cell membranes to major nuclear components, and provide information on their beneficial effects on health. These actions provide evidence for their pharmaceutical exploitation in the treatment of CD and RA. In this review, we discuss different pathways, modulated by polyphenols, which are involved in CD and RA. A search of the most recent relevant publications was carried out with the following criteria: publication date, 2012-2022; language, English; study design, in vitro; and the investigation of polyphenols present in extra virgin olive, grapes, and spices in the context of RA and CD, including, when available, the underlying molecular mechanisms. This review is valuable for clarifying the mechanisms of polyphenols targeting the pathways of senescence and leading to the development of CD and RA treatments. Herein, we focus on research reports that emphasize antioxidant properties.

Cisplatin Chemotherapy and Cochlear Damage: Otoprotective and Chemosensitization Properties of Polyphenols.

Significance: Cisplatin is an important component of treatment regimens for different cancers. Notwithstanding that therapeutic success often results from partial efficacy or stabilizing the disease, chemotherapy failure is driven by resistance to drug treatment and occurrence of side effects, such as progressive irreversible ototoxicity. Cisplatin's side effects, including ototoxicity, are often dose limiting. Recent Advances: Cisplatin ototoxicity results from several mechanisms, including redox imbalance caused by reactive oxygen species production and lipid peroxidation, activation of inflammation, and p53 and its downstream pathways that culminate in apoptosis. Considerable efforts in research have targeted development of molecular interventions that can be concurrently administered with cisplatin or other chemotherapies to reduce side effect toxicities while preserving or enhancing the antineoplastic effects. Evidence from studies has indicated some polyphenols, such as curcumin, can help to regulate redox signaling and inflammatory effects. Furthermore, polyphenols can exert opposing effects in different types of tissues, that is, normal cells undergoing stressful conditions versus cancer cells. Critical Issues: This review article summarizes evidence of curcumin antioxidant effect against cisplatin-induced ototoxicity that is converted to a pro-oxidant activity in cisplatin-treated cancer cells, thus providing an ideal chemosensitivity combined with otoprotection. Polyphenols can modulate the adaptive responses to stress in the cisplatin-exposed cochlea. These adaptive effects can result from the interaction/cross talk between the cell's defenses, inflammatory molecules, and the key signaling molecules of signal transducers and activators of transcription 3 (STAT-3), nuclear factor κ-B (NF-κB), p53, and nuclear factor erythroid 2-related factor 2 (Nrf-2). Future Directions: We provide molecular evidence for alternative strategies for chemotherapy with cisplatin addressing the otoprotection and chemosensitization properties of polyphenols. Antioxid. Redox Signal. 36, 1229-1245.

Asclepain cI, a proteolytic enzyme from Asclepias curassavica L., a south American plant, against Helicobacter pylori.

Helicobacter pylori is a Gram negative bacterium most frequently associated with human gastrointestinal infections worldwide. The increasing occurrence of antibiotic-resistant isolates of H. pylori constitutes a challenge. The eradication of the microorganism is currently being considered a "high priority" by the World Health Organization (WHO). In this context, bioactive compounds found in natural products seem to be an effective therapeutic option to develop new antibiotics against the pathogen. In this study, we investigated the effect of asclepain cI, the main purified proteolytic enzyme of the latex of petioles and stems from Asclepia curassavica L. (Asclepiadaceae), a South American native plant, against H. pylori; in order to obtain a natural therapeutic adjuvant and a safe nutraceutical product. Asclepain cI showed antibacterial activity against reference strains and drug-resistant clinical isolates of H. pylori in vitro. A range of minimal inhibitory concentration (MIC) from 1 to 2 µg/ml and minimal bactericidal concentration (MBC) from 2 to 4 µg/ml was obtained, respectively. The action of asclepain cI on the transcription of omp18, ureA, flaA genes showed a significantly decreased expression of the selected pathogenic factors. Furthermore, asclepain cI did not induce toxic effects at the concentrations assayed. Asclepain cI could be considered a highly feasible option to be used as a natural therapeutic adjuvant and a safe nutraceutical product against H. pylori.

Effect of ethanolic extract of Rosa centifolia against doxorubicin induced nephrotoxicity in albino rats.

BACKGROUND: Efficacy of Anthracycline derivative Doxorubicin (Dox) has been proven in several malignancies such as breast cancer, Hodgkin and non-Hodgkin lymphoma, acute leukemia, lung, thyroid and ovarian cancer. However its clinical usefulness is restricted due to its cardiotoxicity and nephrotoxicity. Rosa centifolia belongs to family Rosaceae and in Ayurveda it is claimed for use in renal disorders. The main phyto-constituents of the plant are terpenoids, glycosides, flavonoids, tannins, phenolic compounds, pro-antroocyanides, pectin and riboflavin. OBJECTIVE: To investigate the ameliorative role of ethanolic extract of petals of R. centifolia in doxorubicin induced nephrotoxicity in rats. MATERIALS AND METHODS: Nephrotoxicity was produced by administration of doxorubicin (2.5 mg/kg b.w., i.p. alternate day) in six equal injections for two weeks to achieve a cumulative concentration of 15 mg/kg. Low (LERC - 100 mg/kg p.o.) and high (HERC - 200 mg/kg p.o.) dosees of ethanolic extract of petals of R. centifolia was administered as a pretreatment prior to doxorubicin administration. The general parameters such as body weight, food and water intake were measured throughout the study period. Serum biomarkers such as blood urea nitrogen (BUN), serum creatinine and albumin were measured before treatment and at the end of the experiments. Anti-oxidant enzymes such as glutathione (GSH), melonldehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) were monitored after the last dose. Nephrotoxicity was assessed through histopathological analysis. RESULTS: The repeated administration of doxorubicin produces several morphological changes including reduction in the body weight as well as decreased food and water consumption. Serum biomarkers such as BUN, serum creatinine were increased and albumin concentration was decreased. The GSH, SOD and CAT concentrations were decreased, whereas MDA concentration was increased. Deteriorating changes in the histological architecture of kidney tissue were observed. In the LERC and HERC pretreated groups following changes were observed in dose dependent manner: increase in body weight, food and water intake (p < 0.05 and p < 0.01), decrease in the BUN (p < 0.05 and p < 0.01) and serum creatinine (p < 0.05 and p < 0.05) concentrations respectively. The significant increase in the albumin (p < 0.01) concentration was observed only in HERC. The pretreatment with LERC and HERC increased the antioxidant enzymes concentrations i.e. GSH (p < 0.01 and p < 0.01), SOD (p < 0.01 and p < 0.01), CAT (p < 0.05 and p < 0.01) and decreased the MDA concentration (p < 0.05 and p < 0.01) respectively. Histopathological studies showed that the pretreatment with low and high doses of ethanolic extract of petals of Rosa centifolia LERC and HERC groups minimized the tubular damage and reduced the inflammation as compared to doxorubicin treated group. CONCLUSION: The biochemical and histopathological data from the present study clearly support the nephroprotective effect of ethanolic extract of petals of R. centifolia, which might be credited to its anti-oxidant property.

Advancements in the Pharmaceutical Applications of Probiotics: Dosage Forms and Formulation Technology.

Probiotics have demonstrated their high potential to treat and/or prevent various diseases including neurodegenerative disorders, cancers, cardiovascular diseases, and inflammatory diseases. Probiotics are also effective against multidrug-resistant pathogens and help maintain a balanced gut microbiota ecosystem. Accordingly, the global market of probiotics is growing rapidly, and research efforts to develop probiotics into therapeutic adjuvants are gaining momentum. However, because probiotics are living microorganisms, many biological and biopharmaceutical barriers limit their clinical application. Probiotics may lose their activity in the harsh gastric conditions of the stomach or in the presence of bile salts. Moreover, they easily lose their viability under thermal or oxidative stress during their preparation and storage. Therefore, stable formulations of probiotics are required to overcome the various physicochemical, biopharmaceutical, and biological barriers and to maximize their therapeutic effectiveness and clinical applicability. This review provides an overview of the pharmaceutical applications of probiotics and covers recent formulation approaches to optimize the delivery of probiotics with particular emphasis on various dosage forms and formulation technologies.

Withania somnifera (L.) Dunal: A potential therapeutic adjuvant in cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal (WS) is one of the moststudied Rasayana botanicals used in Ayurveda practice for its immunomodulatory, anti-aging, adaptogenic, and rejuvenating effects. The botanical is being used for various clinical indications, including cancer. Several studies exploring molecular mechanisms of WS suggest its possible role in improving clinical outcomes in cancer management. Therefore, research on WS may offer new insights in rational development of therapeutic adjuvants for cancer. AIM OF THIS REVIEW: The review aims at providing a detailed analysis of in silico, in vitro, in vivo, and clinical studies related to WS and cancer. It suggests possible role of WS in regulating molecular mechanisms associated with carcinogenesis. The review discusses potential of WS in cancer management in terms of cancer prevention, anti-cancer activity, and enhancing efficacy of cancer therapeutics. MATERIAL AND METHODS: The present narrative review offers a critical analysis of published literature on WS studies in cancer. The reported studies were analysed in the context of pathophysiology of cancer, commonly referred as 'cancer hallmarks'. The review attempts to bridge Ayurveda knowledge with biological insights into molecular mechanisms of cancer. RESULTS: Critical analysisof the published literature suggests an anti-cancer potential of WS with a key role in cancer prevention. The possible mechanisms for these effects are associated with the modulation of apoptotic, proliferative, and metastatic markers in cancer. WS can attenuate inflammatory responses and enzymes involved in invasion and metastatic progression of cancer.The properties of WS are likely to be mediated through withanolides, which may activate tumor suppressor proteins to restrict proliferation of cancer cells. Withanolides also regulate the genomic instability, and energy metabolism of cancer cells. The reported studies indicate the need for deeper understanding of molecular mechanisms of WS in inhibiting angiogenesis and promoting immunosurveillance. Additionally, WS can augment efficacy and safety of cancer therapeutics. CONCLUSION: The experimentally-supported evidence of immunomodulatory, anti-cancer, adaptogenic, and regenerative attributes of WS suggest its therapeutic adjuvant potential in cancer management. The adjuvant properties of withanolides can modulate multidrug resistance and reverse chemotherapy-induced myelosuppression. These mechanisms need to be further explored in systematically designed translational and clinical studies that will pave the way for integration of WS as a therapeutic adjuvant in cancer management.

High Mobility Group Box 1 Influences HSV1716 Spread and Acts as an Adjuvant to Chemotherapy.

High Mobility Group Box 1 (HMGB1) is a multifunctional protein that plays various roles in the processes of inflammation, cancer, and other diseases. Many reports document abundant HMGB1 release following infection with oncolytic viruses (OVs). Further, other groups including previous reports from our laboratory highlight the synergistic effects of OVs with chemotherapy drugs. Here, we show that virus-free supernatants have varying cytotoxic potential, and HMGB1 is actively secreted by two established fibroblast cell lines (NIH 3T3 and 3T6-Swiss albino) following HSV1716 infection in vitro. Further, pharmacologic inhibition or genetic knock-down of HMGB1 reveals a role for HMGB1 in viral restriction, the ability to modulate bystander cell proliferation, and drug sensitivity in 3T6 cells. These data further support the multifactorial role of HMGB1, and suggest it could be a target for modulating the efficacy of oncolytic virus therapies alone or in combination with other frontline cancer treatments.

Evaluación de actividad física como coadyuvante terapéutico para pacientes con enfermedad inflamatoria intestinal: una revisión / Evaluation of physical activity as a therapeutic adjuvant for patients with inflammatory bowel disease: A systematic review

Resumen La enfermedad inflamatoria intestinal (EII) incluye la enfermedad de Crohn (EC) y la colitis ulcerosa (CU). El tratamiento farmacológico en la EII presenta pérdida de eficacia y efectos secundarios, por esta razón es necesario el planteamiento de estrategias alternativas, como la práctica de actividad física (AF), como coadyuvante terapéutico. El propósito de este estudio fue evaluar la efectividad de las intervenciones de AF como herramienta para aumentar la condición física, la calidad de vida relacionada con la salud (CVRS) y mejorar la sintomatología en pacientes con EC y CU, identificando el componente de AF óptimo. Se realizó una revisión mediante una búsqueda en las bases electrónicas de datos Medline (PubMed), SciELO y Cochrane Library Plus, que incluyó ensayos controlados aleatorios de los últimos 10 años que relacionaran la EII y la AF, hasta el 31 de enero de 2022. Se incluyeron 4 estudios con un total de 133 pacientes. La realización de AF de pacientes con EII (CU y EC) aumentó (p>0.05) la capacidad física, la masa muscular esquelética, la densidad mineral ósea y la CVRS, incrementando significativamente (p<0,05) el estado de ánimo. Además, disminuyó significativamente (p<0,05) la inflamación intestinal y las manifestaciones extraintestinales. Se observó una tendencia de reducción (p>0,05) de la fatiga, la tensión arterial y la restauración de la microbiota. La AF moderada y realizada regularmente durante un mínimo de 8 semanas, favorece la mejoría del paciente con EII a nivel físico, psicológico, la CVRS y la sintomatología.

Abstract Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). Pharmacological treatment in IBD presents a loss of efficacy and side effects, inviting to consider alternative strategies, such as the practice of physical activity (PA), as a therapeutic adjuvant. The purpose of this review was to evaluate the effectiveness of PA interventions as a tool to increase physical fitness, and health-related quality of life (HRQoL) and improve the symptomatology in patients with CD and UC, identifying the optimal PA component. The review was performed, by searching the electronic databases Medline (PubMed), SciELO, and Cochrane Library Plus, including randomized controlled trials from the last 10 years that related to IBD and PA, until January 31, 2022. We found four studies with a total of 133 patients. The performance of PA in patients with IBD (UC and CD) increases (p>0.05) physical capacity, skeletal muscle mass, bone mineral density, and HRQoL, significantly (p<0.05) increasing mood. In addition, it significantly (p<0.05) decreases intestinal inflammation and extraintestinal manifestations. A trend of reduction (p>0.05) of fatigue, blood pressure, and microbiota restoration was observed. Moderate PA and performed regularly for a minimum of eight weeks, favors the improvement of the IBD patient at the physical, psychological, HRQoL, and symptomatology levels.