Current trends in gas-synergized phototherapy for improved antitumor theranostics.

Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. STATEMENT OF SIGNIFICANCE: 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field.

Vasopressin and methylprednisolone and hemodynamics after in-hospital cardiac arrest - A post hoc analysis of the VAM-IHCA trial.

INTRODUCTION: The Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) trial demonstrated a significant improvement in return of spontaneous circulation (ROSC) with no clear effect on long-term outcomes. The objective of the current manuscript was to evaluate the hemodynamic effects of intra-cardiac arrest vasopressin and methylprednisolone during the first 24 hours after ROSC. METHODS: The VAM-IHCA trial randomized patients with in-hospital cardiac arrest to a combination of vasopressin and methylprednisolone or placebo during the cardiac arrest. This study is a post hoc analysis focused on the hemodynamic effects of the intervention after ROSC. Post-ROSC data on the administration of glucocorticoids, mean arterial blood pressure, heart rate, blood gases, vasopressor and inotropic therapy, and sedation were collected. Total vasopressor dose between the two groups was calculated based on noradrenaline-equivalent doses for adrenaline, phenylephrine, terlipressin, and vasopressin. RESULTS: The present study included all 186 patients who achieved ROSC in the VAM IHCA-trial of which 100 patients received vasopressin and methylprednisolone and 86 received placebo. The number of patients receiving glucocorticoids during the first 24 hours was 22/86 (26%) in the placebo group and 14/100 (14%) in the methylprednisolone group with no difference in the cumulative hydrocortisone-equivalent dose. There was no significant difference between the groups in the mean cumulative noradrenaline-equivalent dose (vasopressin and methylprednisolone: 603 ug/kg [95CI% 227; 979] vs. placebo: 651 ug/kg [95CI% 296; 1007], mean difference -48 ug/kg [95CI% -140; 42.9], p = 0.30), mean arterial blood pressure, or lactate levels. There was no difference between groups in arterial blood gas values and vital signs. CONCLUSION: Treatment with vasopressin and methylprednisolone during cardiac arrest caused no difference in mean arterial blood pressure, vasopressor use, or arterial blood gases within the first 24 hours after ROSC when compared to placebo.

Prediction of survival in infants with congenital diaphragmatic hernia and the response to inhaled nitric oxide.

The use of inhaled nitric oxide (iNO) in treating pulmonary hypertension in infants with congenital diaphragmatic hernia (CDH) is controversial. Our aims were to identify factors associated with survival in CDH infants and whether this was influenced by the response to iNO. Results of CDH infants treated in a tertiary surgical and medical perinatal centre in a ten year period (2011-2021) were reviewed. Factors affecting survival were determined. To assess the response to iNO, blood gases prior to and 30 to 60 min after initiation of iNO were analysed and PaO2/FiO2 ratios and oxygenation indices (OI) calculated. One hundred and five infants were admitted with CDH; 46 (43.8%) infants died. The CDH infants who died had a lower median observed to expected lung to head ratio (O/E LHR) (p < 0.001) and a higher median highest OI on day 1 (HOId1) (p < 0.001). HOId1 predicted survival after adjusting for gestational age, Apgar score at 5 min and O/E LHR (odds ratio 0.948 (95% confidence intervals 0.913-0.983)). Seventy-two infants (68.6%) received iNO; 28 survived to discharge. The median PaO2 (46.7 versus 58.8 mmHg, p < 0.001) and the median PaO2/FiO2 ratio (49.4 versus 58.8, p = 0.003) improved post iNO initiation. The percentage change in the PaO2/FiO2 ratio post iNO initiation was higher in infants who survived (69.4%) compared to infants who died (10.2%), p = 0.018. CONCLUSION: The highest OI on day 1 predicted survival. iNO improved oxygenation in certain CDH infants and a positive response was more likely in those who survived. WHAT IS KNOWN: • The use of iNO is controversial in infants with CDH with respect to whether it improves survival. WHAT IS NEW: • We have examined predictors of survival in CDH infants including the response to iNO and demonstrated that the highest oxygenation index on day 1 predicted survival (AUCROC =0.908). • Certain infants with CDH responded to iNO and those with a greater response were more likely to survive.

The Advancement of Gas-Generating Nanoplatforms in Biomedical Fields: Current Frontiers and Future Perspectives.

Diverse gases (NO, CO, H2 S, H2 , etc.) have been widely applied in the medical intervention of various diseases, including cancer, cardiovascular disease, ischemia-reperfusion injury, bacterial infection, etc., attributing to their inherent biomedical activities. Although many gases have many biomedical activities, their clinical use is still limited due to the rapid and free diffusion behavior of these gases molecules, which may cause potential side effects and/or ineffective treatment. Gas-generating nanoplatforms (GGNs) are effective strategies to address the aforementioned challenges of gas therapy by preventing gas production or release at nonspecific sites, enhancing GGNs accumulation at targeted sites, and controlling gas release in response to exogenous (UV, NIR, US, etc.) or endogenous (H2 O2 , GSH, pH, etc.) stimuli at the lesion site, further maintaining gas concentration within the effective range and achieving the purpose of disease treatment. This review comprehensively summarizes the advancements of "state-of-the-art" GGNs in the recent three years, with emphasis on the composition, structure, preparation process, and gas release mechanism of the nanocarriers. Furthermore, the therapeutic effects and limitations of GGNs in preclinical studies using cell/animal models are discussed. Overall, this review enlightens the further development of this field and promotes the clinical transformation of gas therapy.

Intelligent Nanomedicine Approaches Using Medical Gas-Mediated Multi-Therapeutic Modalities Against Cancer.

The emerging area of gas-mediated cancer treatment has received widespread attention in the medical community. Featuring unique physical, chemical, and biological properties, nanomaterials can facilitate the delivery and controllable release of medicinal gases at tumor sites, and also serve as ideal platforms for the integration of other therapeutic modalities with gas therapy to augment cancer therapeutic efficacy. This review presents an overview of anti-cancer mechanisms of several therapeutic gases: nitric oxide (NO), hydrogen sulfide (H2S), carbon monoxide (CO), oxygen (O2), and hydrogen (H2). Controlled release behaviors of gases under different endogenous and exogenous stimuli are also briefly discussed, followed by their synergistic effects with different therapeutic modes. Moreover, the potential challenges and future prospects regarding gas therapy based on nanomaterials are also described, aiming to facilitate the advancement of gas therapeutic nanomedicine in new frontiers for highly efficient cancer treatment.

Near-infrared light-triggered nano-prodrug for cancer gas therapy.

Gas therapy (GT) has attracted increasing attention in recent years as a new cancer treatment method with favorable therapeutic efficacy and reduced side effects. Several gas molecules, such as nitric oxide (NO), carbon monoxide (CO), hydrogen (H2), hydrogen sulfide (H2S) and sulfur dioxide (SO2), have been employed to treat cancers by directly killing tumor cells, enhancing drug accumulation in tumors or sensitizing tumor cells to chemotherapy, photodynamic therapy or radiotherapy. Despite the great progress of gas therapy, most gas molecules are prone to nonspecific distribution when administered systemically, resulting in strong toxicity to normal tissues. Therefore, how to deliver and release gas molecules to targeted tissues on demand is the main issue to be considered before clinical applications of gas therapy. As a specific and noninvasive stimulus with deep penetration, near-infrared (NIR) light has been widely used to trigger the cleavage and release of gas from nano-prodrugs via photothermal or photodynamic effects, achieving the on-demand release of gas molecules with high controllability. In this review, we will summarize the recent progress in cancer gas therapy triggered by NIR light. Furthermore, the prospects and challenges in this field are presented, with the hope for ongoing development.

Recent progress in nanomedicine for enhanced cancer chemotherapy.

As one of the most important cancer treatment strategies, conventional chemotherapy has substantial side effects and leads easily to cancer treatment failure. Therefore, exploring and developing more efficient methods to enhance cancer chemotherapy is an urgently important problem that must be solved. With the development of nanotechnology, nanomedicine has showed a good application prospect in improving cancer chemotherapy. In this review, we aim to present a discussion on the significant research progress in nanomedicine for enhanced cancer chemotherapy. First, increased enrichment of drugs in tumor tissues relying on different targeting ligands and promoting tissue penetration are summarized. Second, specific subcellular organelle-targeted chemotherapy is discussed. Next, different combinational strategies to reverse multidrug resistance (MDR) and improve the effective intracellular concentration of therapeutics are discussed. Furthermore, the advantages of combination therapy for cancer treatment are emphasized. Finally, we discuss the major problems facing therapeutic nanomedicine for cancer chemotherapy, and propose possible future directions in this field.

Targeting endogenous gaseous signaling molecules as novel host-directed therapies against tuberculosis infection.

Tuberculosis (TB) is a chronic pulmonary disease caused by Mycobacterium tuberculosis which is a major cause of morbidity and mortality worldwide. Due to the complexity of disease and its continuous global spread, there is an urgent need to improvise the strategies for prevention, diagnosis, and treatment. The current anti-TB regimen lasts for months and warrants strict compliance to clear infection and to minimize the risk of development of multi drug-resistant tuberculosis. This underscores the need to have new and improved therapeutics for TB treatment. Several studies have highlighted the unique ability of Mycobacterium tuberculosis to exploit host factors to support its survival inside the intracellular environment. One of the key players to mycobacterial disease susceptibility and infection are endogenous gases such as oxygen, nitric oxide, carbon monoxide and hydrogen sulfide. Nitric oxide and carbon monoxide as the physiological gaseous messengers are considered important to the outcome of Mycobacterium tuberculosis infection. The role of hydrogen sulfide in human tuberculosis is yet not fully elucidated, but this gas has been shown to play a significant role in bacterial respiration, growth and pathogenesis. This review will focus on the host factors majorly endogenous gaseous signaling molecules which contributes to Mycobacterium tuberculosis survival inside the intracellular environment and highlight the potential therapeutic targets.

A continuous stimuli-responsive system for NIR-II fluorescence/photoacoustic imaging guided photothermal/gas synergistic therapy.

Nanosystems responsive to a tumor microenvironment (TME) have recently attracted great attention due to their potential in precision cancer theranostics. However, theranostic nanosystems with a TME-activated consecutive cascade for the accurate diagnosis and treatment of cancer have rarely been exploited. Herein, an activatable theranostic nanosystem (Bi2S3-Ag2S-DATS@BSA-N3 NYs) is designed and constructed on the basis of a one-pot biomineralization method and surface functional modification to improve second near-infrared (NIR-II) fluorescence/photoacoustic (PA) imaging-guided photothermal therapy (PTT)/gas therapy (GT). Based on enhanced penetration and retention (EPR) effect-mediated tumor accumulation, the tumor-overexpressed glutathione (GSH) can accelerate hydrogen sulfide (H2S) generation from the nanoparticles by reacting with the encapsulated diallyl trisulfide (DATS). Meanwhile, the in situ released H2S can be used not only for gas therapy, but also to start the reduction of -N3(-) to -NH2(+), thereby enhancing the tumor-specific aggregation of NYs. As a result, the activatable nanosystems with excellent tumor accumulation and biodistribution could achieve an accurate NIR-II/PA dual-modality imaging for guiding the synergistic anticancer efficacy (PTT/GT). Thus, this work provides a promising TME-mediated continuously responsive strategy for efficient anticancer therapy.

Hydrogen gas (XEN) inhalation ameliorates airway inflammation in asthma and COPD patients.

BACKGROUND: Hydrogen was proven to have anti-oxidative and anti-inflammation effects to various diseases. AIM: We wish to investigate the acute effects of inhaled hydrogen on airway inflammation in patients with asthma and chronic obstructive pulmonary disease (COPD). DESIGN: Prospective study. METHODS: In total, 2.4% hydrogen containing steam mixed gas (XEN) was inhaled once for 45 min in 10 patients with asthma and 10 patients with COPD. The levels of granulocyte-macrophage colony stimulating factor, interferon-γ, interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6 and so on in peripheral blood and exhaled breath condensate (EBC) before and after 'XEN' inhalation were measured. RESULTS: 45 minutes 'XEN' inhalation once decreased monocyte chemotactic protein 1 level in both COPD (564.70-451.51 pg/mL, P = 0.019) and asthma (386.39-332.76 pg/mL, P = 0.033) group, while decreased IL-8 level only in asthma group (5.25-4.49 pg/mL, P = 0.023). The level of EBC soluble cluster of differentiation-40 ligand in COPD group increased after inhalation (1.07-1.16 pg/mL, P = 0.031), while IL-4 and IL-6 levels in EBC were significantly lower after inhalation in the COPD (0.80-0.64 pg/mL, P = 0.025) and asthma (0.06-0.05 pg/mL, P = 0.007) group, respectively. CONCLUSIONS: A single inhalation of hydrogen for 45 min attenuated inflammatory status in airways in patients with asthma and COPD.

Organ preservation solution containing dissolved hydrogen gas from a hydrogen-absorbing alloy canister improves function of transplanted ischemic kidneys in miniature pigs.

Various methods have been devised to dissolve hydrogen gas in organ preservation solutions, including use of a hydrogen gas cylinder, electrolysis, or a hydrogen-generating agent. However, these methods require considerable time and effort for preparation. We investigated a practical technique for rapidly dissolving hydrogen gas in organ preservation solutions by using a canister containing hydrogen-absorbing alloy. The efficacy of hydrogen-containing organ preservation solution created by this method was tested in a miniature pig model of kidney transplantation from donors with circulatory arrest. The time required for dissolution of hydrogen gas was only 2-3 minutes. When hydrogen gas was infused into a bag containing cold ETK organ preservation solution at a pressure of 0.06 MPa and the bag was subsequently opened to the air, the dissolved hydrogen concentration remained at 1.0 mg/L or more for 4 hours. After warm ischemic injury was induced by circulatory arrest for 30 minutes, donor kidneys were harvested and perfused for 5 minutes with hydrogen-containing cold ETK solution or hydrogen-free cold ETK solution. The perfusion rate was faster from the initial stage with hydrogen-containing cold ETK solution than with hydrogen-free ETK solution. After storage of the kidney in hydrogen-free preservation solution for 1 hour before transplantation, no urine production was observed and blood flow was not detected in the transplanted kidney at sacrifice on postoperative day 6. In contrast, after storage in hydrogen-containing preservation solution for either 1 or 4 hours, urine was detected in the bladder and blood flow was confirmed in the transplanted kidney. This method of dissolving hydrogen gas in organ preservation solution is a practical technique for potentially converting damaged organs to transplantable organs that can be used safely in any clinical setting where organs are removed from donors.

Gas-Mediated Cancer Bioimaging and Therapy.

Gas-involving cancer theranostics have attracted considerable attention in recent years due to their high therapeutic efficacy and biosafety. We have reviewed the recent significant advances in the development of stimuli-responsive gas releasing molecules (GRMs) and gas nanogenerators for cancer bioimaging, targeted and controlled gas therapy, and gas-sensitized synergistic therapy. We have focused on gases with known anticancer effects, such as oxygen (O2), carbon monoxide (CO), nitric oxide (NO), hydrogen sulfide (H2S), hydrogen (H2), sulfur dioxide (SO2), carbon dioxide (CO2), and heavy gases that act via the gas-generating process. The GRMs and gas nanogenerators for each gas have been described in terms of the stimulation method, followed by their applications in ultrasound and multimodal imaging, and finally their primary and synergistic actions with other cancer therapeutic modalities. The current challenges and future possibilities of gas therapy and imaging vis-à-vis clinical translation have also been discussed.

Aplicación del ozono interescalénico en la radiculopatía cervical por hernia discal / Application of intercalenic ozone in cervical radiculopathy due to herniated disc

Introducción: el ozono es un gas médico descrito desde el siglo XIX que ha tenido su evolución hasta a la fecha en cuanto a sus aplicaciones y su utilidad en diversas enfermedades por su actuación a nivel molecular y en disímiles enfermedades asociadas a procesos dolorosos de origen inflamatorio como los presentes en las hernia discales de la columna vertebral. Método: estudio retrospectivo con 20 pacientes atendidos en la consulta externa de Neurocirugía del Hospital Miguel Enríquez desde de Diciembre 2016 hasta Abril 2017 con el diagnostico de una radiculopatía cervical por hernia discal. Se le aplicó 10 ML de ozono con una concentración 22 mg/litro tres veces en la semana durante 10 semanas solamente se utilizó este tipo de terapia; obteniendo mejoría en 15 pacientes. Resultados: predominando los mayores de 51 años para un 50 por ciento, en nuestra serie predominó el sexo femenino para un 80 por ciento. En cuanto al cuadro clínico prevaleció la disminución de la fuerza muscular para un 60 por ciento en 12 pacientes, seguidos del dolor cervical y el interescapular para un 75 por ciento y 55 por ciento respectivamente. Se halló mejoría en 15 pacientes para un 75 por ciento y en los otros 5, en tres pacientes no continuaron el tratamiento y en dos no se obtuvo mejoría. Conclusiones: tenemos otra alternativa en la aplicación del ozono por el espacio interescalénico como tratamiento analgésicos y antiinflamatorio en las radiculopatía por hernia discales cervicales(AU)

Introduction: Ozone is a medical gas described since the nineteenth century that has had its evolution up to date in terms of its applications and its usefulness in various diseases for its performance at the molecular level and dissimilar diseases associated with painful processes of inflammatory origin such as those present in herniated discs of the spine. Method: Retrospective study with 20 patients assisted in the outpatient consultation of the Miguel Enríquez Hospital from December 2016 to April 2017 with the diagnosis of a cervical radiculopathy by herniated disc. 10 ML of ozone applied with a concentration of 22 mg/liter three times in the week for 10 weeks only this type of therapy used getting improvement in 15 patients. Results: predominating the older than 51 years for 50 percent, in our series predominated the female sex for 80 percent .As for the clinical picture, decreased muscle strength was prevailed for 60 percent in 12 patients, followed by cervical pain and interescapular for 75 percent and 55 percent respectively. We found improvement in 15 patients for 75 percent and in the other 5, in 3 patients did not continue the treatment and in two, no improvement obtained. Conclusions: We have another alternative in the application of ozone by the intercalenic space as analgesic and anti-inflammatory treatment in cervical herniated discus radiculopathy(AU)

Recent advances in the neuroprotective effects of medical gases.

Central nervous system injuries are a leading cause of death and disability worldwide. Although the exact pathophysiological mechanisms of various brain injuries vary, central nervous system injuries often result in an inflammatory response, and subsequently lead to brain damage. This suggests that neuroprotection may be necessany in the treatment of multiple disease models. The use of medical gases as neuroprotective agents has gained great attention in the medical field. Medical gases include common gases, such as oxygen, hydrogen and carbon dioxide; hydrogen sulphide and nitric oxide that have been considered toxic; volatile anesthetic gases, such as isoflurane and sevoflurane; and inert gases like helium, argon, and xenon. The neuroprotection from these medical gases has been investigated in experimental animal models of various types of brain injuries, such as traumatic brain injury, stroke, subarachnoid hemorrhage, cerebral ischemic/reperfusion injury, and neurodegenerative diseases. Nevertheless, the transition into the clinical practice is still lagging. This delay could be attributed to the contradictory paradigms and the conflicting results that have been obtained from experimental models, as well as the presence of inconsistent reports regarding their safety. In this review, we summarize the potential mechanisms underlying the neuroprotective effects of medical gases and discuss possible candidates that could improve the outcomes of brain injury.

Emerging Technologies in Ultrasonic and Pneumatic Lithotripsy.

Percutaneous nephrolithotomy is the treatment of choice for large renal stones. Larger, straight access tracts allow for use of rigid pneumatic and ultrasonic lithotripsy devices. Through advanced technologies, more efficient fragmentation has become possible, allowing for a variety of treatment options depending on stone location, size, and composition. As novel methods of lithotripsy enter the clinical sphere, it is a requirement that the operating urologist understand the available surgical options and the associated mechanisms used to best treat their patients. This article discusses the mechanisms of basic pneumatic and ultrasonic devices, and examines the data regarding current and novel combination lithotrites.

The role of medical gas in stroke: an updated review.

Medical gas is a large class of bioactive gases used in clinical medicine and basic scientific research. At present, the role of medical gas in neuroprotection has received growing attention. Stroke is a leading cause of death and disability in adults worldwide, but current treatment is still very limited. The common pathological changes of these two types of stroke may include excitotoxicity, free radical release, inflammation, cell death, mitochondrial disorder, and blood-brain barrier disruption. In this review, we will discuss the pathological mechanisms of stroke and the role of two medical gases (hydrogen and hydrogen sulfide) in stroke, which may potentially provide a new insight into the treatment of stroke.

Hydrogen gas improves left ventricular hypertrophy in Dahl rat of salt-sensitive hypertension.

PURPOSE: Hypertension is an important risk factor for death resulting from stroke, myocardial infarction, and end-stage renal failure. Hydrogen (H2) gas protects against many diseases, including ischemia-reperfusion injury and stroke. The effects of H2 on hypertension and its related left ventricular (LV) function have not been fully elucidated. The purpose of this study was to investigate the effects of H2 gas on hypertension and LV hypertrophy using echocardiography. METHODS: Dahl salt-sensitive (DS) rats were randomly divided into three groups: those fed an 8% NaCl diet until 12 weeks of age (8% NaCl group), those additionally treated with 2% H2 gas (8% NaCl + 2% H2 group), and control rats maintained on a diet containing 0.3% NaCl until 12 weeks of age (0.3% NaCl group). H2 gas was supplied through a gas flowmeter and delivered by room air (2% hydrogenated room air, flow rate of 10 L/min) into a cage surrounded by an acrylic chamber. We evaluated interventricular septal wall thickness (IVST), LV posterior wall thickness (LVPWT), and LV mass using echocardiography. RESULTS: IVST, LVPWT, and LV mass were significantly higher in the 8% NaCl group than the 0.3% NaCl group at 12 weeks of age, whereas they were significantly lower in the 8% NaCl + 2% H2 group than the 8% NaCl group. There was no significant difference in systolic blood pressure between the two groups. CONCLUSION: Our findings suggest that chronic H2 gas inhalation may help prevent LV hypertrophy in hypertensive DS rats.

Natural medicinal resources and their therapeutic applications

Natural medicinal resources are a country's natural wealth. Natural medicinal waters, medicinal gases, and peloids have many properties that enable their use in the treatment of gastrointestinal, circulatory, respiratory, bone and joint, and skin and soft tissue disorders. Balneotherapy can be also applicable in prevention of many diseases and rehabilitation. At present, because there are several chemicals of synthetic origin, there is a need to search for nonpharmacological approaches and explore natural healing sources, which better fit the human body. Compared to synthetic drugs, these resources rarely show side effects, which increases the comfort of therapy. The use of natural medicinal resources in the form of treatments in health resort medicine centers under the supervision of balneologists, combined with the healing properties of the climate, contributes not only to the reduction of treatment time for many diseases but also to improvement of therapy's results. The article discusses natural medicinal resources and some of their therapeutic applications.