Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity.

Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target eukaryotic type IIA topoisomerases. Fluoroquinolones bind and stabilize type IIA topoisomerase-DNA covalent complexes that contain a double-strand break. This unique mode of action is referred to as 'topoisomerase poisoning'. We discovered that two novel fluoroquinolones having aryl functionality at the N-1 position, UITT-3-217 (217) and UITT-3-227 (227), could inhibit the catalytic activity of human topoisomerase II without stabilizing topoisomerase-DNA complexes, i.e., without poisoning it. Surprisingly, these compounds are more effective in inhibiting the catalytic activities of human and bacterial topoisomerase I. The National Cancer Institute's 60 human tumor cell lines screen revealed significant anti-proliferative activities with 217 and 227 against the majority of 60 cancer cell lines. A proof of concept in vivo efficacy study using an HT-29 xenograft model of human colorectal cancer showed that 217 could inhibit the proliferation of human colorectal cancer cells to a degree comparable to fluorouracil in mice. Although 227 also exhibited anti-proliferative activity, it was not as effective as 217 in this xenograft model. These novel fluoroquinolones may serve as promising lead compounds for the development of new anticancer drugs.

Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase.

Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 position were designed to probe for binding contacts with the phosphotyrosine residue in ternary complex. While alkylamine, alkylphthalimide, and alkylphenyl groups introduced at the N-1 position afforded derivatives that maintained modest inhibition of the supercoiling activity of DNA gyrase, none retained ability to poison DNA gyrase. Thus, the addition of a large and/or long moiety at the N-1 position disrupts ternary complex formation, and retained ability to inhibit supercoiling is likely through interference with the strand breakage reaction. Two derivatives were found to possess inhibitory effects on the decatenation activity of human topoisomerase II.

The Impact of Physical Therapy in Individuals With Benign Paroxysmal Positional Vertigo: A Case Report.

Benign paroxysmal positional vertigo (BPPV) is a mechanical condition of the peripheral vestibular system. It is characterized by recurrent, short-lived episodes of vertigo caused by calcium carbonate crystals that get dislodged from the utricle and move into the semicircular canals. In this case report, a 33-year-old female presenting with complaints of neck pain and dizziness upon head movement was diagnosed with BPPV following a comprehensive evaluation, which included a thorough history, assessment, and investigations. The Dix-Hallpike maneuver was positive on the right side. The patient was then treated with canalith repositioning manuever (CRM) and conventional physiotherapy. There was a reduction in pain, improvement in range of motion, and reduction in the duration and frequency of vertigo. Therefore, it can be concluded that the application of CRM or Epley's maneuver decreases the duration and frequency of vertigo and improves quality of life.

Impact of Tai Chi and Aerobic Exercise on Cognitive Function, Balance, Cardiovascular Fitness, and Quality of Life in Older Adults: Randomized Control Trial.

Introduction Tai chi, an ancient Chinese martial art, was originally developed for combat and self-defense. Over time, it has evolved into both a sport and a form of exercise. This gentle, low-impact exercise involves performing a series of deliberate, flowing motions while focusing on deep, slow breaths. This study investigates the effects of chen tai chi and aerobic exercises on cognition, balance, cardiopulmonary fitness, and quality of life in older adults. Methodology This study employed a single-blinded randomized control trial design, enrolling 60 participants aged between 60 and 75 years. Participants were divided into three groups: Group A (aerobics), Group B (chen tai chi), and Group C (control). Exercise sessions were held four days per week over a period of four weeks. Evaluations included the Montreal Cognitive Assessment for cognition, a one-leg stand test for static balance, a Timed Up and Go Test for dynamic balance, a six-minute walk test for cardiopulmonary fitness, and a health-related quality-of-life scale. Assessments were conducted at baseline, immediately after the intervention, and at follow-up was taken after eight weeks. Results Post-intervention, improvements were observed in cognition and static balance across all groups. Within-group analysis revealed that the aerobics group experienced statistically significant enhancements in cognition (p = 0.0001) and static balance (p = 0.01). Although no statistically significant differences were found between groups in terms of dynamic balance, cardiopulmonary fitness, and quality of life, the within-group analysis showed significant improvements in the aerobics group in dynamic balance (p = 0.0009), cardiopulmonary fitness (p = 0.03), and quality of life (p = 0.0001). Conclusion Compared to chen tai chi and no intervention, the study concludes that aerobic exercise has a more pronounced effect on improving cognition, balance, cardiopulmonary fitness, and quality of life in older adults. Aerobic exercise is recommended as an effective method to prevent frailty and promote independence among the elderly.

Rebound Exercises in Rehabilitation: A Scoping Review.

The term "trampoline" was coined in 1969, introducing a dynamic feedback mechanism for exercise. Rebounding exercise on a mini-trampoline utilizes an elastic surface supported by springs and gravity, potentially reducing cumulative trauma from repetitive loading. This type of physical activity provides enjoyable and engaging exercise for adolescents, especially those who are overweight, thereby reducing the likelihood of injuries associated with exercise. Mini-trampoline exercises enhance blood circulation, oxygen delivery, and bone health, impacting lower limb strength, balance, motor performance, blood glucose levels, executive function, physiological markers, and overall quality of life. The study focused on examining the overall impact of rebounding exercises in the field of rehabilitation. Its main goal was to assess how these exercises affect the rehabilitation process and different health measures. By investigating the comprehensive influence of rebounding exercises, the study aimed to determine their effectiveness in aiding physical and functional recovery, targeting specific rehabilitation goals, and enhancing overall health outcomes. We systematically reviewed medical literature databases such as PubMed, MEDLINE, Scopus, Google Scholar, and EBSCO. We included research articles, systematic reviews, meta-analyses, clinical trials, case studies, and observational studies published in English up to 10 years before the review's cutoff in December 2023. We considered participants across all age groups. Articles not in English were excluded from the review. The outcome measures were body composition, waist-hip ratio, Bruininks-Oseretsky test for motor proficiency, reaction time, insulin resistance, lipid profile, blood cholesterol level, forced expiratory volume in one second, and forced vital capacity, bone health indicators, blood lactate level, balance, strength: repetitive maximum, brief pain inventory (short form). A total of 11 reports met these criteria. In conclusion, this review provides a thorough look into the use, challenges, and future potential of rebound exercises in rehabilitation and fitness. Despite their wide-ranging applications, issues such as insufficient research, equipment variability, and safety concerns persist. Advancement requires more research for evidence-based guidelines, improved equipment design and safety measures, and collaboration among researchers, clinicians, and manufacturers. Overcoming challenges and fostering innovation can establish rebound exercises as a valuable tool in rehabilitation and fitness.

The Power of Movement: A Comprehensive Case Study of Physiotherapeutic Approaches in Electrical Injury Rehabilitation.

Electrical injuries are common phenomena in developing countries, due to inadequate safety measures followed during day-to-day electrical repairs. Workplace injuries account for 20% of these. In some severe cases, electrical injuries lead to burns, indirect fracture dislocations, speech impairments, etc. Falls due to electrical injuries leading to secondary complications are very common and, even though not very severe, they do require immediate treatment and adequate rehabilitation. A 53-year-old male suffered a shoulder injury following an electrical shock. The patient also experienced irritation and speech disturbances. Examination revealed a reduced range of shoulder joints and tightness of muscles of the shoulder complex. Physiotherapy intervention included counseling for the patient and his family members, energy conservation methods for ease in daily activities, a rehabilitation protocol, and modified music therapy. Outcome measures used to assess the progression constituted the Shoulder Pain and Disability Index (SPADI), the Tampa Scale for Kinesiophobia (TSK), and the Depression and Anxiety and Stress Scale. Rehabilitation with adjunct therapy is effective in the overall improvement of the patient's condition concerning their mental health as well as physical health by early strength training.

Revitalizing Recovery: Unveiling the Transformative Impact of Physiotherapy in Rehabilitating a Neglected Case of Shoulder Hemiarthroplasty.

The shoulder joint has a complex anatomy and biomechanics. It is a ball and socket joint made by the articulation surface of the humeral head (ball) and glenoidal fossa (socket) of the scapula. Shoulder arthroplasty is done when parts of the shoulder joint are severely affected and damaged beyond repair. The damaged parts are replaced with artificial parts. Prosthetic implants are typically made of metal or plastic material. Implants come in various sizes and shapes. There are three types of surgical arthroplasty: total shoulder arthroplasty, partial shoulder arthroplasty, and reverse arthroplasty. Indications of shoulder arthroplasty may include osteoarthritis, fractures, rotator cuff injuries, osteonecrosis, and rheumatoid arthritis. This case study aims to provide a case of anteroinferior dislocation of the left shoulder with humeral head comminuted fracture confirmed by an investigation like radiograph and CT scan operatively managed by left shoulder hemiarthroplasty. In this case study, a 58-year-old male cannot lift his arm and perform actions of the shoulder joint independently after the operative procedure, thus reducing the functional status and quality of life. After the left shoulder hemiarthroplasty repair post due to inadequate rehabilitation, there was a failure in achieving the ranges and gaining back the strength of the muscles. The patient has a combined plan of action, which consists of pharmacological interventions along with physiotherapy rehabilitation. The physiotherapy protocol consists of goals like using electrical muscle stimulation, activation exercises of muscles, strengthening protocol, stretches, and counselling. By the end of the physiotherapy treatment, the patient showed significant progress in re-establishing the ranges and enhanced muscle strength, which resulted in a positive self-boost along with improved functional independence quotient, thereby increasing quality of life.

Coordinated metabolic responses to cyclophilin D deletion in the developing heart.

In the embryonic heart, the activation of the mitochondrial electron transport chain (ETC) coincides with the closure of the cyclophilin D (CypD) regulated mitochondrial permeability transition pore (mPTP). However, it remains to be established whether the absence of CypD has a regulatory effect on mitochondria during cardiac development. Using a variety of assays to analyze cardiac tissue from wildtype and CypD knockout mice from embryonic day (E)9.5 to adult, we found that mitochondrial structure, function, and metabolism show distinct transitions. Deletion of CypD altered the timing of these transitions as the mPTP was closed at all ages, leading to coupled ETC activity in the early embryo, decreased citrate synthase activity, and an altered metabolome particularly after birth. Our results suggest that manipulating CypD activity may control myocyte proliferation and differentiation and could be a tool to increase ATP production and cardiac function in immature hearts.

Virtual reality a technological miracle transforming physical rehabilitation: A scoping review.

Physical rehabilitation is evolving day by day. In the same way, simulation in rehabilitation is increasing and has now become a cornerstone for rehabilitation programs. Increase in the number of new protocols, clinical methods, and treatment standardization, virtual reality is appearing as a new medium to deliver the simulation. Virtual reality gives the benefits of forming standardized treatment protocols on demand for various conditions repetitively with a cost-effective delivery system. This was an observational retrospective study. The PubMed database was used to obtain the available material related to virtual reality and rehabilitation and was searched using the same keywords. The articles were then sorted as the subject to the recent decade. The basic information was then obtained, which included timespan, sources of the document, average years of publication, document types we collected, and average citation per year per document. Analysis of the literature that was available online related to virtual reality and rehabilitation between 2011 and 2021 generated a list of 813 documents from 275 sources, of which 810 were from journal articles and 3 were book chapters with an average year of publication of 2.16. The highest number of publications was 480 in 2020, followed by 150 in 2019, 95 in 2018, and 28 in 2017. The annual growth rate percentage of scientific publications was 26.1%. Therefore, more studies should be performed on virtual reality.

Changing Trends in Publication Regarding Temporomandibular Joint Dysfunction From 1975 to 2021: A Bibliometric Analysis.

Temporomandibular joint (TMJ) is a bicondylar joint. Various conditions have the same clinical presentation as TMJ dysfunction, which requires a thorough assessment of active and passive movements and palpation of the joints surrounding the joint. Many times, TMJ dysfunction occurs due to an alteration in the cervical spine. The patient complains of clicking or popping sound at the jaw and a reduced maximum mouth opening. The conditions that lead to TMJ dysfunction include bruxism, arthritis, stress, injury to the jaw, and overuse. The trend of the available literature has changed from 1972 to 2021 to assess changing trends in the publication on TMJ about authors, country, collaboration of the institutes, and the journal. We have done this bibliometric assessment. The articles were collected from the PubMed database; the keywords used were temporomandibular dysfunction (TMD), neck pain, physiotherapy, and rehabilitation. A total of 437 articles were found from 1975 to 2021, which were then converted into pictorial forms using the CiteSapce R software, and the data were interpreted. The analysis of the bibliometrics of publications on TMD, neck pain, and functional disability between the years 1975 and 2021 shows a total of 437 articles were published. The articles were from 196 sources; the highest number of publications were seen from 2014 until 2021, with the highest number of published papers by author Yoo WG and the highest number of articles published by the Journal of Physical Therapy Science. This bibliometric analysis depicts that the quantity of literature on TMD and the forward head has increased, as has the effectiveness of physical therapy interventions on the forward head in terms of correcting temporomandibular dysfunction.

Growing Trends in Scientific Publication in Physiotherapy Treatment of Knee Osteoarthritis: A Bibliometric Literature Analysis.

There has been an increase in the life expectancy of people worldwide, especially in developing countries like India. Osteoarthritis, a condition that usually onsets during later decades of life, has also been on the rise, even with advancing technology. This has led osteoarthritis of the knee to become a global disabling condition of the lower extremity that increases dependency on the affected individual. A bibliometric study has not been conducted on knee osteoarthritis research. Therefore, a bibliometric analysis which includes statistical analysis of recent articles, books, and other forms of publications is done for evaluation of scientific output and to find the importance of scientific studies in terms of quality as well as quantity. The aim of this analysis was to evaluate the productivity of research articles indexed in PubMed related to the condition. The PubMed database was used and articles related to osteoarthritis of the knee, phonophoresis, and start excursion balance test were extracted. In the bib text format, all the files were downloaded and placed together. The R studio software (R Foundation for Statistical Computing, Vienna, Austria) for bibliometric analysis was then used, into which the research data was uploaded and a data framework of bibliometric analysis was made. Analysis of bibliometric publications related to knee osteoarthritis, phonophoresis, Otago exercises, star excursion balance test, ultrasound, and exercise therapy generated between 1989 and 2021 lists a total of 120 relevant documents from 75 sources with an average of 4.53 articles per year of publication. The use of an advanced PubMed database enables the extraction of adequate articles and powerful bibliometric analysis of the studies conducted on osteoarthritis of the knee published from 1989 to 2021. It includes an assessment of the contributions from major countries. This study allowed us to validate our methodology which can be used to evaluate research policies and promote international collaboration.

Resurgence to Life: A Case Report on Inpatient Rehabilitation in Organophosphate Poisoning Followed by Intermediate Syndrome.

Organophosphate poisoning (OPP) results from the occupational, accidental, or suicidal intake of organophosphate pesticides (OPs). There is a huge limitation in the available literature on OPP cases and the role of physiotherapy in such cases. We report a case of a 33-year-old farmer, found in a state of ingested insecticide and admitted to the emergency department. The patient had two to three episodes of vomiting, associated with continuous tremors in his hands and legs. Immediately infused with atropine, the patient's general condition deteriorated, and he was intubated with an endotracheal tube. With the signs of long-term intubation, a tracheostomy was done. A respiratory therapy consult was taken for indications of intermediate syndrome and to achieve early weaning. The patient's referral was received in view of the long-term requirement of bronchial hygiene and the need for early ambulation as well as psychological support. Informed consent was taken from the family prior to the commencement of the treatment. Respiratory therapy interventions included body positioning, bronchial hygiene techniques, chest proprioceptive neuromuscular facilitation (PNF) techniques, and mobility exercises to achieve early ambulation. Physiotherapists have the appropriate training, knowledge, and skills to deliver the exercise components and help patients return to their activities of daily living. Significant levels of improvement have been seen in the general condition of the patient. The overall functioning of the patient's health was seen as improved on the scales of consciousness, early mobility in the step-down unit, and quality of life.

Rehabilitation and Management of Complex Multiple Para-Symphysis Mandible Fracture: A Case Report.

Fractures of the parasymphysis occur in 15% of all cases of mandibular fracture. The mandible occupies the lowest portion of the face. The prominent bone of the face is severely injured when the lower face is hit by high impacts with upward or obliquely directed force. In this case study, we discussed the alleged trauma case of a 20-year-old man who fell from a height on August 27, 2022, at about 9:00 p.m. near Wardha. His family took him to the hospital in Wardha due to pain that was aggravated during chewing and swelling in his jaw. On investigation, an X-ray was done, and a left parasymphysis and right-side body fracture were noticed. Later, the patient underwent surgery, where open reduction and internal fixation of the left parasymphysis and the right-side body fracture with plating and intermaxillary fixation (IMF) were done. Then he was referred to the physiotherapy department for therapeutic intervention. Rehabilitation was given to reduce pain and swelling, regain full range of motion, gradually increase mobility, and keep associated muscles strong. A six-week protocol was administered to the patient. It was found that the therapeutic approach was quite effective for the patient.

Physical Therapy Management in a Severe Case of Overlapping of Bone Post Crush Injury: A Case Report.

Crush injuries are sustained due to high velocity and usually have a poor outcome. Since the compressive forces are of high energy, such injuries are usually seen in road traffic accidents or in industrial workers. Crush injuries of the hand account for relatively a smaller percentage of the injuries to the hand and include an open wound along with fracture dislocation of the carpometacarpal, interphalangeal, and radiocarpal joints. Since these injuries are uncommon, they are often overlooked in radiological findings or misdiagnosed. Their recognition depends on a careful physical and radiographic examination that may require trispiral computed tomograms. Physical therapy rehabilitation post-surgery becomes a necessity, especially in cases where the dominant hand is affected. Functional rehabilitation to improve the independence and efficiency of activities of daily living is a goal of utmost importance.

A Comprehensive Physiotherapy Rehabilitation for Lower Limb Amputation as a Consequence of Cannabis and Alcohol Dependency: A Case Report.

Chronic marijuana and alcohol consumption leads to many forms of physical and physiological deterioration in the human body, mainly affecting the neurological system. A ​​​​65-year-old male patient suffered from stroke with the involvement of middle cerebral artery of the left side. Nine years later, patient presented with gangrene due to a traumatic unhealed wound on his left leg. The patient was under the influence of alcohol when he was injured. The infection spread, causing peripheral arterial disease, which eventually led to the development of gangrene till mid-calf of the left leg, for which he was amputated. Above-knee amputation with a fish-mouth incision was performed. Physiotherapy management focused on prehension and grip exercises for right upper limb, strengthening of all the limb musculature, stump management, transfer training, gait training with walker/crutches and prosthesis, and home exercise program, retraining activities of daily living. This case study embodies a rehabilitation program for this patient who suffered from stroke followed by amputation of the left leg. It focuses on bringing the patient back to his near-normal life. Regular physiotherapy helped the patient build up confidence, helped in resolving his addictions, and provided individual structure management. We present a rare case of above-knee amputation secondary to complications of alcohol abuse where an extensive post-op care and elaborate physiotherapy program resulted in a successful recovery.

Immediate Effectiveness of Chest Proprioceptive Neuromuscular Facilitation (PNF) Technique on Hemodynamic Status in COVID-19 Patients: An Original Research.

Introduction COVID-19 is an infectious illness that first appeared in Wuhan, China in December 2019, and subsequently spread over the entire world. Those who were affected suffered from fever, cough, weakness, and breathlessness, along with the probability of developing pneumonia which sometimes leads to respiratory failure. The older population with co-morbidities was at higher risk. Methods In this experimental study, 59 subjects with COVID-19 were included according to pre-decided inclusion and exclusion criteria. Pre-vitals before the treatment were noted such as heart rate, respiratory rate, and oxygen saturation (SPO2), and then the chest proprioceptive neuromuscular facilitation (PNF) technique was given as a treatment regime, and its immediate effect was calculated. Post-vitals were noted immediately after the treatment session. The statistical analysis was made using the student's paired t-test. Results We found a mean difference of 9.45±5.27 in heart rate before and after the intervention provided which is suggestive of a statistically significant increase within normal limits. Also, the mean value of respiratory rate immediately after the intervention was shown as 22.91 and pre-intervention was 19.18 with a mean difference of 2.93±3.95, showing a statistically significant increase in respiratory rate. Additionally, the mean value of SPO2 immediately after the intervention was shown as 92.76 and pre-intervention was 94.64 and had a mean difference of 1.88±1.67 suggestive of high improvement in oxygen saturation immediately after the intervention. Conclusion The present study concludes from the available statistical analysis that chest PNF techniques such as intercostal stretch and anterior basal stretch lift have an immediate impact on improvement in oxygen saturation in COVID-19 patients and can be incorporated as an inpatient treatment regime in the rehabilitation protocol.

Postoperative Physiotherapy Approach for a Rare Case of Adult Ileocecal Intussusception.

We report a rare case of a 32-year-old male diagnosed with a mass of intussusception in the right lumbar region. Adult intussusception has a prevalence of less than 5%. Among all cases of intestinal obstructions, adult intussusception is found to be only 1-3%. Adult intussusception of the bowel is uncommon. In contrast to intussusception in children, the traditional trio of palpable sausage, jelly stools, and discomfort is rarely seen. Adults usually present with nonspecific findings that last for a long time. We share the case of a patient who presented with complaints of pain in the abdomen and loss of appetite for six months. In addition, the patient also complained of constipation. The patient had a history of easy fatigue on moderate-intensity activity. Ultrasonography of the abdomen was suggested which revealed bowel wall thickening in the subhepatic region, with likely intussusception and formation of a lump with few enlarged lymph nodes adjacent to it. A confirmatory diagnosis was made after a computed tomography scan. In all cases, surgical intervention is required, and an organic lesion inside the invaginated section of the colon is discovered to be the lead point in up to 90% of cases. The laparoscopic procedure can be used for both diagnostic and therapeutic purposes. A right hemicolectomy was performed through a vertical midline incision. The patient was referred to the physiotherapy department for further management.

Effect of Dance Movement Therapy on Cancer-Related Fatigue in Breast Cancer Patients Undergoing Radiation Therapy: A Pre-post Intervention Study.

Introduction Dance movement therapy (DMT) is a movement-based psychosocial intervention that incorporates the therapeutic components of dance movements and group psychotherapy. DMT, also known as creative movement therapy (CMT) is a psychotherapy used as a complementary therapy in cancer care. It helps in enhancing mood, emotions, self-expression and helps to rebuild self-confidence. Besides, it allows the patients to recognise their own strengths and weaknesses as well as helps to improve physical capabilities. Methods By simple random sampling method, 30 breast cancer patients were recruited at Pravara Rural Hospital, Loni, Maharashtra, India. The participants were in the age range of 30-60 years based on the inclusion and exclusion criteria. Pre-intervention scores of cancer-related fatigue (CRF) were taken using the Brief Fatigue Inventory (BFI) scale and intervention was given for 45 minutes each day for 5 days a week, over a span of 2 weeks. Thereafter, post-intervention assessment was done and the scores were noted. Pre-intervention and post-intervention scores were compared using paired t-test. Results The mean and standard deviation (SD) of pre- and post-BFI scores derived by using paired t-test was 73.76 (8.6) and 69.33 (9.8), respectively, with a p-value of < 0.001, which is highly significant. Conclusion The results of the present study revealed that DMT seems to be effective in reducing some amount of CRF in breast cancer patients undergoing radiation therapy. Besides, it turned out to be an engaging, entertaining and cost-effective approach. The investigation showed that DMT appears to be beneficial in reducing the side effects of radiation therapy such as pain, stress, anxiety and fear, giving a psychotherapeutic relief but did not completely remove the persistent fatigue experienced by the breast cancer patients. Thus, further investigation with long-term follow-up is recommended.

Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.

Type 2 diabetes is associated with insulin resistance, impaired pancreatic ß-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs ß-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and ß-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity*.

Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition and their effect on cancer cells for the first time. A 15-fold increase in CII inhibition was achieved over diazoxide, albeit with micromolar IC50 values. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with much greater antineoplastic effect than diazoxide, the most potent of which possesses an IC50 of 2.93±0.07 µM in a cellular model of triple-negative breast cancer, with high selectivity over nonmalignant cells and more than double the potency of the clinical agent 5-fluorouracil. No correlation between cytotoxicity and CII inhibition was found, thus indicating an as-yet-undefined mechanism of action of this scaffold. The derivatives described herein represent valuable hit compounds for therapeutic discovery in triple-negative breast cancer.